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9682112a41bc67a2767bf4ba72a9c30f48e4935f | wikidoc | Rumen | Rumen
# Overview
The rumen, also known as the fardingbag or paunch forms the larger part of the reticulorumen, which is the first chamber in the alimentary canal of ruminant animals. It serves as the primary site for microbial fermentation of ingested feed. The smaller part of the reticulorumen is the reticulum, which is fully continuous with the rumen, but differs from it with regard to the texture of its lining.
# Brief anatomy
The reticulorumen is composed of several muscular sacs, the cranial sac, ventral sac, ventral blindsac, and reticulum.
The lining of the rumen wall is covered in small finger like projections called papillae, which are flattened, approximately 5 mm in length and 3 mm wide in cattle. The reticulum is lined with ridges that form a hexagonal honeycomb pattern. The ridges are approximately 0.1 - 0.2 mm wide and are raised 5 mm above the reticulum wall. The hexagons in the reticulum are approximately 2-5 cm wide in cattle. These features increase the surface area of the reticulorumen wall, facilitating the absorption of volatile fatty acids. Despite the differences in the texture of the lining of the two parts of the reticulorumen, it represents one functional space.
# Stratification and mixing of digesta
Digesta in rumen is not uniform, but rather is stratified into gas, liquid, and particles of different sizes, densities, and other physical characteristics. Additionally, digesta does not merely enter and exit the rumen without event, but it is subject to extensive mixing and travels along complicated flow paths. Though they may seem trivial at first, these complicated stratification, mixing, and flow patterns of digesta are a key aspect of digestive activity in the ruminant and thus warrant detailed discussion.
After being swallowed, ingesta travels down the esophagus and is deposited in the dorsal part of the reticulum. Contractions of the reticulorumen propel and mix the recently ingested feed into the ruminal mat. The mat is a thick mass of digesta, consisting of partially degraded, long, fibrous material. Most material in the mat has been recently ingested, and as such, has considerable fermentable substrate remaining. Microbial fermentation proceeds rapidly in the mat, releasing many gasses. Some of these gasses are trapped in the mat, causing the mat to be buoyant. As fermentation proceeds, fermentable substrate is exhausted, gas production decreases, and particles lose buoyancy due to loss of entrapped gas. Digesta in the mat hence goes through a phase of increasing buoyancy followed by decreasing buoyancy. Simultaneously, the size of digesta particles–relatively large when ingested–is reduced by microbial fermentation and, later, rumination. At a certain point, particles are dense and small enough that they may “fall” through the rumen mat into the ventral sac below, or they may be swept out of the rumen mat into the reticulum by liquid gushing through the mat during ruminal contractions.
Once in the ventral sac, digesta continues to ferment at decreased rates, further losing buoyancy and decreasing in particle size. It is soon swept into the ventral reticulum by ruminal contractions.
In the ventral reticulum, less dense, larger digesta particles may be propelled up into the oesophagus and mouth during contractions of the reticulum. Digesta is chewed in the mouth in a process known as rumination, then expelled back down the oesophagus and deposited in the dorsal sac of the reticulum, to be lodged and mixed into the ruminal mat again. Denser, small particles stay in the ventral reticulum during reticular contraction, and then during the next contraction may be swept out of the reticulorumen with liquid through the reticulo-omasal orifice, which leads to the next chamber in the ruminant animal's alimentary canal, the omasum.
Water and saliva enter through the rumen to form a liquid pool. Liquid will ultimately escape from the reticulorumen from absorption through the wall, or through passing through the reticulo-omosal orifice, as digesta does. However, since liquid cannot be trapped in the mat as digesta can, liquid passes through the rumen much more quickly than digesta does. Liquid often acts as a carrier for very small digesta particles, such that the dynamics of small particles is similar to that of liquid.
The uppermost area of the rumen, the headspace, is filled with gases (such as methane, carbon dioxide, and, to a much lower degree, molecular hydrogen) released from fermentation and anaerobic respiration of feed. These gasses are regularly expelled from the reticulorumen through the mouth, in a process called eructation.
# Digestion
Digestion in the reticulorumen is a complex process. Digestion occurs through fermentation by microbes in the reticulorumen rather than the animal per se. The reticulorumen is one of the few organs present in animals in which digestion of cellulose and other recalcitrant carbohydrates can proceed to any appreciable degree.
The main substrates of digestion in the reticulorumen are non-structural carbohydrates (starch, sugar, and pectin), structural carbohydrates (hemicellulose and cellulose), and nitrogen-containing compounds (protein, peptides, and ammonia). Both non-structural and structural carbohydrates are hydrolyzed to monosaccharides or disaccharides by microbial enzymes. The resulting mono- and disaccharides are transported into the microbes. Once within microbial cell walls, the mono- and disaccharides may be assimilated into microbial biomass or fermented to volatile fatty acids (VFAs) acetate, propionate, butyrate, lactate, galactate and other branched-chain VFAs via glycolysis and other biochemical pathways to yield energy for the microbial cell. Most VFAs are absorbed across the reticulorumen wall, directly into the blood stream, and are used by the ruminant as substrates for energy production and biosynthesis. Some branched chained VFAs are incorporated into the lipid membrane of rumen microbes. Protein is hydrolyzed to peptides and amino acids by microbial enzymes, which are subsequently transported across the microbial cell wall for assimilation into cell biomass, primarily. Peptides, amino acids, ammonia, and other sources of nitrogen originally present in the feed can also be utilized directly by microbes with little to no hydrolysis. Non-amino acid nitrogen is used for synthesis of microbial amino acids. In situations in which nitrogen for microbial growth is in excess, protein and its derivatives can also be fermented to produce energy.
Lipids, lignin, minerals, and vitamins play a less prominent role in digestion than carbohydrates and protein, but they are still critical in many ways. Lipids are hydrogenated, and glycerol, if present in the lipid, is fermented. Lipids are otherwise inert in the rumen. Some carbon from carbohydrate may be used for de novo synthesis of microbial lipid. High levels of lipid, particularly unsaturated lipid, in the rumen are thought to poison microbes and suppress fermentation activity. Lignin, a phenolic compound, is recalcitrant to digestion, through it can be solubolized by fungi. Lignin is thought to shield associated nutrients from digestion and hence limits degradation. Minerals are absorbed by microbes and are necessary to their growth. Microbes in turn synthesize many vitamins, such as cyanocobalamin, in great quantities--often great enough to sustain the ruminant even when vitamins are highly deficient in the diet.
# Microbes in the reticulorumen
Microbes in the reticulorumen include bacteria, protozoa, fungi, archaea, and viruses. Bacteria, along with protozoa, are the predominant microbes and by mass account for 40-60% of total microbial matter in the rumen. They are categorized into several functional groups, such as fibrolytic, amylolytic, and proteolytic types, which preferentially digest structural carbohydrates, non-structural carbohydrates, and protein, respectively. Protozoa (40-60% of microbial mass) derive most of their nutrients through phagocytosis of other microbes, though they also degrade and digest food carbohydrates, especially structural carbohydrates, and protein. Ruminal fungi make up only 5-10% of microbes. Despite their low numbers, the fungi still occupy an important niche in the rumen because they solubolize lignin and help break down digesta particles. Rumen Archaea, approximately 3% of total microbes, are mostly autotrophic methanogens and produce methane through anaerobic respiration. Viruses are present in unknown numbers and do not contribute to any fermentation or respiration activity. However, they do lyse microbes, releasing their contents for other microbes to assimilate and ferment in a process called microbial recycling.
Microbes in the reticulorumen eventually flow out into the omasum and the remainder of the alimentary canal, where they are digested and absorbed by the ruminant. This is a major source of nutrition, as microbes can supply more than 50% of the animal's protein needs, and they often provide the predominant if not sole source of starch past the reticulorumen.
de:Pansen
eo:Rumeno
it:Rumine
mk:Бураг
nl:Pens
fi:Pötsi
sv:Våm
wa:Panse
vls:Pense | Rumen
# Overview
The rumen, also known as the fardingbag or paunch forms the larger part of the reticulorumen, which is the first chamber in the alimentary canal of ruminant animals. It serves as the primary site for microbial fermentation of ingested feed. The smaller part of the reticulorumen is the reticulum, which is fully continuous with the rumen, but differs from it with regard to the texture of its lining.
# Brief anatomy
The reticulorumen is composed of several muscular sacs, the cranial sac, ventral sac, ventral blindsac, and reticulum.
The lining of the rumen wall is covered in small finger like projections called papillae, which are flattened, approximately 5 mm in length and 3 mm wide in cattle. The reticulum is lined with ridges that form a hexagonal honeycomb pattern. The ridges are approximately 0.1 - 0.2 mm wide and are raised 5 mm above the reticulum wall. The hexagons in the reticulum are approximately 2-5 cm wide in cattle. These features increase the surface area of the reticulorumen wall, facilitating the absorption of volatile fatty acids. Despite the differences in the texture of the lining of the two parts of the reticulorumen, it represents one functional space.
# Stratification and mixing of digesta
Digesta in rumen is not uniform, but rather is stratified into gas, liquid, and particles of different sizes, densities, and other physical characteristics. Additionally, digesta does not merely enter and exit the rumen without event, but it is subject to extensive mixing and travels along complicated flow paths. Though they may seem trivial at first, these complicated stratification, mixing, and flow patterns of digesta are a key aspect of digestive activity in the ruminant and thus warrant detailed discussion.
After being swallowed, ingesta travels down the esophagus and is deposited in the dorsal part of the reticulum. Contractions of the reticulorumen propel and mix the recently ingested feed into the ruminal mat. The mat is a thick mass of digesta, consisting of partially degraded, long, fibrous material. Most material in the mat has been recently ingested, and as such, has considerable fermentable substrate remaining. Microbial fermentation proceeds rapidly in the mat, releasing many gasses. Some of these gasses are trapped in the mat, causing the mat to be buoyant. As fermentation proceeds, fermentable substrate is exhausted, gas production decreases, and particles lose buoyancy due to loss of entrapped gas. Digesta in the mat hence goes through a phase of increasing buoyancy followed by decreasing buoyancy. Simultaneously, the size of digesta particles–relatively large when ingested–is reduced by microbial fermentation and, later, rumination. At a certain point, particles are dense and small enough that they may “fall” through the rumen mat into the ventral sac below, or they may be swept out of the rumen mat into the reticulum by liquid gushing through the mat during ruminal contractions.
Once in the ventral sac, digesta continues to ferment at decreased rates, further losing buoyancy and decreasing in particle size. It is soon swept into the ventral reticulum by ruminal contractions.
In the ventral reticulum, less dense, larger digesta particles may be propelled up into the oesophagus and mouth during contractions of the reticulum. Digesta is chewed in the mouth in a process known as rumination, then expelled back down the oesophagus and deposited in the dorsal sac of the reticulum, to be lodged and mixed into the ruminal mat again. Denser, small particles stay in the ventral reticulum during reticular contraction, and then during the next contraction may be swept out of the reticulorumen with liquid through the reticulo-omasal orifice, which leads to the next chamber in the ruminant animal's alimentary canal, the omasum.
Water and saliva enter through the rumen to form a liquid pool. Liquid will ultimately escape from the reticulorumen from absorption through the wall, or through passing through the reticulo-omosal orifice, as digesta does. However, since liquid cannot be trapped in the mat as digesta can, liquid passes through the rumen much more quickly than digesta does. Liquid often acts as a carrier for very small digesta particles, such that the dynamics of small particles is similar to that of liquid.
The uppermost area of the rumen, the headspace, is filled with gases (such as methane, carbon dioxide, and, to a much lower degree, molecular hydrogen) released from fermentation and anaerobic respiration of feed. These gasses are regularly expelled from the reticulorumen through the mouth, in a process called eructation.
# Digestion
Digestion in the reticulorumen is a complex process. Digestion occurs through fermentation by microbes in the reticulorumen rather than the animal per se. The reticulorumen is one of the few organs present in animals in which digestion of cellulose and other recalcitrant carbohydrates can proceed to any appreciable degree.
The main substrates of digestion in the reticulorumen are non-structural carbohydrates (starch, sugar, and pectin), structural carbohydrates (hemicellulose and cellulose), and nitrogen-containing compounds (protein, peptides, and ammonia). Both non-structural and structural carbohydrates are hydrolyzed to monosaccharides or disaccharides by microbial enzymes. The resulting mono- and disaccharides are transported into the microbes. Once within microbial cell walls, the mono- and disaccharides may be assimilated into microbial biomass or fermented to volatile fatty acids (VFAs) acetate, propionate, butyrate, lactate, galactate and other branched-chain VFAs via glycolysis and other biochemical pathways to yield energy for the microbial cell. Most VFAs are absorbed across the reticulorumen wall, directly into the blood stream, and are used by the ruminant as substrates for energy production and biosynthesis. Some branched chained VFAs are incorporated into the lipid membrane of rumen microbes. Protein is hydrolyzed to peptides and amino acids by microbial enzymes, which are subsequently transported across the microbial cell wall for assimilation into cell biomass, primarily. Peptides, amino acids, ammonia, and other sources of nitrogen originally present in the feed can also be utilized directly by microbes with little to no hydrolysis. Non-amino acid nitrogen is used for synthesis of microbial amino acids. In situations in which nitrogen for microbial growth is in excess, protein and its derivatives can also be fermented to produce energy.
Lipids, lignin, minerals, and vitamins play a less prominent role in digestion than carbohydrates and protein, but they are still critical in many ways. Lipids are hydrogenated, and glycerol, if present in the lipid, is fermented. Lipids are otherwise inert in the rumen. Some carbon from carbohydrate may be used for de novo synthesis of microbial lipid. High levels of lipid, particularly unsaturated lipid, in the rumen are thought to poison microbes and suppress fermentation activity. Lignin, a phenolic compound, is recalcitrant to digestion, through it can be solubolized by fungi. Lignin is thought to shield associated nutrients from digestion and hence limits degradation. Minerals are absorbed by microbes and are necessary to their growth. Microbes in turn synthesize many vitamins, such as cyanocobalamin, in great quantities--often great enough to sustain the ruminant even when vitamins are highly deficient in the diet.
# Microbes in the reticulorumen
Microbes in the reticulorumen include bacteria, protozoa, fungi, archaea, and viruses. Bacteria, along with protozoa, are the predominant microbes and by mass account for 40-60% of total microbial matter in the rumen. They are categorized into several functional groups, such as fibrolytic, amylolytic, and proteolytic types, which preferentially digest structural carbohydrates, non-structural carbohydrates, and protein, respectively. Protozoa (40-60% of microbial mass) derive most of their nutrients through phagocytosis of other microbes, though they also degrade and digest food carbohydrates, especially structural carbohydrates, and protein. Ruminal fungi make up only 5-10% of microbes. Despite their low numbers, the fungi still occupy an important niche in the rumen because they solubolize lignin and help break down digesta particles. Rumen Archaea, approximately 3% of total microbes, are mostly autotrophic methanogens and produce methane through anaerobic respiration. Viruses are present in unknown numbers and do not contribute to any fermentation or respiration activity. However, they do lyse microbes, releasing their contents for other microbes to assimilate and ferment in a process called microbial recycling.
Microbes in the reticulorumen eventually flow out into the omasum and the remainder of the alimentary canal, where they are digested and absorbed by the ruminant. This is a major source of nutrition, as microbes can supply more than 50% of the animal's protein needs, and they often provide the predominant if not sole source of starch past the reticulorumen.
Template:Link FA
de:Pansen
eo:Rumeno
it:Rumine
mk:Бураг
nl:Pens
fi:Pötsi
sv:Våm
wa:Panse
vls:Pense
Template:WH
Template:WS | https://www.wikidoc.org/index.php/Rumen | |
8e1045bb3977b918089470eab806fc7a8ebf438d | wikidoc | Rutin | Rutin
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
NOTE: Most over the counter (OTC) are not reviewed and approved by the FDA. However, they may be marketed if they comply with applicable regulations and policies. FDA has not evaluated whether this product complies.
# Overview
Rutin is a bioflavonoid that is FDA approved for the treatment of temporary relief of food and pollen sensitivities including rhinitis, sinusitis, nasal congestion, hay fever; impotence, lactose intolerance, and bladder infection.. Common adverse reactions include abdominal discomfort, palpitations, dizziness, headache, alopecia, tiredness, dry mouth, pruritus, leg edema, gastritis, vomiting, diarrhea, dyspepsia, skin rash, muscle stiffness.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- For temporary relief of food and pollen sensitivities including rhinitis, sinusitis, nasal congestion, hay fever; impotence, lactose intolerance, and bladder infection.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Rutin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Rutin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Rutin in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Rutin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Rutin in pediatric patients.
# Contraindications
There is limited information regarding Rutin Contraindications in the drug label.
# Warnings
- Keep out of reach of children. In case of overdose, contact physician or Poison Control Center right away.
- If pregnant or breast-feeding, seek advice of a health professional before use.
- Tamper seal: "Sealed for Your Protection." Do not use if seal is broken or missing.
- Decrease in hematocrit, red blood cell count, beta globulin, increase in prothrombin time, abdominal discomfort, palpitations, dizziness, headache, alopecia, tiredness, dry mouth, pruritus, leg edema, gastritis, vomiting, diarrhea, dyspepsia, skin rash, muscle stiffness
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Rutin in the drug label.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Rutin in the drug label.
# Drug Interactions
There is limited information regarding Rutin Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Rutin in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Rutin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Rutin during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Rutin with respect to nursing mothers.
### Pediatric Use
- In case of overdose, contact physician or Poison Control Center right away.
### Geriatic Use
There is no FDA guidance on the use of Rutin with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Rutin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Rutin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Rutin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Rutin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Rutin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Rutin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
- Intravenous
### Monitoring
There is limited information regarding Monitoring of Rutin in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Rutin in the drug label.
# Overdosage
There is limited information regarding Chronic Overdose of Rutin in the drug label.
# Pharmacology
## Mechanism of Action
There is limited information regarding Rutin Mechanism of Action in the drug label.
## Structure
There is limited information regarding Rutin Structure in the drug label.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Rutin in the drug label.
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Rutin in the drug label.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Rutin in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Rutin in the drug label.
# How Supplied
There is limited information regarding Rutin How Supplied in the drug label.
## Storage
There is limited information regarding Rutin Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Rutin in the drug label.
# Precautions with Alcohol
- Alcohol-Rutin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
There is limited information regarding Rutin Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Rutin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | Rutin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aparna Vuppala, M.B.B.S. [2]
# Disclaimer
WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.
NOTE: Most over the counter (OTC) are not reviewed and approved by the FDA. However, they may be marketed if they comply with applicable regulations and policies. FDA has not evaluated whether this product complies.
# Overview
Rutin is a bioflavonoid that is FDA approved for the treatment of temporary relief of food and pollen sensitivities including rhinitis, sinusitis, nasal congestion, hay fever; impotence, lactose intolerance, and bladder infection.. Common adverse reactions include abdominal discomfort, palpitations, dizziness, headache, alopecia, tiredness, dry mouth, pruritus, leg edema, gastritis, vomiting, diarrhea, dyspepsia, skin rash, muscle stiffness.
# Adult Indications and Dosage
## FDA-Labeled Indications and Dosage (Adult)
- For temporary relief of food and pollen sensitivities including rhinitis, sinusitis, nasal congestion, hay fever; impotence, lactose intolerance, and bladder infection.
## Off-Label Use and Dosage (Adult)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Rutin in adult patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Rutin in adult patients.
# Pediatric Indications and Dosage
## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Rutin in pediatric patients.
## Off-Label Use and Dosage (Pediatric)
### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Rutin in pediatric patients.
### Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Rutin in pediatric patients.
# Contraindications
There is limited information regarding Rutin Contraindications in the drug label.
# Warnings
- Keep out of reach of children. In case of overdose, contact physician or Poison Control Center right away.
- If pregnant or breast-feeding, seek advice of a health professional before use.
- Tamper seal: "Sealed for Your Protection." Do not use if seal is broken or missing.
- Decrease in hematocrit, red blood cell count, beta globulin, increase in prothrombin time, abdominal discomfort, palpitations, dizziness, headache, alopecia, tiredness, dry mouth, pruritus, leg edema, gastritis, vomiting, diarrhea, dyspepsia, skin rash, muscle stiffness
# Adverse Reactions
## Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Rutin in the drug label.
## Postmarketing Experience
There is limited information regarding Postmarketing Experience of Rutin in the drug label.
# Drug Interactions
There is limited information regarding Rutin Drug Interactions in the drug label.
# Use in Specific Populations
### Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Rutin in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Rutin in women who are pregnant.
### Labor and Delivery
There is no FDA guidance on use of Rutin during labor and delivery.
### Nursing Mothers
There is no FDA guidance on the use of Rutin with respect to nursing mothers.
### Pediatric Use
- In case of overdose, contact physician or Poison Control Center right away.
### Geriatic Use
There is no FDA guidance on the use of Rutin with respect to geriatric patients.
### Gender
There is no FDA guidance on the use of Rutin with respect to specific gender populations.
### Race
There is no FDA guidance on the use of Rutin with respect to specific racial populations.
### Renal Impairment
There is no FDA guidance on the use of Rutin in patients with renal impairment.
### Hepatic Impairment
There is no FDA guidance on the use of Rutin in patients with hepatic impairment.
### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Rutin in women of reproductive potentials and males.
### Immunocompromised Patients
There is no FDA guidance one the use of Rutin in patients who are immunocompromised.
# Administration and Monitoring
### Administration
- Oral
- Intravenous
### Monitoring
There is limited information regarding Monitoring of Rutin in the drug label.
# IV Compatibility
There is limited information regarding IV Compatibility of Rutin in the drug label.
# Overdosage
There is limited information regarding Chronic Overdose of Rutin in the drug label.
# Pharmacology
## Mechanism of Action
There is limited information regarding Rutin Mechanism of Action in the drug label.
## Structure
There is limited information regarding Rutin Structure in the drug label.
## Pharmacodynamics
There is limited information regarding Pharmacodynamics of Rutin in the drug label.
## Pharmacokinetics
There is limited information regarding Pharmacokinetics of Rutin in the drug label.
## Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Rutin in the drug label.
# Clinical Studies
There is limited information regarding Clinical Studies of Rutin in the drug label.
# How Supplied
There is limited information regarding Rutin How Supplied in the drug label.
## Storage
There is limited information regarding Rutin Storage in the drug label.
# Images
## Drug Images
## Package and Label Display Panel
# Patient Counseling Information
There is limited information regarding Patient Counseling Information of Rutin in the drug label.
# Precautions with Alcohol
- Alcohol-Rutin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
# Brand Names
There is limited information regarding Rutin Brand Names in the drug label.
# Look-Alike Drug Names
There is limited information regarding Rutin Look-Alike Drug Names in the drug label.
# Drug Shortage Status
# Price | https://www.wikidoc.org/index.php/Rutin | |
31c4306ad5e74c8f24c0e33a1baa71529aa7aebe | wikidoc | S100B | S100B
S100 calcium-binding protein B (S100B) is a protein of the S-100 protein family.
S100 proteins are localized in the cytoplasm and nucleus of a wide range of cells, and involved in the regulation of a number of cellular processes such as cell cycle progression and differentiation. S100 genes include at least 13 members which are located as a cluster on chromosome 1q21; however, this gene is located at 21q22.3.
# Function
S100B is glial-specific and is expressed primarily by astrocytes, but not all astrocytes express S100B. It has been shown that S100B is only expressed by a subtype of mature astrocytes that ensheath blood vessels and by NG2-expressing cells.
This protein may function in neurite extension, proliferation of melanoma cells, stimulation of Ca2+ fluxes, inhibition of PKC-mediated phosphorylation, astrocytosis and axonal proliferation, and inhibition of microtubule assembly. In the developing CNS it acts as a neurotrophic factor and neuronal survival protein. In the adult organism it is usually elevated due to nervous system damage, which makes it a potential clinical marker.
# Clinical significance
Chromosomal rearrangements and altered expression of this gene have been implicated in several neurological, neoplastic, and other types of diseases, including Alzheimer's disease, Down's syndrome, epilepsy, amyotrophic lateral sclerosis, schwannoma, melanoma, and type I diabetes.
It has been suggested that the regulation of S100B by melittin has potential for the treatment of epilepsy.
# Diagnostic use
S100B is secreted by astrocytes or can spill from injured cells and enter the extracellular space or bloodstream. Serum levels of S100B increase in patients during the acute phase of brain damage. Over the last decade, S100B has emerged as a candidate peripheral biomarker of blood–brain barrier (BBB) permeability and CNS injury. Elevated S100B levels accurately reflect the presence of neuropathological conditions including traumatic head injury or neurodegenerative diseases. Normal S100B levels reliably exclude major CNS pathology. Its potential clinical use in the therapeutic decision making process is substantiated by a vast body of literature validating variations in serum 100B levels with standard modalities for prognosticating the extent of CNS damage: alterations in neuroimaging, cerebrospinal pressure, and other brain molecular markers (neuron specific enolase and glial fibrillary acidic protein). However, more importantly, S100B levels have been reported to rise prior to any detectable changes in intracerebral pressure, neuroimaging, and neurological examination findings. Thus, the major advantage of using S100B is that elevations in serum or CSF levels provide a sensitive measure for determining CNS injury at the molecular level before gross changes develop, enabling timely delivery of crucial medical intervention before irreversible damage occurs. S100B serum levels are elevated before seizures suggesting that BBB leakage may be an early event in seizure development.
An extremely important application of serum S100B testing is in the selection of patients with minor head injury who do not need further neuroradiological evaluation, as studies comparing CT scans and S100B levels have demonstrated S100B values below 0.12 ng/mL are associated with low risk of obvious neuroradiological changes (such as intracranial hemorrhage or brain swelling) or significant clinical sequelae. The excellent negative predictive value of S100B in several neurological conditions is due to the fact that serum S100B levels reflect blood–brain barrier permeability changes even in absence of neuronal injury.
In addition, S100B, which is also present in human melanocytes, is a reliable marker for melanoma malignancy both in bioptic tissue and in serum.
# Model organisms
Model organisms have been used in the study of S100B function. A conditional knockout mouse line, called S100btm1a(EUCOMM)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty three tests were carried out on mutant mice, but no significant abnormalities have yet been observed.
# Interactions
S100B has been shown to interact with:
- AHNAK,
- IMPA1,
- IQGAP1,
- MAPT, and
- P53,
- PGM1,
- S100A1,
- S100A6,
- S100A11,
- VAV1. | S100B
S100 calcium-binding protein B (S100B) is a protein of the S-100 protein family.
S100 proteins are localized in the cytoplasm and nucleus of a wide range of cells, and involved in the regulation of a number of cellular processes such as cell cycle progression and differentiation. S100 genes include at least 13 members which are located as a cluster on chromosome 1q21; however, this gene is located at 21q22.3.
# Function
S100B is glial-specific and is expressed primarily by astrocytes, but not all astrocytes express S100B. It has been shown that S100B is only expressed by a subtype of mature astrocytes that ensheath blood vessels and by NG2-expressing cells.[1]
This protein may function in neurite extension, proliferation of melanoma cells, stimulation of Ca2+ fluxes, inhibition of PKC-mediated phosphorylation, astrocytosis and axonal proliferation, and inhibition of microtubule assembly. In the developing CNS it acts as a neurotrophic factor and neuronal survival protein. In the adult organism it is usually elevated due to nervous system damage, which makes it a potential clinical marker.
# Clinical significance
Chromosomal rearrangements and altered expression of this gene have been implicated in several neurological, neoplastic, and other types of diseases, including Alzheimer's disease, Down's syndrome, epilepsy, amyotrophic lateral sclerosis, schwannoma, melanoma, and type I diabetes.[2]
It has been suggested that the regulation of S100B by melittin has potential for the treatment of epilepsy.[3]
# Diagnostic use
S100B is secreted by astrocytes or can spill from injured cells and enter the extracellular space or bloodstream. Serum levels of S100B increase in patients during the acute phase of brain damage. Over the last decade, S100B has emerged as a candidate peripheral biomarker of blood–brain barrier (BBB) permeability and CNS injury. Elevated S100B levels accurately reflect the presence of neuropathological conditions including traumatic head injury or neurodegenerative diseases. Normal S100B levels reliably exclude major CNS pathology. Its potential clinical use in the therapeutic decision making process is substantiated by a vast body of literature validating variations in serum 100B levels with standard modalities for prognosticating the extent of CNS damage: alterations in neuroimaging, cerebrospinal pressure, and other brain molecular markers (neuron specific enolase and glial fibrillary acidic protein). However, more importantly, S100B levels have been reported to rise prior to any detectable changes in intracerebral pressure, neuroimaging, and neurological examination findings. Thus, the major advantage of using S100B is that elevations in serum or CSF levels provide a sensitive measure for determining CNS injury at the molecular level before gross changes develop, enabling timely delivery of crucial medical intervention before irreversible damage occurs. S100B serum levels are elevated before seizures suggesting that BBB leakage may be an early event in seizure development.
[4]
An extremely important application of serum S100B testing is in the selection of patients with minor head injury who do not need further neuroradiological evaluation, as studies comparing CT scans and S100B levels have demonstrated S100B values below 0.12 ng/mL are associated with low risk of obvious neuroradiological changes (such as intracranial hemorrhage or brain swelling) or significant clinical sequelae.[5] The excellent negative predictive value of S100B in several neurological conditions is due to the fact that serum S100B levels reflect blood–brain barrier permeability changes even in absence of neuronal injury.[6][7]
In addition, S100B, which is also present in human melanocytes, is a reliable marker for melanoma malignancy both in bioptic tissue and in serum.[8][9]
# Model organisms
Model organisms have been used in the study of S100B function. A conditional knockout mouse line, called S100btm1a(EUCOMM)Wtsi[14][15] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute.[16][17][18]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[12][19] Twenty three tests were carried out on mutant mice, but no significant abnormalities have yet been observed.[12]
# Interactions
S100B has been shown to interact with:
- AHNAK,[20]
- IMPA1,[21]
- IQGAP1,[22]
- MAPT,[23][24] and
- P53,[25]
- PGM1,[26]
- S100A1,[27][28]
- S100A6,[28][29]
- S100A11,[29]
- VAV1.[30] | https://www.wikidoc.org/index.php/S100B | |
20cfa2cf4c58fe169e1ffb4ab0f7b45efe2fe2b8 | wikidoc | S100P | S100P
S100 calcium-binding protein P (S100P) is a protein that in humans is encoded by the S100P gene.
# Function
The protein encoded by this gene is a member of the S100 family of proteins containing 2 EF-hand calcium-binding motifs. S100 proteins are localized in the cytoplasm and/or nucleus of a wide range of cells, and involved in the regulation of a number of cellular processes such as cell cycle progression and differentiation. S100 genes include at least 13 members which are located as a cluster on chromosome 1q21; however, this gene is located at 4p16. This protein, in addition to binding Ca2+, also binds Zn2+ and Mg2+. This protein may play a role in the etiology of prostate cancer.
# Interactions
S100P has been shown to interact with EZR and RAGE. The interactions between S100P and RAGE are disrupted by cromolyn and pentamidine. | S100P
S100 calcium-binding protein P (S100P) is a protein that in humans is encoded by the S100P gene.[1][2][3]
# Function
The protein encoded by this gene is a member of the S100 family of proteins containing 2 EF-hand calcium-binding motifs. S100 proteins are localized in the cytoplasm and/or nucleus of a wide range of cells, and involved in the regulation of a number of cellular processes such as cell cycle progression and differentiation. S100 genes include at least 13 members which are located as a cluster on chromosome 1q21; however, this gene is located at 4p16. This protein, in addition to binding Ca2+, also binds Zn2+ and Mg2+. This protein may play a role in the etiology of prostate cancer.[3]
# Interactions
S100P has been shown to interact with EZR [4] and RAGE.[5] The interactions between S100P and RAGE are disrupted by cromolyn[6] and pentamidine.[5] | https://www.wikidoc.org/index.php/S100P | |
ce0cf134014900166932e20fc78d739e7387bab8 | wikidoc | S1PR1 | S1PR1
Sphingosine-1-phosphate receptor 1 (S1P receptor 1 or S1P1), also known as endothelial differentiation gene 1 (EDG1) is a protein that in humans is encoded by the S1PR1 gene. S1PR1 is a G-protein-coupled receptor which binds the bioactive signaling molecule sphingosine 1-phosphate (S1P). S1PR1 belongs to a sphingosine-1-phosphate receptor subfamily comprising five members (S1PR1-5). S1PR1 was originally identified as an abundant transcript in endothelial cells and it has an important role in regulating endothelial cell cytoskeletal structure, migration, capillary-like network formation and vascular maturation. In addition, S1PR1 signaling is important in the regulation of lymphocyte maturation, migration and trafficking.
# Structure
S1PR1 like the other members of the GPCR family is composed of seven-transmembrane helices arranged in a structurally conserved bundle. As well as the other GPCRs, in the extracellular region S1PR1 is composed of three loops: ECL1 between helices II and III, ECL2 between helices IV and V and ECL3 between helices VI and VII. Compared to the other members of the family, S1PR1 has some specific features. The N-terminal of the protein folds as a helical cap above the top of the receptor and therefore it limits the access of the ligands to the amphipathic binding pocket. This marked amphipathicity is indeed in agreement with the zwitterionic nature of S1P. In addition, helices ECL1 and ECL2 pack tightly against the N-terminal helix, further occluding the access of the ligand from the extracellular space. S1P or S1P analogs are likely to reach the binding pocket from within the cell membrane and not from the extracellular space, may be through an opening between helices I and VII. Compared to the other GPCRs, this region is more open due to a different positioning of helices I and II toward helix III. This occlusion of the ligand access space from the extracellular space could also explain the slow saturation of receptor binding in the presence of excess of ligand.
# Function
Like the other members of the GPCR family, S1PR1 senses its ligand from outside the cell and activates intracellular signal pathways that at last lead to cellular responses. The signal is transduced through the association of the receptor with different G proteins, which recruits a series of systems for downstream amplification of the signal.
## Immune system
S1PR1 activation is heavily involved in immune cell regulation and development. Sphingosine-1-phosphate receptor 1 is also involved in immune-modulation and directly involved in suppression of innate immune responses from T cells. Depending on the G protein coupled with the S1PR1, diverse cellular effects are achieved: Gαi and Gαo modulate cellular survival, proliferation and motility; Gα12 and Gα13 modulate cytoskeletal remodeling and cell-shape changes and Gαq modulates several cellular effector functions. All the intracellular functions occur via the interaction with Gαi and Gαo: these two proteins recruit other proteins for downstream amplification of the signal. The main functions of S1P-S1PR1 system are as follows:
- The phosphatidylinositol 3-kinase (PI3K) and the lipid dependent protein kinase B (PKB) signaling pathway increases the survival of lymphocytes and other immune cells by inhibiting apoptosis.
- Phosphoinositide 3-kinase (PI3K) and the GTPase RAC are responsible of the lymphocytes migration and their interactions with other cells or with connective-tissue surfaces. S1PR1-deficient thymocytes do not emigrate from the thymus, resulting in an increased numbers of mature thymocytes in the thymus and in medullary hyperplasia, and few S1PR1-deficient T cells can be detected in the blood, lymph nodes, spleen or non-lymphoid organs in these mouse models. The proliferation of immune cells is due to S1P-mediated signals via the GTPase RAS and extracellular-signal regulated kinase (ERK). IV) The Phospholipase C (PLC)-induced increases in intracellular calcium levels allow the secretion of cytokines and other immune mediators.
## Vasculogenesis
S1PR1 is one of the main receptors responsible for vascular growth and development, at least during embryogenesis. In vascular endothelial cells the binding of S1P to S1PR1 induces migration, proliferation, cell survival and morphogenesis into capillary-like structures. Moreover, the binding of S1P to S1PR1 is implicated in the formation of cell-cell adherens junctions, therefore inhibiting paracellular permeability of solutes and macromolecules. It was also shown in vivo that S1P synergizes with angiogenic factors such as FGF-2 and VEGF in inducing angiogenesis and vascular maturation through S1PR1. showed that S1PR1-KO mice died during development due to a defect in vascular stabilization, suggesting that this receptor is essential for vascular development. In conclusion, several evidences confirm that S1P via S1PR1 is a potent regulator of vascular growth and development, at least during embryogenesis.
# Clinical significance
## Cancer
S1PR1 is involved in the motility of cancer cells upon stimulation by S1P. The signal pathway involves RAC-CDC42 and correlates with ERK1 and ERK2 activation. The RAC-CDC42 pathway leads to cell migration, whereas the ERK pathway leads to proliferation and neovascularization demonstrated that S1PR1 is strongly induced in endothelial cells during tumor angiogenesis and a siRNA against S1PR1 was able to inhibit angiogenesis and tumor growth. S1PR1 is also involved in other types of cancer: fibrosarcoma cells migrate upon activation of S1PR1 by S1P via RAC1–CDC42 dependent pathway) and ovarian cancer cell invasion involves S1PR1 or S1PR3 and calcium mobilization.
## Multiple sclerosis
S1PR1 is involved in multiple sclerosis. Fingolimod, a drug which internalizes the receptor, is approved as a disease modifying agent in MS. There are other Sphingosine-1-phosphate receptor modulators.
Van Doorn et al. (2010) observed a strong increase in S1PR1 (and S1PR3) expression in hypertrophic astrocytes both in the active and inactive MS lesions from MS patients compared to the unaffected patients.
# Interactions
S1PR1 has been shown to interact with 5-HT1A receptor, GNAI1, and GNAI3. | S1PR1
Sphingosine-1-phosphate receptor 1 (S1P receptor 1 or S1P1), also known as endothelial differentiation gene 1 (EDG1) is a protein that in humans is encoded by the S1PR1 gene. S1PR1 is a G-protein-coupled receptor which binds the bioactive signaling molecule sphingosine 1-phosphate (S1P). S1PR1 belongs to a sphingosine-1-phosphate receptor subfamily comprising five members (S1PR1-5).[1] S1PR1 was originally identified as an abundant transcript in endothelial cells[2] and it has an important role in regulating endothelial cell cytoskeletal structure, migration, capillary-like network formation and vascular maturation.[3][4] In addition, S1PR1 signaling is important in the regulation of lymphocyte maturation, migration and trafficking.[5][6]
# Structure
S1PR1 like the other members of the GPCR family is composed of seven-transmembrane helices arranged in a structurally conserved bundle.[1] As well as the other GPCRs, in the extracellular region S1PR1 is composed of three loops: ECL1 between helices II and III, ECL2 between helices IV and V and ECL3 between helices VI and VII. Compared to the other members of the family, S1PR1 has some specific features. The N-terminal of the protein folds as a helical cap above the top of the receptor and therefore it limits the access of the ligands to the amphipathic binding pocket. This marked amphipathicity is indeed in agreement with the zwitterionic nature of S1P. In addition, helices ECL1 and ECL2 pack tightly against the N-terminal helix, further occluding the access of the ligand from the extracellular space. S1P or S1P analogs are likely to reach the binding pocket from within the cell membrane and not from the extracellular space, may be through an opening between helices I and VII. Compared to the other GPCRs, this region is more open due to a different positioning of helices I and II toward helix III.[1] This occlusion of the ligand access space from the extracellular space could also explain the slow saturation of receptor binding in the presence of excess of ligand.[7]
# Function
Like the other members of the GPCR family, S1PR1 senses its ligand from outside the cell and activates intracellular signal pathways that at last lead to cellular responses. The signal is transduced through the association of the receptor with different G proteins, which recruits a series of systems for downstream amplification of the signal.[8]
## Immune system
S1PR1 activation is heavily involved in immune cell regulation and development. Sphingosine-1-phosphate receptor 1 is also involved in immune-modulation and directly involved in suppression of innate immune responses from T cells.[9] Depending on the G protein coupled with the S1PR1, diverse cellular effects are achieved: Gαi and Gαo modulate cellular survival, proliferation and motility; Gα12 and Gα13 modulate cytoskeletal remodeling and cell-shape changes and Gαq modulates several cellular effector functions.[8] All the intracellular functions occur via the interaction with Gαi and Gαo: these two proteins recruit other proteins for downstream amplification of the signal.[8] The main functions of S1P-S1PR1 system are as follows:
- The phosphatidylinositol 3-kinase (PI3K) and the lipid dependent protein kinase B (PKB) signaling pathway increases the survival of lymphocytes and other immune cells by inhibiting apoptosis.
- Phosphoinositide 3-kinase (PI3K) and the GTPase RAC are responsible of the lymphocytes migration and their interactions with other cells or with connective-tissue surfaces.[8] S1PR1-deficient thymocytes do not emigrate from the thymus, resulting in an increased numbers of mature thymocytes in the thymus and in medullary hyperplasia, and few S1PR1-deficient T cells can be detected in the blood, lymph nodes, spleen or non-lymphoid organs in these mouse models.[5][6] The proliferation of immune cells is due to S1P-mediated signals via the GTPase RAS and extracellular-signal regulated kinase (ERK). IV) The Phospholipase C (PLC)-induced increases in intracellular calcium levels allow the secretion of cytokines and other immune mediators.[8]
## Vasculogenesis
S1PR1 is one of the main receptors responsible for vascular growth and development, at least during embryogenesis.[10] In vascular endothelial cells the binding of S1P to S1PR1 induces migration, proliferation, cell survival and morphogenesis into capillary-like structures.[11] Moreover, the binding of S1P to S1PR1 is implicated in the formation of cell-cell adherens junctions, therefore inhibiting paracellular permeability of solutes and macromolecules.[12][13] It was also shown in vivo that S1P synergizes with angiogenic factors such as FGF-2 and VEGF in inducing angiogenesis and vascular maturation through S1PR1.[13][14] showed that S1PR1-KO mice died during development due to a defect in vascular stabilization, suggesting that this receptor is essential for vascular development. In conclusion, several evidences confirm that S1P via S1PR1 is a potent regulator of vascular growth and development, at least during embryogenesis.[10]
# Clinical significance
## Cancer
S1PR1 is involved in the motility of cancer cells upon stimulation by S1P. The signal pathway involves RAC-CDC42 and correlates with ERK1 and ERK2 activation. The RAC-CDC42 pathway leads to cell migration, whereas the ERK pathway leads to proliferation and neovascularization[15][16] demonstrated that S1PR1 is strongly induced in endothelial cells during tumor angiogenesis and a siRNA against S1PR1 was able to inhibit angiogenesis and tumor growth. S1PR1 is also involved in other types of cancer: fibrosarcoma cells migrate upon activation of S1PR1 by S1P via RAC1–CDC42 dependent pathway)[17][18] and ovarian cancer cell invasion involves S1PR1 or S1PR3 and calcium mobilization.[19]
## Multiple sclerosis
S1PR1 is involved in multiple sclerosis. Fingolimod, a drug which internalizes the receptor, is approved as a disease modifying agent in MS. There are other Sphingosine-1-phosphate receptor modulators.
Van Doorn et al. (2010)[20] observed a strong increase in S1PR1 (and S1PR3) expression in hypertrophic astrocytes both in the active and inactive MS lesions from MS patients compared to the unaffected patients.
# Interactions
S1PR1 has been shown to interact with 5-HT1A receptor,[21] GNAI1,[22] and GNAI3.[22] | https://www.wikidoc.org/index.php/S1PR1 | |
6921f1c555f50ad4e76f40b8c1c96ab7ef92f53f | wikidoc | SALL1 | SALL1
Sal-like 1 (Drosophila), also known as SALL1, is a protein which in humans is encoded by the SALL1 gene. As the full name suggests, it is one of the human versions of the spalt (sal) gene known in Drosophila.
# Function
The protein encoded by this gene is a zinc finger transcriptional repressor and may be part of the NuRD histone deacetylase (HDAC) complex.
# Clinical significance
Defects in this gene are a cause of Townes–Brocks syndrome (TBS) as well as branchio-oto-renal syndrome (BOR). Two transcript variants encoding different isoforms have been found for this gene.
# Interactions
SALL1 has been shown to interact with TERF1 and UBE2I. | SALL1
Sal-like 1 (Drosophila), also known as SALL1, is a protein which in humans is encoded by the SALL1 gene.[1][2] As the full name suggests, it is one of the human versions of the spalt (sal) gene known in Drosophila.
# Function
The protein encoded by this gene is a zinc finger transcriptional repressor and may be part of the NuRD histone deacetylase (HDAC) complex.[1]
# Clinical significance
Defects in this gene are a cause of Townes–Brocks syndrome (TBS) as well as branchio-oto-renal syndrome (BOR). Two transcript variants encoding different isoforms have been found for this gene.[1]
# Interactions
SALL1 has been shown to interact with TERF1[3] and UBE2I.[4] | https://www.wikidoc.org/index.php/SALL1 | |
a905340d3bc0e08e7ae7d4186e52b0d530437c72 | wikidoc | SALL4 | SALL4
Sal-like protein 4 (SALL4) is a transcription factor encoded by a member of the Spalt-like (SALL) gene family, SALL4. The SALL genes were identified based on their sequence homology to Spalt, which is a homeotic gene originally cloned in Drosophila melanogaster that is important for terminal trunk structure formation in embryogenesis and imaginal disc development in the larval stages. There are four human SALL proteins (SALL1, 2, 3, and 4) with structural homology and playing diverse roles in embryonic development, kidney function, and cancer. The SALL4 gene encodes at least three isoforms, termed A, B, and C, through alternative splicing, with the A and B forms being the most studied. SALL4 can alter gene expression changes through its interaction with many co-factors and epigenetic complexes. It is also known as a key embryonic stem cell (ESC) factor.
# Structure, interaction partners, and DNA binding activity
SALL4 contains one zinc finger in its amino (N-) terminus and three clusters of zinc fingers that each coordinates zinc with two cysteines and two histidines (Cys2His2-type) that potentially confer nucleic acid binding activity. SALL4B lacks two of the zinc finger clusters found in the A isoform. Although it remains unclear which zinc finger cluster is responsible for SALL4’s DNA binding property
Different SALL family members can form hetero- or homodimers via their conserved glutamine (Q)-rich region. SALL4 has at least one canonical nuclear localization signal (NLS) with the K-K/R-X-K/R motif in the N-terminal portion of the protein shared among both A and B isoforms (residues 64-67). One report has suggested that with a mutated NLS sequence, SALL4 cannot localize to the nucleus. Through a 12-amino acid sequence in its N-terminus (N-12a.a.), SALL4 binds to retinoblastoma binding protein 4 (RBBP4), a subunit of the nucleosome remodeling and histone deacetylation (NuRD) complex, which also contains chromodomain-helicase-DNA binding proteins (CHD3/4 or Mi-2a/b), metastasis-associated proteins (MTA), methyl-CpG-binding domain proteins (MBD2 or MBD3), and histone deacetylases (HDAC1 and HDAC2). This association allows SALL4 to act as a transcriptional repressor. Accordingly, SALL4 has been shown to localize to heterochromatin regions in cells, for which its last zinc finger cluster (shared between SALL4A and B) is necessary. Beside the NuRD complex, SALL4 is reportedly able to bind to other epigenetic modifiers such as histone lysine-specific demethylase 1 (LSD1), which is frequently associated with the NuRD complex and subsequently gene repression. In addition, SALL4 can also activate gene expression via the recruitment of the mixed lineage leukemia (MLL) protein, which is a homolog of Drosophila Trithorax and yeast Set1 proteins and has histone 3 lysine 4 (H3K4) trimethylation activity. This interaction is best characterized in the co-regulation of HOXA9 gene by SALL4 and MLL in leukemic cells.
In mouse ESCs, Sall4 was found to bind the essential stem cell factor, octamer-binding transcription factor 4 (Oct4), in two separate unbiased mass spectrometry (spec) screens Sall4 can also bind other important pluripotency proteins such as Nanog and sex determining region Y (SRY)-box 2 protein (Sox2). Together these proteins can affect each other’s expression patterns as well as their own, thus forming a mESC-specific transcriptional regulatory circuit. SALL4 has also been reported to bind T-box 5 protein (Tbx5) in cardiac tissues as well as genetically interact with Tbx5 in mouse limb development. Other binding partners of SALL4 include promyelocytic leukemia zinc finger protein (PLZF) in sperm precursor cells, Rad50 during DNA damage repair, and b-catenin downstream of the Wnt signaling pathway. Since most of these interactions were identified by mass-spec or co-immunoprecipitation, whether they are direct are unknown. Through chromatin immunoprecipitation (ChIP) followed by next-generation sequencing or microarray, some SALL4 targets have been identified. A key verified target gene encodes the enzyme phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase (PTEN). PTEN is a tumor suppressor that keeps uncontrolled cell growth in check through inducing programmed cell death, or apoptosis. SALL4 binds the PTEN promoter and recruits the NuRD complex to mediate its repression, thus leads to proliferation of cells.
# Expression and role in stem cells and development
In mouse embryos, SALL4 expression is detectable as early as the two-cell stage. Its expression persists through 8- and 16-cell stages to the blastocyst, where it is found in some cells of the trophectoderm and inner cell mass (ICM), from which mouse ESCs are derived. SALL4 is an important factor for maintaining the “stemness” of ESCs of both mouse and human origin, since loss of Sall4 leads to differentiation of these pluripotent cells down the trophectoderm lineage. This is possibly due to down-regulation of Pou5f1 (encoding Oct4) expression and up-regulation of caudal-type homeobox 2 (Cdx2) gene expression. Sall4 is part of the transcriptional regulatory network that includes other pluripotent factors such as Oct4, Nanog, and Sox2 Because of its important role in early development, genetically mutated mice without functioning SALL4 die early on at the peri-implantation stage, while heterozygous mice have neural, kidney, heart defects and limb abnormalities.
# Clinical significance
The various SALL4-null mouse models mimic human mutations in the SALL4 gene, which were shown to cause developmental problems in patients with Okihiro/Duane-Radial-ray syndrome. These individuals frequently have family history of hand malformation and eye movement disorders.
SALL4 expression is low to undetectable in most adult tissues with the exception of germ cells and human blood progenitor cells. However, SALL4 is re-activated and mis-regulated in various cancers such as acute myeloid leukemia (AML), B-cell acute lymphocytic leukemia (B-ALL), germ cell tumors, gastric cancer, breast cancer, hepatocellular carcinoma (HCC), lung cancer, and glioma. In many of these cancers, SALL4 expression was compared in tumor cells to the normal tissue counterpart, e.g. it is expressed in nearly half of primary human endometrial cancer samples, but not in normal or hyperplastic endometrial tissue samples. Often, SALL4 expression is correlated with worse survival and poor prognosis such as in HCC, or with metastasis such as in endometrial cancer, colorectal carcinoma, and esophageal squamous cell carcinoma. It is unclear how SALL4 expression is de-regulated in malignant cells, but DNA hypomethylation in its intron 1 region has been observed in B-ALL.
In breast cancer, Signal transducer and activator of transcription 3 (STAT3) has been reported to directly activate SALL4 expression. Furthermore, canonical Wnt signaling has been proposed to activate SALL4 gene expression in both development and in cancer. In leukemia, the mechanism of SALL4 function is better characterized; mice with over-expression of human SALL4 develop myelodysplatic syndromes (MDS)-like symptoms and eventually AML. This is consistent with high level of SALL4 expression correlating with high-risk MDS patients. Further elucidating its tumorigenesis function, knocking down SALL4 expression with short hairpin-RNA in leukemic cells or treating these cells with a peptide that mimics the N-12aa of SALL4 to inhibit its interaction with the NuRD complex both result in cell death. These suggest the primary cancer-maintaining property of SALL4 is mediated through its transcriptional repressing function. These observations have led to growing interest in SALL4 as both a diagnostic tool as well as target in cancer therapy. For example, in solid tumors such as germ cell tumors, SALL4 protein expression has become a standard diagnostic biomarker.
# Notes | SALL4
Sal-like protein 4 (SALL4) is a transcription factor encoded by a member of the Spalt-like (SALL) gene family, SALL4.[1][2] The SALL genes were identified based on their sequence homology to Spalt, which is a homeotic gene originally cloned in Drosophila melanogaster that is important for terminal trunk structure formation in embryogenesis and imaginal disc development in the larval stages.[3][4] There are four human SALL proteins (SALL1, 2, 3, and 4) with structural homology and playing diverse roles in embryonic development, kidney function, and cancer.[5] The SALL4 gene encodes at least three isoforms, termed A, B, and C, through alternative splicing, with the A and B forms being the most studied. SALL4 can alter gene expression changes through its interaction with many co-factors and epigenetic complexes.[6] It is also known as a key embryonic stem cell (ESC) factor.
# Structure, interaction partners, and DNA binding activity
SALL4 contains one zinc finger in its amino (N-) terminus and three clusters of zinc fingers that each coordinates zinc with two cysteines and two histidines (Cys2His2-type) that potentially confer nucleic acid binding activity. SALL4B lacks two of the zinc finger clusters found in the A isoform. Although it remains unclear which zinc finger cluster is responsible for SALL4’s DNA binding property
Different SALL family members can form hetero- or homodimers via their conserved glutamine (Q)-rich region.[7] SALL4 has at least one canonical nuclear localization signal (NLS) with the K-K/R-X-K/R motif in the N-terminal portion of the protein shared among both A and B isoforms (residues 64-67).[8] One report has suggested that with a mutated NLS sequence, SALL4 cannot localize to the nucleus.[8] Through a 12-amino acid sequence in its N-terminus (N-12a.a.), SALL4 binds to retinoblastoma binding protein 4 (RBBP4), a subunit of the nucleosome remodeling and histone deacetylation (NuRD) complex, which also contains chromodomain-helicase-DNA binding proteins (CHD3/4 or Mi-2a/b), metastasis-associated proteins (MTA), methyl-CpG-binding domain proteins (MBD2 or MBD3), and histone deacetylases (HDAC1 and HDAC2).[9][10][11][12] This association allows SALL4 to act as a transcriptional repressor. Accordingly, SALL4 has been shown to localize to heterochromatin regions in cells, for which its last zinc finger cluster (shared between SALL4A and B) is necessary.[13] Beside the NuRD complex, SALL4 is reportedly able to bind to other epigenetic modifiers such as histone lysine-specific demethylase 1 (LSD1), which is frequently associated with the NuRD complex and subsequently gene repression.[14] In addition, SALL4 can also activate gene expression via the recruitment of the mixed lineage leukemia (MLL) protein, which is a homolog of Drosophila Trithorax and yeast Set1 proteins and has histone 3 lysine 4 (H3K4) trimethylation activity.[15] This interaction is best characterized in the co-regulation of HOXA9 gene by SALL4 and MLL in leukemic cells.[15]
In mouse ESCs, Sall4 was found to bind the essential stem cell factor, octamer-binding transcription factor 4 (Oct4), in two separate unbiased mass spectrometry (spec) screens[16][17] Sall4 can also bind other important pluripotency proteins such as Nanog and sex determining region Y (SRY)-box 2 protein (Sox2).[18][19] Together these proteins can affect each other’s expression patterns as well as their own, thus forming a mESC-specific transcriptional regulatory circuit.[20] SALL4 has also been reported to bind T-box 5 protein (Tbx5) in cardiac tissues as well as genetically interact with Tbx5 in mouse limb development.[21] Other binding partners of SALL4 include promyelocytic leukemia zinc finger protein (PLZF) in sperm precursor cells,[22] Rad50 during DNA damage repair,[23] and b-catenin downstream of the Wnt signaling pathway.[24] Since most of these interactions were identified by mass-spec or co-immunoprecipitation, whether they are direct are unknown. Through chromatin immunoprecipitation (ChIP) followed by next-generation sequencing or microarray, some SALL4 targets have been identified.[25] A key verified target gene encodes the enzyme phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase (PTEN). PTEN is a tumor suppressor that keeps uncontrolled cell growth in check through inducing programmed cell death, or apoptosis. SALL4 binds the PTEN promoter and recruits the NuRD complex to mediate its repression, thus leads to proliferation of cells.[12]
# Expression and role in stem cells and development
In mouse embryos, SALL4 expression is detectable as early as the two-cell stage. Its expression persists through 8- and 16-cell stages to the blastocyst, where it is found in some cells of the trophectoderm and inner cell mass (ICM), from which mouse ESCs are derived.[26] SALL4 is an important factor for maintaining the “stemness” of ESCs of both mouse and human origin, since loss of Sall4 leads to differentiation of these pluripotent cells down the trophectoderm lineage.[13][26][27] This is possibly due to down-regulation of Pou5f1 (encoding Oct4) expression and up-regulation of caudal-type homeobox 2 (Cdx2) gene expression.[27] Sall4 is part of the transcriptional regulatory network that includes other pluripotent factors such as Oct4, Nanog, and Sox2[28][29] Because of its important role in early development, genetically mutated mice without functioning SALL4 die early on at the peri-implantation stage, while heterozygous mice have neural, kidney, heart defects and limb abnormalities.[13][21][30]
# Clinical significance
The various SALL4-null mouse models mimic human mutations in the SALL4 gene, which were shown to cause developmental problems in patients with Okihiro/Duane-Radial-ray syndrome.[31][32] These individuals frequently have family history of hand malformation and eye movement disorders.
SALL4 expression is low to undetectable in most adult tissues with the exception of germ cells and human blood progenitor cells.[31][33] However, SALL4 is re-activated and mis-regulated in various cancers[34][35] such as acute myeloid leukemia (AML),[24] B-cell acute lymphocytic leukemia (B-ALL),[36] germ cell tumors,[37] gastric cancer,[38] breast cancer,[39] hepatocellular carcinoma (HCC),[40][41] lung cancer,[42] and glioma.[43] In many of these cancers, SALL4 expression was compared in tumor cells to the normal tissue counterpart, e.g. it is expressed in nearly half of primary human endometrial cancer samples, but not in normal or hyperplastic endometrial tissue samples.[44] Often, SALL4 expression is correlated with worse survival and poor prognosis such as in HCC,[40] or with metastasis such as in endometrial cancer,[44] colorectal carcinoma,[45] and esophageal squamous cell carcinoma.[46][47] It is unclear how SALL4 expression is de-regulated in malignant cells, but DNA hypomethylation in its intron 1 region has been observed in B-ALL.[36]
In breast cancer, Signal transducer and activator of transcription 3 (STAT3) has been reported to directly activate SALL4 expression.[48] Furthermore, canonical Wnt signaling has been proposed to activate SALL4 gene expression in both development[49][50] and in cancer.[24] In leukemia, the mechanism of SALL4 function is better characterized; mice with over-expression of human SALL4 develop myelodysplatic syndromes (MDS)-like symptoms and eventually AML.[24] This is consistent with high level of SALL4 expression correlating with high-risk MDS patients.[51][52] Further elucidating its tumorigenesis function, knocking down SALL4 expression with short hairpin-RNA in leukemic cells or treating these cells with a peptide that mimics the N-12aa of SALL4 to inhibit its interaction with the NuRD complex both result in cell death.[9][40] These suggest the primary cancer-maintaining property of SALL4 is mediated through its transcriptional repressing function. These observations have led to growing interest in SALL4 as both a diagnostic tool as well as target in cancer therapy. For example, in solid tumors such as germ cell tumors, SALL4 protein expression has become a standard diagnostic biomarker.[53]
# Notes | https://www.wikidoc.org/index.php/SALL4 | |
a7e43af3b7da3c87e1dc5f988ba2e928467651fa | wikidoc | SAP30 | SAP30
Sin3A-associated protein, 30kDa, also known as SAP30, is a protein which in humans is encoded by the SAP30 gene.
# Function
Histone acetylation plays a key role in the regulation of eukaryotic gene expression. Histone acetylation and deacetylation are catalyzed by multisubunit complexes. The protein encoded by this gene is a component of the histone deacetylase complex, which includes SIN3A, SAP18, HDAC1, HDAC2, RbAp46, RbAp48, and other polypeptides. This complex is active in deacetylating core histone octamers, but inactive in deacetylating nucleosomal histones. A pseudogene of this gene is located on chromosome 3.
Mammals have one paralog of SAP30, named SAP30-like (SAP30L), which shares 70% sequence identity with SAP30. SAP30 and SAP30L together constitute a well-conserved SAP30 protein family. Also SAP30L interacts with several components of the Sin3A corepressor complex and induces transcriptional repression via recruitment of Sin3A and histone deacetylases.
Proteins of the SAP30 family (SAP30 proteins) have a functional nucleolar localization signal and they are able to target Sin3A to the nucleolus. SAP30 proteins have sequence-independent contact with DNA by their N-terminal zinc-dependent module and their acidic central region contributes to histone and nucleosome interactions. The DNA binding of SAP30 proteins is regulated by the nuclear signalling lipids, phosphoinositides (PI). SAP30 proteins provide the first example in which the DNA and PIs seem to stand in a mutually antagonizing interrelationship in regard to their interaction with zinc finger proteins and thus exemplifies the molecular mechanism how these lipids can contribute for gene regulation.
# Interactions
SAP30 has been shown to interact with:
- HDAC1,
- Histone deacetylase 2,
- ING1 and
- Nuclear receptor co-repressor 1,
- RBBP4,
- RBBP7,
- SIN3A, and
- YY1. | SAP30
Sin3A-associated protein, 30kDa, also known as SAP30, is a protein which in humans is encoded by the SAP30 gene.[1]
# Function
Histone acetylation plays a key role in the regulation of eukaryotic gene expression. Histone acetylation and deacetylation are catalyzed by multisubunit complexes. The protein encoded by this gene is a component of the histone deacetylase complex, which includes SIN3A, SAP18, HDAC1, HDAC2, RbAp46, RbAp48, and other polypeptides. This complex is active in deacetylating core histone octamers, but inactive in deacetylating nucleosomal histones. A pseudogene of this gene is located on chromosome 3.[1]
Mammals have one paralog of SAP30, named SAP30-like (SAP30L), which shares 70% sequence identity with SAP30.[2] SAP30 and SAP30L together constitute a well-conserved SAP30 protein family. Also SAP30L interacts with several components of the Sin3A corepressor complex and induces transcriptional repression via recruitment of Sin3A and histone deacetylases.[3]
Proteins of the SAP30 family (SAP30 proteins) have a functional nucleolar localization signal and they are able to target Sin3A to the nucleolus.[3] SAP30 proteins have sequence-independent contact with DNA by their N-terminal zinc-dependent module and their acidic central region contributes to histone and nucleosome interactions. The DNA binding of SAP30 proteins is regulated by the nuclear signalling lipids, phosphoinositides (PI).[4] SAP30 proteins provide the first example in which the DNA and PIs seem to stand in a mutually antagonizing interrelationship in regard to their interaction with zinc finger proteins and thus exemplifies the molecular mechanism how these lipids can contribute for gene regulation.[4][5]
# Interactions
SAP30 has been shown to interact with:
- HDAC1,[6][7][8][9][10][11]
- Histone deacetylase 2,[7][8][11]
- ING1[11] and
- Nuclear receptor co-repressor 1,[12][13]
- RBBP4,[7][8][11]
- RBBP7,[7][8][11]
- SIN3A,[7][8][10][11][14][12] and
- YY1.[6] | https://www.wikidoc.org/index.php/SAP30 | |
740a15880dafd33cfb752135f38c37b8936e6829 | wikidoc | SAR1B | SAR1B
SAR1 gene homolog B (S. cerevisiae), also known as SAR1B, is a protein which in humans is encoded by the SAR1B gene.
# Function
SAR1B belongs to the Sar1-ADP ribosylation factor family of small GTPases, which govern the intracellular trafficking of proteins in coat protein (COP)-coated vesicles.
# Clinical significance
Mutations in the SAR1B gene are associated with chylomicron retention disease (also known as Anderson disease) which is an autosomal recessive disorder of severe fat malabsorption. | SAR1B
SAR1 gene homolog B (S. cerevisiae), also known as SAR1B, is a protein which in humans is encoded by the SAR1B gene.[1][2]
# Function
SAR1B belongs to the Sar1-ADP ribosylation factor family of small GTPases,[3] which govern the intracellular trafficking of proteins in coat protein (COP)-coated vesicles.[4]
# Clinical significance
Mutations in the SAR1B gene are associated with chylomicron retention disease (also known as Anderson disease) which is an autosomal recessive disorder of severe fat malabsorption.[5] | https://www.wikidoc.org/index.php/SAR1B | |
fdc704882f3ae7e1609b36aca6c05b6583ebc5db | wikidoc | SART3 | SART3
Squamous cell carcinoma antigen recognized by T-cells 3 is a protein that in humans is encoded by the SART3 gene.
The protein encoded by this gene is an RNA-binding nuclear protein that is a tumor-rejection antigen. This antigen possesses tumor epitopes capable of inducing HLA-A24-restricted and tumor-specific cytotoxic T lymphocytes in cancer patients and may be useful for specific immunotherapy. This gene product is found to be an important cellular factor for HIV-1 gene expression and viral replication. It also associates transiently with U6 and U4/U6 snRNPs during the recycling phase of the spliceosome cycle. This encoded protein is thought to be involved in the regulation of mRNA splicing.
# Interactions
SART3 has been shown to interact with RNPS1 and Androgen receptor. | SART3
Squamous cell carcinoma antigen recognized by T-cells 3 is a protein that in humans is encoded by the SART3 gene.[1][1][2][2][3]
The protein encoded by this gene is an RNA-binding nuclear protein that is a tumor-rejection antigen. This antigen possesses tumor epitopes capable of inducing HLA-A24-restricted and tumor-specific cytotoxic T lymphocytes in cancer patients and may be useful for specific immunotherapy. This gene product is found to be an important cellular factor for HIV-1 gene expression and viral replication. It also associates transiently with U6 and U4/U6 snRNPs during the recycling phase of the spliceosome cycle. This encoded protein is thought to be involved in the regulation of mRNA splicing.[3]
# Interactions
SART3 has been shown to interact with RNPS1[4] and Androgen receptor.[5] | https://www.wikidoc.org/index.php/SART3 | |
043073fb2f19273d458edec827dd25301f00f852 | wikidoc | SASS6 | SASS6
Spindle assembly abnormal protein 6 homolog (SAS-6) is a protein that in humans is encoded by the SASS6 gene.
# Function
SAS-6 is necessary for centrosome duplication and functions during procentriole formation; SAS-6 functions to ensure that each centriole seeds the formation of a single procentriole per cell cycle.
# Clinical significance
Mutations in SASS6 are associated to MCPH . | SASS6
Spindle assembly abnormal protein 6 homolog (SAS-6) is a protein that in humans is encoded by the SASS6 gene.[1][2][3]
# Function
SAS-6 is necessary for centrosome duplication and functions during procentriole formation; SAS-6 functions to ensure that each centriole seeds the formation of a single procentriole per cell cycle.[4]
# Clinical significance
Mutations in SASS6 are associated to MCPH .[5] | https://www.wikidoc.org/index.php/SASS6 | |
49e566702a1a442aca8e4ac827f49047e8be4fea | wikidoc | SATB2 | SATB2
Special AT-rich sequence-binding protein 2 (SATB2) also known as DNA-binding protein SATB2 is a protein that in humans is encoded by the SATB2 gene. SATB2 is a DNA-binding protein that specifically binds nuclear matrix attachment regions and is involved in transcriptional regulation and chromatin remodeling. SATB2 shows a restricted mode of expression and is expressed in certain cell nuclei . The SATB2 protein is mainly expressed in the epithelial cells of the colon and rectum, followed by the nuclei of neurons in the brain.
# Function
With an average worldwide prevalence of 1/800 live births, oral clefts are one of the most common birth defects. Although over 300 malformation syndromes can include an oral cleft, non-syndromic forms represent about 70% of cases with cleft lip with or without cleft palate (CL/P) and roughly 50% of cases with cleft palate (CP) only. Non-syndromic oral clefts are considered ‘complex’ or ‘multifactorial’ in that both genes and environmental factors contribute to the etiology. Current research suggests that several genes are likely to control risk, as well as environmental factors such as maternal smoking.
Re-sequencing studies to identify specific mutations suggest several different genes may control risk to oral clefts, and many distinct variants or mutations in apparently causal genes have been found reflecting a high degree of allelic heterogeneity. Although most of these mutations are extremely rare and often show incomplete penetrance (i.e., an unaffected parent or other relative may also carry the mutation), combined they may account for up to 5% of non-syndromic oral cleft.
Mutations in the SATB2 gene have been found to cause isolated cleft palates. SATB2 also likely influences brain development. This is consistent with mouse studies that show SATB2 is necessary for proper establishment of cortical neuron connections across the corpus callosum, despite the apparently normal corpus callosum in heterozygous knockout mice.
# Structure
SATB2 is a 733 amino-acid homeodomain-containing human protein with a molecular weight of 82.5 kDa encoded by the SATB2 gene on 2q33. The protein contains two degenerate homeodomain regions known as CUT domains (amino acid 352–437 and 482–560) and a classical homeodomain (amino acid 614–677). There is an extraordinarily high degree of sequence conservation, with only three predicted amino-acid substitutions in the 733 residue protein with I481V, A590T and I730T being amino acid differences between the human and the mouse protein.
# Clinical significance
SATB2 has been implicated as causative in the cleft or high palate of individuals with 2q32q33 microdeletion syndrome.
SATB2 was found to be disrupted in two unrelated cases with de novo apparently balanced chromosome translocations associated with cleft palate and Pierre Robin sequence.
The role of SATB2 in tooth and jaw development is supported by the identification of a de novo SATB2 mutation in a male with profound mental retardation and jaw and tooth abnormalities and a translocation interrupting SATB2 in an individual with Robin sequence. In addition, mouse models have demonstrated haploinsufficiency of SATB2 results in craniofacial defects that phenocopy those caused by 2q32q33 deletion in humans; moreover, full functional loss of SATB2 amplifies these defects.
SATB2 expression is highly specific for cancer in the lower GI-tract and has been implicated as a cancer biomarker for colorectal cancer. | SATB2
Special AT-rich sequence-binding protein 2 (SATB2) also known as DNA-binding protein SATB2 is a protein that in humans is encoded by the SATB2 gene.[1] SATB2 is a DNA-binding protein that specifically binds nuclear matrix attachment regions and is involved in transcriptional regulation and chromatin remodeling.[2] SATB2 shows a restricted mode of expression [2] and is expressed in certain cell nuclei [3]. The SATB2 protein is mainly expressed in the epithelial cells of the colon and rectum, followed by the nuclei of neurons in the brain.[3]
# Function
With an average worldwide prevalence of 1/800 live births, oral clefts are one of the most common birth defects.[4] Although over 300 malformation syndromes can include an oral cleft, non-syndromic forms represent about 70% of cases with cleft lip with or without cleft palate (CL/P) and roughly 50% of cases with cleft palate (CP) only. Non-syndromic oral clefts are considered ‘complex’ or ‘multifactorial’ in that both genes and environmental factors contribute to the etiology. Current research suggests that several genes are likely to control risk, as well as environmental factors such as maternal smoking.[5]
Re-sequencing studies to identify specific mutations suggest several different genes may control risk to oral clefts, and many distinct variants or mutations in apparently causal genes have been found reflecting a high degree of allelic heterogeneity. Although most of these mutations are extremely rare and often show incomplete penetrance (i.e., an unaffected parent or other relative may also carry the mutation), combined they may account for up to 5% of non-syndromic oral cleft.[5]
Mutations in the SATB2 gene have been found to cause isolated cleft palates.[6] SATB2 also likely influences brain development. This is consistent with mouse studies that show SATB2 is necessary for proper establishment of cortical neuron connections across the corpus callosum, despite the apparently normal corpus callosum in heterozygous knockout mice.[7]
# Structure
SATB2 is a 733 amino-acid homeodomain-containing human protein with a molecular weight of 82.5 kDa encoded by the SATB2 gene on 2q33. The protein contains two degenerate homeodomain regions known as CUT domains (amino acid 352–437 and 482–560) and a classical homeodomain (amino acid 614–677). There is an extraordinarily high degree of sequence conservation, with only three predicted amino-acid substitutions in the 733 residue protein with I481V, A590T and I730T being amino acid differences between the human and the mouse protein.
# Clinical significance
SATB2 has been implicated as causative in the cleft or high palate of individuals with 2q32q33 microdeletion syndrome.[7]
SATB2 was found to be disrupted in two unrelated cases with de novo apparently balanced chromosome translocations associated with cleft palate and Pierre Robin sequence.[8]
The role of SATB2 in tooth and jaw development is supported by the identification of a de novo SATB2 mutation in a male with profound mental retardation and jaw and tooth abnormalities and a translocation interrupting SATB2 in an individual with Robin sequence. In addition, mouse models have demonstrated haploinsufficiency of SATB2 results in craniofacial defects that phenocopy those caused by 2q32q33 deletion in humans; moreover, full functional loss of SATB2 amplifies these defects.[7]
SATB2 expression is highly specific for cancer in the lower GI-tract and has been implicated as a cancer biomarker for colorectal cancer.[9][10] | https://www.wikidoc.org/index.php/SATB2 | |
e2886366d7a8c814322207b2bd563d18f5de036f | wikidoc | SCN1B | SCN1B
Sodium channel subunit beta-1 is a protein that in humans is encoded by the SCN1B gene.
Voltage-gated sodium channels are essential for the generation and propagation of action potentials in striated muscle and neuronal tissues. Biochemically, they consist of a large alpha subunit and 1 or 2 smaller beta subunits, such as SCN1B. The alpha subunit alone can exhibit all the functional attributes of a voltage-gated Na+ channel, but requires a beta-1 subunit for normal inactivation kinetics.
# Clinical significance
Mutation in the SCN1B gene are associated with disorders such as Brugada syndrome and GEFS. | SCN1B
Sodium channel subunit beta-1 is a protein that in humans is encoded by the SCN1B gene.[1][2]
Voltage-gated sodium channels are essential for the generation and propagation of action potentials in striated muscle and neuronal tissues. Biochemically, they consist of a large alpha subunit and 1 or 2 smaller beta subunits, such as SCN1B. The alpha subunit alone can exhibit all the functional attributes of a voltage-gated Na+ channel, but requires a beta-1 subunit for normal inactivation kinetics.[supplied by OMIM][2]
# Clinical significance
Mutation in the SCN1B gene are associated with disorders such as Brugada syndrome and GEFS. | https://www.wikidoc.org/index.php/SCN1B | |
39c45edaedaa4a5eb74dffb973c84c3257b30a1a | wikidoc | SCN3A | SCN3A
Sodium channel, voltage-gated, type III, alpha subunit (SCN3A) is a protein that in humans is encoded by the Nav1.3 gene.
# Function
Voltage-gated sodium channels are transmembrane glycoprotein complexes composed of a large alpha subunit with 24 transmembrane domains and one or more regulatory beta subunits. They are responsible for the generation and propagation of action potentials in neurons and muscle. This gene encodes one member of the sodium channel alpha subunit gene family, and is found in a cluster of five alpha subunit genes on chromosome 2. Multiple transcript variants encoding different isoforms have been found for this gene.
SCN3A is involved in folding the human cerebral cortex, a process called "gyrification". | SCN3A
Sodium channel, voltage-gated, type III, alpha subunit (SCN3A) is a protein that in humans is encoded by the Nav1.3 gene.[1]
# Function
Voltage-gated sodium channels are transmembrane glycoprotein complexes composed of a large alpha subunit with 24 transmembrane domains and one or more regulatory beta subunits. They are responsible for the generation and propagation of action potentials in neurons and muscle. This gene encodes one member of the sodium channel alpha subunit gene family, and is found in a cluster of five alpha subunit genes on chromosome 2. Multiple transcript variants encoding different isoforms have been found for this gene.[1]
SCN3A is involved in folding the human cerebral cortex, a process called "gyrification".[2] | https://www.wikidoc.org/index.php/SCN3A | |
ff6ed1f38c484ebb5200965ca4024b9a0065049d | wikidoc | SCN8A | SCN8A
Sodium channel, voltage gated, type VIII, alpha subunit also known as SCN8A or Nav1.6 is a membrane protein encoded by the SCN8A gene. Nav1.6 is one sodium channel isoform and is the primary voltage-gated sodium channel at the nodes of Ranvier. The channels are highly concentrated in sensory and motor axons in the peripheral nervous system and cluster at the nodes in the central nervous system.
# Structure
Nav1.6 is encoded by the SCN8A gene which contains 27 exons and measures 170 kb. The voltage gated sodium channel is composed of 1980 residues. Like other sodium channels, Nav1.6 is a monomer composed of four homologous domains (I-IV) and 25 transmembrane segments. SCN8A encodes S3-S4 transmembrane segments which form an intracellular loop.
# Function
Like other sodium ion channels, Nav1.6 facilitates action potential propagation when the membrane potential is depolarized by an influx of Na+ ions. However, Nav1.6 is able to sustain repetitive excitation and firing. The high frequency firing characteristic of Nav1.6 is caused by a persistent and resurgent sodium current. This characteristic is caused by slow activation of the sodium channel following repolarization, which allows a steady-state sodium current after the initial action potential propagation. The steady-state sodium current contributes to the depolarization of the following action potential. Additionally, the activation threshold of Nav1.6 is lower compared to other common sodium channels such as Nav1.2. This feature allows Nav1.6 channels to rapidly recover from inactivation and sustain a high rate of activity.
Nav1.6 is expressed primarily in the nodes of Ranvier in myelinated axons but is also highly concentrated at the distal end of the axon hillock, cerebellar granule cells and Purkinje neurons and to a lower extent in non-myelinated axons and dendrites. Given the location of Nav1.6, the channel contributes to the firing threshold of a given neuron, as the electrical impulses from various inputs are summed at the axon hillock in order to reach firing threshold before propagating down the axon. Other sodium channel isoforms are expressed at the distal end of the axon hillock, including Nav1.1 and Nav1.2.
NaV1.6 channels demonstrate resistance against protein phosphorylation regulation. Sodium channels are modulated by protein kinase A and protein kinase C (PKC) phosphorylation, which reduce peak sodium currents. Dopamine and acetylcholine decrease sodium currents in hippocampal pyramidal neurons through phosphorylation. Similarly, serotonin receptors in the prefrontal cortex are regulated by PKC in order to reduce sodium currents. Phosphorylated regulation in sodium channels helps to slow inactivation. However, NaV1.6 channels lacks adequate protein kinase sites. Phosphorylation sites at amino acid residues Ser573 and Ser687 are found in other sodium channels but are not well conserved in NaV1.6. The lack of serine residues lead to the channel's ability to consistently and quickly fire following inactivation.
NaV1.6 is conversely regulated by Calmodulin (CaM). CaM interacts with the isoleucine-glutamine (IQ) motif of NaV1.6 in order to inactivate the channel. The IQ motif folds into a helix when interacting with CaM and CaM will inactivate NaV1.6 depending on the concentration of calcium. The NaV1.6 IQ demonstrates moderate affinity for CaM compared to other sodium channel isoforms such as NaV1.6. The difference in CaM affinity contributes to NaV1.6's resistance to inactivation.
# Clinical significance
The first known mutation in humans was discovered by Krishna Veeramah and Michael Hammer in 2012. The genome of a child demonstrating epileptic encephalopathy was sequenced and revealed a de novo missense mutation, p.Asn1768Asp. The missense mutations in Nav1.6 increased channel function by increasing the duration of the persistent sodium current and prevented complete inactivation following hyperpolarization. 20% of the initial current persisted 100 ms after hyperpolarization resulting in hyperexcitability of the neuron and increasing the likelihood of premature or unintentional firing. In addition to epileptic encephalopathy, the patient presented with developmental delay, autistic features, intellectual disability and ataxia.
Sodium channel conversion has been implicated in the demyelination of axons related multiple sclerosis (MS). In early stages of myelination, immature Nav1.2 channels outnumber Nav1.6 in axons. However, mature Nav1.6 channels gradually replace the other channels as myelination continues, allowing increased conduction velocity given the lower threshold of Nav1.6. However, in MS models, sodium channel conversion from mature Nav1.6 to Nav1.2 is observed. | SCN8A
Sodium channel, voltage gated, type VIII, alpha subunit also known as SCN8A or Nav1.6 is a membrane protein encoded by the SCN8A gene.[1] Nav1.6 is one sodium channel isoform and is the primary voltage-gated sodium channel at the nodes of Ranvier. The channels are highly concentrated in sensory and motor axons in the peripheral nervous system and cluster at the nodes in the central nervous system.[2][3][4]
# Structure
Nav1.6 is encoded by the SCN8A gene which contains 27 exons and measures 170 kb. The voltage gated sodium channel is composed of 1980 residues. Like other sodium channels, Nav1.6 is a monomer composed of four homologous domains (I-IV) and 25 transmembrane segments. SCN8A encodes S3-S4 transmembrane segments which form an intracellular loop.[5]
# Function
Like other sodium ion channels, Nav1.6 facilitates action potential propagation when the membrane potential is depolarized by an influx of Na+ ions. However, Nav1.6 is able to sustain repetitive excitation and firing. The high frequency firing characteristic of Nav1.6 is caused by a persistent and resurgent sodium current. This characteristic is caused by slow activation of the sodium channel following repolarization,[6] which allows a steady-state sodium current after the initial action potential propagation. The steady-state sodium current contributes to the depolarization of the following action potential. Additionally, the activation threshold of Nav1.6 is lower compared to other common sodium channels such as Nav1.2. This feature allows Nav1.6 channels to rapidly recover from inactivation and sustain a high rate of activity.[7]
Nav1.6 is expressed primarily in the nodes of Ranvier in myelinated axons but is also highly concentrated at the distal end of the axon hillock, cerebellar granule cells and Purkinje neurons and to a lower extent in non-myelinated axons and dendrites.[7] Given the location of Nav1.6, the channel contributes to the firing threshold of a given neuron, as the electrical impulses from various inputs are summed at the axon hillock in order to reach firing threshold before propagating down the axon. Other sodium channel isoforms are expressed at the distal end of the axon hillock, including Nav1.1 and Nav1.2.[3]
NaV1.6 channels demonstrate resistance against protein phosphorylation regulation. Sodium channels are modulated by protein kinase A and protein kinase C (PKC) phosphorylation, which reduce peak sodium currents. Dopamine and acetylcholine decrease sodium currents in hippocampal pyramidal neurons through phosphorylation. Similarly, serotonin receptors in the prefrontal cortex are regulated by PKC in order to reduce sodium currents.[6] Phosphorylated regulation in sodium channels helps to slow inactivation. However, NaV1.6 channels lacks adequate protein kinase sites. Phosphorylation sites at amino acid residues Ser573 and Ser687 are found in other sodium channels but are not well conserved in NaV1.6. The lack of serine residues lead to the channel's ability to consistently and quickly fire following inactivation.[9]
NaV1.6 is conversely regulated by Calmodulin (CaM). CaM interacts with the isoleucine-glutamine (IQ) motif of NaV1.6 in order to inactivate the channel. The IQ motif folds into a helix when interacting with CaM and CaM will inactivate NaV1.6 depending on the concentration of calcium. The NaV1.6 IQ demonstrates moderate affinity for CaM compared to other sodium channel isoforms such as NaV1.6. The difference in CaM affinity contributes to NaV1.6's resistance to inactivation.[10]
# Clinical significance
The first known mutation in humans was discovered by Krishna Veeramah and Michael Hammer in 2012.[11] The genome of a child demonstrating epileptic encephalopathy was sequenced and revealed a de novo missense mutation, p.Asn1768Asp. The missense mutations in Nav1.6 increased channel function by increasing the duration of the persistent sodium current and prevented complete inactivation following hyperpolarization. 20% of the initial current persisted 100 ms after hyperpolarization resulting in hyperexcitability of the neuron and increasing the likelihood of premature or unintentional firing. In addition to epileptic encephalopathy, the patient presented with developmental delay, autistic features, intellectual disability and ataxia.
Sodium channel conversion has been implicated in the demyelination of axons related multiple sclerosis (MS). In early stages of myelination, immature Nav1.2 channels outnumber Nav1.6 in axons. However, mature Nav1.6 channels gradually replace the other channels as myelination continues, allowing increased conduction velocity given the lower threshold of Nav1.6.[3] However, in MS models, sodium channel conversion from mature Nav1.6 to Nav1.2 is observed.[12] | https://www.wikidoc.org/index.php/SCN8A | |
c3eb8fda8fbbe8f1809df0d8efbf7b1d0784abfd | wikidoc | SCRIB | SCRIB
SCRIB, also known as Scribble, SCRIBL, or Scribbled homolog (Drosophila), is a scaffold protein which in humans is encoded by the SCRIB gene. It was originally isolated in Drosophila melanogaster in a pathway (also known as the Scribble complex) with DLGAP5 (Discs large) and LLGL1 (Lethal giant larvae) as a tumor suppressor. In humans, SCRIB is found as a membrane protein and is involved in cell migration, cell polarity, and cell proliferation in epithelial cells. There is also strong evidence that SCRIB may play a role in cancer progression because of its strong homology to the Drosophila protein.
# Function
In Drosophila melanogaster, SCRIB is involved in synaptic function, neuroblast differentiation, and epithelial polarization. Mechanistically, the human homolog is a scaffold protein linked to cellular differentiation centered on the regulation of epithelial as well as neuronal morphogenesis. Deficiency in SCRIB impairs many aspects of cell polarity and cell movement. SCRIB is also likely involved in establishing apical-basal polarity as well as progression from the G1 phase to S phase in the cell cycle as a result of its relationship with cell proliferation and exocytosis.
The transcribed protein products of the SCRIB gene along with DLGAP5 (Discs large) and LLGL1 (Lethal giant larvae) are components of the Scribble complex that is localized in the basolateral membrane. The Scribble complex plays a role in determining cell polarity and cell proliferation in epithelial cells. The precise mechanism by which these proteins function together is currently unknown, but they have been implicated in several signaling pathways, vesicle trafficking, and in the myosin II-actin cytoskeleton. The Scribble complex has been shown to promote basolateral membrane identity by antagonizing both the Par complex and the Crumbs complex, which promote apical membrane identity. These genes have also been identified as tumor suppressors in Drosophila melanogaster. Since these genes are highly conserved in humans, there is evidence that they play a role in cancer progression.
# Structure
The human homolog is a LAP protein, it contains 16 leucine-rich repeats and four PDZ domains. SCRIB belongs to a protein complex containing betaPIX, an exchange factor for Rac/Cdc42, and GIT1, a GTPase activating protein for ARF6 implicated in receptor recycling and exocytosis.
# Subcellular and tissue distribution
SCRIB is found in the cell membrane most often as a peripheral membrane protein. The Scribble complex is localized at the basolateral membrane. SCRIB is also found in cellular junctions such as adherens junctions and tight junctions. Specifically, it is located in the kidney, skeletal muscles, liver, lung, breast, intestine, placenta and epithelial cells.
# Clinical significance
The PDZ domain of SCRIB binds directly to the human papillomavirus E6 protein. SCRIB is targeted for ubiquitination by a complex of E6 and UBE3A and E6 induces degradation of SCRIB.
## Role as a tumor suppressor
As mentioned above, SCRIB has been identified as a tumor suppressor along with DLGAP5 (Discs large) and LLGL1 (Lethal giant larvae). Specifically, SCRIB deficient mutants have been shown to promote the activity of numerous oncogenes. For example, SCRIB is known to inhibit breast cancer formation and the depletion of SCRIB promotes neoplastic growth by disrupting morphogenesis and inhibiting cell death through an association with Myc. In human cells expressing oncogenic Ras or Raf, it was found the loss of SCRIB resulted in the invasion of the extracellular matrix by various cell types. This is believed to be a direct result of regulation of the MAP Kinase pathway by SCRIB.
## Role in epithelial mesenchymal transition (EMT)
Due to its role in cell polarity and cell motility, SCRIB has also been implicated in epithelial mesenchymal transition (EMT), which is linked to tumor metastasis and proliferation in many cancers. EMT is implicated in cancer progression by allowing static epithelial cells to become migratory and allowing these cells to adapt to as well as colonize new environments. In cancerous epithelial tissues, SCRIB is found primarily in the cytosol as opposed to its usual location in the membrane, thus further implicating a role in tumor progression and EMT for SCRIB.
Knockdown mutants have resulted in the loss of adhesion between Madin-Darby canine kidney epithelial cells. This loss of adhesion was correlated with an acquired mesenchymal appearance, an increase in motility, and loss of directionality. These effects were a direct result of the interruption of E-cadherin-mediated cellular adhesion. A decrease in cell migration and an overall decrease in cell motility markers as well as epithelial mesenchymal transition mediators was also observed in small lung adenocarcinoma cells that were depleted of SCRIB. | SCRIB
SCRIB, also known as Scribble, SCRIBL, or Scribbled homolog (Drosophila), is a scaffold protein which in humans is encoded by the SCRIB gene.[1][2] It was originally isolated in Drosophila melanogaster in a pathway (also known as the Scribble complex) with DLGAP5 (Discs large) and LLGL1 (Lethal giant larvae) as a tumor suppressor.[3] In humans, SCRIB is found as a membrane protein and is involved in cell migration, cell polarity, and cell proliferation in epithelial cells.[3][4] There is also strong evidence that SCRIB may play a role in cancer progression because of its strong homology to the Drosophila protein.[3]
# Function
In Drosophila melanogaster, SCRIB is involved in synaptic function, neuroblast differentiation, and epithelial polarization. Mechanistically, the human homolog is a scaffold protein linked to cellular differentiation centered on the regulation of epithelial as well as neuronal morphogenesis. Deficiency in SCRIB impairs many aspects of cell polarity and cell movement. SCRIB is also likely involved in establishing apical-basal polarity as well as progression from the G1 phase to S phase in the cell cycle as a result of its relationship with cell proliferation and exocytosis.[4]
The transcribed protein products of the SCRIB gene along with DLGAP5 (Discs large) and LLGL1 (Lethal giant larvae) are components of the Scribble complex that is localized in the basolateral membrane. The Scribble complex plays a role in determining cell polarity and cell proliferation in epithelial cells.[5] The precise mechanism by which these proteins function together is currently unknown, but they have been implicated in several signaling pathways, vesicle trafficking, and in the myosin II-actin cytoskeleton.[3] The Scribble complex has been shown to promote basolateral membrane identity by antagonizing both the Par complex and the Crumbs complex, which promote apical membrane identity.[5] These genes have also been identified as tumor suppressors in Drosophila melanogaster. Since these genes are highly conserved in humans, there is evidence that they play a role in cancer progression.[3]
# Structure
The human homolog is a LAP protein, it contains 16 leucine-rich repeats and four PDZ domains.[6] SCRIB belongs to a protein complex containing betaPIX, an exchange factor for Rac/Cdc42, and GIT1, a GTPase activating protein for ARF6 implicated in receptor recycling and exocytosis.[7]
# Subcellular and tissue distribution
SCRIB is found in the cell membrane most often as a peripheral membrane protein. The Scribble complex is localized at the basolateral membrane.[5] SCRIB is also found in cellular junctions such as adherens junctions and tight junctions.[8] Specifically, it is located in the kidney, skeletal muscles, liver, lung, breast, intestine, placenta and epithelial cells.[9]
# Clinical significance
The PDZ domain of SCRIB binds directly to the human papillomavirus E6 protein.[10] SCRIB is targeted for ubiquitination by a complex of E6 and UBE3A and E6 induces degradation of SCRIB.[10]
## Role as a tumor suppressor
As mentioned above, SCRIB has been identified as a tumor suppressor along with DLGAP5 (Discs large) and LLGL1 (Lethal giant larvae).[3] Specifically, SCRIB deficient mutants have been shown to promote the activity of numerous oncogenes.[5] For example, SCRIB is known to inhibit breast cancer formation and the depletion of SCRIB promotes neoplastic growth by disrupting morphogenesis and inhibiting cell death through an association with Myc.[5][11] In human cells expressing oncogenic Ras or Raf, it was found the loss of SCRIB resulted in the invasion of the extracellular matrix by various cell types. This is believed to be a direct result of regulation of the MAP Kinase pathway by SCRIB.[12]
## Role in epithelial mesenchymal transition (EMT)
Due to its role in cell polarity and cell motility, SCRIB has also been implicated in epithelial mesenchymal transition (EMT), which is linked to tumor metastasis and proliferation in many cancers. EMT is implicated in cancer progression by allowing static epithelial cells to become migratory and allowing these cells to adapt to as well as colonize new environments. In cancerous epithelial tissues, SCRIB is found primarily in the cytosol as opposed to its usual location in the membrane, thus further implicating a role in tumor progression and EMT for SCRIB.[13]
Knockdown mutants have resulted in the loss of adhesion between Madin-Darby canine kidney epithelial cells. This loss of adhesion was correlated with an acquired mesenchymal appearance, an increase in motility, and loss of directionality. These effects were a direct result of the interruption of E-cadherin-mediated cellular adhesion.[14] A decrease in cell migration and an overall decrease in cell motility markers as well as epithelial mesenchymal transition mediators was also observed in small lung adenocarcinoma cells that were depleted of SCRIB.[13] | https://www.wikidoc.org/index.php/SCRIB | |
3de65e1f8962bcb79a4a232765cdc2f3f11f703a | wikidoc | SCYL1 | SCYL1
SCY1-like 1 (S. cerevisiae), also known as SCYL1, is a human gene which is highly conserved throughout evolution.
# Function
This gene encodes a transcriptional regulator belonging to the SCY1-like family of kinase-like proteins. The protein has a divergent N-terminal kinase domain that is thought to be catalytically inactive, and can bind specific DNA sequences through its C-terminal domain. It activates transcription of the telomerase reverse transcriptase and DNA polymerase beta genes. The protein has been localized to the nucleus, and also to the cytoplasm and centrosomes during mitosis. Multiple transcript variants encoding different isoforms have been found for this gene. At least three of the transcripts code for a protein containing all exons, referred to as full-length (FL).
The mouse homolog of FL-Scyl1 is 90% identical and 93% similar in amino acid content to human FL-Scyl1. In Mus Musculus FL-Scyl1 encodes an 806-amino acid polypeptide. The FL protein contains HEAT repeats and a C-terminal coiled coil domain that also contains multiple dibasic motifs, and ends in the dibasic motif RKLD-COOH.
Scyl1 localizes to the cis-Golgi and ER-Golgi Intermediate Compartment (ERGIC). Scyl1 binds to Coatomer I (COPI) and colocalizes with beta-COPI and ERGIC53. siRNA mediated knockdown of the protein disrupted retrograde flow of the KDEL receptor from the Golgi to the ER. Furthermore, Scyl1 localization in rat hippocampal neurons also demonstrates a similar relationship to COPI.
# Clinical significance
Mutations in Scyl1 are the genetic defect resulting in the phenotype of muscle deficient mice (mdf mice) that suffer from a progressive neurodegeneration of the cerebellum and lower motor neurons. Mdf mice model human spinocerebellar ataxia type disorders. | SCYL1
SCY1-like 1 (S. cerevisiae), also known as SCYL1, is a human gene which is highly conserved throughout evolution.[1][2]
# Function
This gene encodes a transcriptional regulator belonging to the SCY1-like family of kinase-like proteins. The protein has a divergent N-terminal kinase domain that is thought to be catalytically inactive, and can bind specific DNA sequences through its C-terminal domain. It activates transcription of the telomerase reverse transcriptase and DNA polymerase beta genes. The protein has been localized to the nucleus, and also to the cytoplasm and centrosomes during mitosis. Multiple transcript variants encoding different isoforms have been found for this gene. At least three of the transcripts code for a protein containing all exons, referred to as full-length (FL).[1]
The mouse homolog of FL-Scyl1 is 90% identical and 93% similar in amino acid content to human FL-Scyl1. In Mus Musculus FL-Scyl1 encodes an 806-amino acid polypeptide. The FL protein contains HEAT repeats and a C-terminal coiled coil domain that also contains multiple dibasic motifs, and ends in the dibasic motif RKLD-COOH.
Scyl1 localizes to the cis-Golgi and ER-Golgi Intermediate Compartment (ERGIC). Scyl1 binds to Coatomer I (COPI) and colocalizes with beta-COPI and ERGIC53. siRNA mediated knockdown of the protein disrupted retrograde flow of the KDEL receptor from the Golgi to the ER.[3] Furthermore, Scyl1 localization in rat hippocampal neurons also demonstrates a similar relationship to COPI.[4]
# Clinical significance
Mutations in Scyl1 are the genetic defect resulting in the phenotype of muscle deficient mice (mdf mice) that suffer from a progressive neurodegeneration of the cerebellum and lower motor neurons. Mdf mice model human spinocerebellar ataxia type disorders.[5] | https://www.wikidoc.org/index.php/SCYL1 | |
1cdc9e83a35d8e42fafe750eff0108e9b76273d5 | wikidoc | SEC63 | SEC63
Translocation protein SEC63 homolog is a protein that in humans is encoded by the SEC63 gene.
# Function
The Sec61 complex is the central component of the protein translocation apparatus of the endoplasmic reticulum (ER) membrane. The protein encoded by this gene and SEC62 protein are found to be associated with ribosome-free SEC61 complex. It is speculated that Sec61-Sec62-Sec63 may perform post-translational protein translocation into the ER. The Sec61-Sec62-Sec63 complex might also perform the backward transport of ER proteins that are subject to the ubiquitin-proteasome-dependent degradation pathway. The encoded protein is an integral membrane protein located in the rough ER.
# Clinical significance
Mutations of this gene have been linked with autosomal dominant polycystic liver disease. | SEC63
Translocation protein SEC63 homolog is a protein that in humans is encoded by the SEC63 gene.[1][2][3]
# Function
The Sec61 complex is the central component of the protein translocation apparatus of the endoplasmic reticulum (ER) membrane. The protein encoded by this gene and SEC62 protein are found to be associated with ribosome-free SEC61 complex. It is speculated that Sec61-Sec62-Sec63 may perform post-translational protein translocation into the ER. The Sec61-Sec62-Sec63 complex might also perform the backward transport of ER proteins that are subject to the ubiquitin-proteasome-dependent degradation pathway. The encoded protein is an integral membrane protein located in the rough ER.[3]
# Clinical significance
Mutations of this gene have been linked with autosomal dominant polycystic liver disease.[4] | https://www.wikidoc.org/index.php/SEC63 | |
9bbaed6d52f8043854634e0a4a9ab5917893bb7e | wikidoc | SENP1 | SENP1
Sentrin-specific protease 1 is an enzyme that in humans is encoded by the SENP1 gene.
# General
So far there are six SUMO proteases in humans that have been designated SENP1-3 and SENP5-7 (sentrin/SUMO-specific protease).1 The six proteases possess a conserved C-terminal domain which are variable in size, and with a distinct N-terminal domain between them. The C-terminal domain shows catalytic activity and N-terminal domain regulates cell localization and substrate specificity.
# Features
SENP1 (Sentrin-specific protease 1) is a human protease of 643 amino acids with a weight of 73 kDa, EC number in humans 3.4.22.B70, which adopts a conformation that identifies it as a member of the superfamily of cysteine proteases contain a catalytic triad with characterized three amino acids: a cysteine at position 602, a histidine at position 533 and aspartic acid at position 550.
The important nucleophile is cysteine located at the N-terminal alpha helix of the protein core, the other two amino acids, aspartate and histidine, are located in a beta sheet end.
# Location
Both SENP1 are located in the nucleus and cytosol depending on the cell type, although it has been seen that is exported out from the nucleus to the cytosol through a sequence of nuclear export (NES) that is located at the C-terminus. The mammalian SENP1 is localized mainly in the nucleus.
# Function
SENP1 catalyzes maturation SUMO protein (small ubiquitin-related modifier), which causes hydrolysis peptide bond of SUMO is in a conserved sequence Gly-Gly-|-Ala-Thr-Tyr at the C-terminal to be added to the conjugation of other proteins (sumoylation).
In vertebrates there are three members of the family of SUMO: SUMO-1, -2 and -3. SENP1 can catalyze any of these three.
This conjugation of SUMO toward other proteins is a lot like ubiquitination, however these modifications leads to different results depending on the type of protein been modified. | SENP1
Sentrin-specific protease 1 is an enzyme that in humans is encoded by the SENP1 gene.[1][2][3]
# General
So far there are six SUMO proteases in humans that have been designated SENP1-3 and SENP5-7 (sentrin/SUMO-specific protease).1 The six proteases possess a conserved C-terminal domain which are variable in size, and with a distinct N-terminal domain between them. The C-terminal domain shows catalytic activity and N-terminal domain regulates cell localization and substrate specificity.[4]
# Features
SENP1 (Sentrin-specific protease 1) is a human protease of 643 amino acids with a weight of 73 kDa, EC number in humans 3.4.22.B70, which adopts a conformation that identifies it as a member of the superfamily of cysteine proteases contain a catalytic triad with characterized three amino acids: a cysteine at position 602, a histidine at position 533 and aspartic acid at position 550.
The important nucleophile is cysteine located at the N-terminal alpha helix of the protein core, the other two amino acids, aspartate and histidine, are located in a beta sheet end.
[5]
# Location
Both SENP1 are located in the nucleus and cytosol depending on the cell type, although it has been seen that is exported out from the nucleus to the cytosol through a sequence of nuclear export (NES) that is located at the C-terminus. The mammalian SENP1 is localized mainly in the nucleus.[6]
# Function
SENP1 catalyzes maturation SUMO protein (small ubiquitin-related modifier), which causes hydrolysis peptide bond of SUMO is in a conserved sequence Gly-Gly-|-Ala-Thr-Tyr at the C-terminal [7] to be added to the conjugation of other proteins (sumoylation).[8]
In vertebrates there are three members of the family of SUMO: SUMO-1, -2 and -3. SENP1 can catalyze any of these three.
This conjugation of SUMO toward other proteins is a lot like ubiquitination, however these modifications leads to different results depending on the type of protein been modified.[9] | https://www.wikidoc.org/index.php/SENP1 | |
99f5de698b84f4e4fd18a19e400d6bd253c6c953 | wikidoc | SENP3 | SENP3
SUMO1/sentrin/SMT3 specific peptidase 3, also known as SENP3, is a protein which in humans is encoded by the SENP3 gene.
SENP3 together with SENP5, belongs to the Ulp1 branch in yeast and localize to nucleolus through B23/NPM1. SENP3 is associated and regulated by B23/nucleophosmin/NPM1 and involved in the regulation of ribosome biogenesis. SENP3 may be regulated by Arf-Mdm2-p53 pathway.
# Further reading
- Yeh ET, Gong L, Kamitani T (2000). "Ubiquitin-like proteins: new wines in new bottles". Gene. 248 (1–2): 1–14. doi:10.1016/S0378-1119(00)00139-6. PMID 10806345..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- Nishida T, Tanaka H, Yasuda H (2000). "A novel mammalian Smt3-specific isopeptidase 1 (SMT3IP1) localized in the nucleolus at interphase". Eur. J. Biochem. 267 (21): 6423–7. doi:10.1046/j.1432-1327.2000.01729.x. PMID 11029585.
- Hartley JL, Temple GF, Brasch MA (2001). "DNA cloning using in vitro site-specific recombination". Genome Res. 10 (11): 1788–95. doi:10.1101/gr.143000. PMC 310948. PMID 11076863.
- Wiemann S, Weil B, Wellenreuther R, et al. (2001). "Toward a catalog of human genes and proteins: sequencing and analysis of 500 novel complete protein coding human cDNAs". Genome Res. 11 (3): 422–35. doi:10.1101/gr.GR1547R. PMC 311072. PMID 11230166.
- Simpson JC, Wellenreuther R, Poustka A, et al. (2001). "Systematic subcellular localization of novel proteins identified by large-scale cDNA sequencing". EMBO Rep. 1 (3): 287–92. doi:10.1093/embo-reports/kvd058. PMC 1083732. PMID 11256614.
- Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
- Ota T, Suzuki Y, Nishikawa T, et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs". Nat. Genet. 36 (1): 40–5. doi:10.1038/ng1285. PMID 14702039.
- Colland F, Jacq X, Trouplin V, et al. (2004). "Functional proteomics mapping of a human signaling pathway". Genome Res. 14 (7): 1324–32. doi:10.1101/gr.2334104. PMC 442148. PMID 15231748.
- Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–7. doi:10.1101/gr.2596504. PMC 528928. PMID 15489334.
- Wiemann S, Arlt D, Huber W, et al. (2004). "From ORFeome to biology: a functional genomics pipeline". Genome Res. 14 (10B): 2136–44. doi:10.1101/gr.2576704. PMC 528930. PMID 15489336.
- Bouras T, Fu M, Sauve AA, et al. (2005). "SIRT1 deacetylation and repression of p300 involves lysine residues 1020/1024 within the cell cycle regulatory domain 1". J. Biol. Chem. 280 (11): 10264–76. doi:10.1074/jbc.M408748200. PMID 15632193.
- Andersen JS, Lam YW, Leung AK, et al. (2005). "Nucleolar proteome dynamics". Nature. 433 (7021): 77–83. doi:10.1038/nature03207. PMID 15635413.
- Grégoire S, Yang XJ (2005). "Association with class IIa histone deacetylases upregulates the sumoylation of MEF2 transcription factors". Mol. Cell. Biol. 25 (6): 2273–87. doi:10.1128/MCB.25.6.2273-2287.2005. PMC 1061617. PMID 15743823.
- Mehrle A, Rosenfelder H, Schupp I, et al. (2006). "The LIFEdb database in 2006". Nucleic Acids Res. 34 (Database issue): D415–8. doi:10.1093/nar/gkj139. PMC 1347501. PMID 16381901.
- Nousiainen M, Silljé HH, Sauer G, et al. (2006). "Phosphoproteome analysis of the human mitotic spindle". Proc. Natl. Acad. Sci. U.S.A. 103 (14): 5391–6. doi:10.1073/pnas.0507066103. PMC 1459365. PMID 16565220.
- Gong L, Yeh ET (2006). "Characterization of a family of nucleolar SUMO-specific proteases with preference for SUMO-2 or SUMO-3". J. Biol. Chem. 281 (23): 15869–77. doi:10.1074/jbc.M511658200. PMID 16608850.
- Olsen JV, Blagoev B, Gnad F, et al. (2006). "Global, in vivo, and site-specific phosphorylation dynamics in signaling networks". Cell. 127 (3): 635–48. doi:10.1016/j.cell.2006.09.026. PMID 17081983.
- Yun C, Wang Y, Mukhopadhyay D, et al. (2008). "Nucleolar protein B23/nucleophosmin regulates the vertebrate SUMO pathway through SENP3 and SENP5 proteases". J. Cell Biol. 183 (4): 589–95. doi:10.1083/jcb.200807185. PMC 2582899. PMID 19015314.
- Haindl M, Harasim T, Eick D, Muller S (March 2008). "The nucleolar SUMO-specific protease SENP3 reverses SUMO modification of nucleophosmin and is required for rRNA processing". EMBO Rep. 9 (3): 273–9. doi:10.1038/embor.2008.3. PMC 2267381. PMID 18259216.
- Kuo ML, den Besten W, Thomas MC, et al. (2008). "Arf-induced turnover of the nucleolar nucleophosmin-associated SUMO-2/3 protease Senp3". Cell Cycle. 7 (21): 3378–87. doi:10.4161/cc.7.21.6930. PMID 18948745. | SENP3
SUMO1/sentrin/SMT3 specific peptidase 3, also known as SENP3, is a protein which in humans is encoded by the SENP3 gene.[1][2]
SENP3 together with SENP5, belongs to the Ulp1 branch in yeast and localize to nucleolus through B23/NPM1. SENP3 is associated and regulated by B23/nucleophosmin/NPM1 and involved in the regulation of ribosome biogenesis. SENP3 may be regulated by Arf-Mdm2-p53 pathway.[3]
# Further reading
- Yeh ET, Gong L, Kamitani T (2000). "Ubiquitin-like proteins: new wines in new bottles". Gene. 248 (1–2): 1–14. doi:10.1016/S0378-1119(00)00139-6. PMID 10806345..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
- Nishida T, Tanaka H, Yasuda H (2000). "A novel mammalian Smt3-specific isopeptidase 1 (SMT3IP1) localized in the nucleolus at interphase". Eur. J. Biochem. 267 (21): 6423–7. doi:10.1046/j.1432-1327.2000.01729.x. PMID 11029585.
- Hartley JL, Temple GF, Brasch MA (2001). "DNA cloning using in vitro site-specific recombination". Genome Res. 10 (11): 1788–95. doi:10.1101/gr.143000. PMC 310948. PMID 11076863.
- Wiemann S, Weil B, Wellenreuther R, et al. (2001). "Toward a catalog of human genes and proteins: sequencing and analysis of 500 novel complete protein coding human cDNAs". Genome Res. 11 (3): 422–35. doi:10.1101/gr.GR1547R. PMC 311072. PMID 11230166.
- Simpson JC, Wellenreuther R, Poustka A, et al. (2001). "Systematic subcellular localization of novel proteins identified by large-scale cDNA sequencing". EMBO Rep. 1 (3): 287–92. doi:10.1093/embo-reports/kvd058. PMC 1083732. PMID 11256614.
- Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
- Ota T, Suzuki Y, Nishikawa T, et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs". Nat. Genet. 36 (1): 40–5. doi:10.1038/ng1285. PMID 14702039.
- Colland F, Jacq X, Trouplin V, et al. (2004). "Functional proteomics mapping of a human signaling pathway". Genome Res. 14 (7): 1324–32. doi:10.1101/gr.2334104. PMC 442148. PMID 15231748.
- Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–7. doi:10.1101/gr.2596504. PMC 528928. PMID 15489334.
- Wiemann S, Arlt D, Huber W, et al. (2004). "From ORFeome to biology: a functional genomics pipeline". Genome Res. 14 (10B): 2136–44. doi:10.1101/gr.2576704. PMC 528930. PMID 15489336.
- Bouras T, Fu M, Sauve AA, et al. (2005). "SIRT1 deacetylation and repression of p300 involves lysine residues 1020/1024 within the cell cycle regulatory domain 1". J. Biol. Chem. 280 (11): 10264–76. doi:10.1074/jbc.M408748200. PMID 15632193.
- Andersen JS, Lam YW, Leung AK, et al. (2005). "Nucleolar proteome dynamics". Nature. 433 (7021): 77–83. doi:10.1038/nature03207. PMID 15635413.
- Grégoire S, Yang XJ (2005). "Association with class IIa histone deacetylases upregulates the sumoylation of MEF2 transcription factors". Mol. Cell. Biol. 25 (6): 2273–87. doi:10.1128/MCB.25.6.2273-2287.2005. PMC 1061617. PMID 15743823.
- Mehrle A, Rosenfelder H, Schupp I, et al. (2006). "The LIFEdb database in 2006". Nucleic Acids Res. 34 (Database issue): D415–8. doi:10.1093/nar/gkj139. PMC 1347501. PMID 16381901.
- Nousiainen M, Silljé HH, Sauer G, et al. (2006). "Phosphoproteome analysis of the human mitotic spindle". Proc. Natl. Acad. Sci. U.S.A. 103 (14): 5391–6. doi:10.1073/pnas.0507066103. PMC 1459365. PMID 16565220.
- Gong L, Yeh ET (2006). "Characterization of a family of nucleolar SUMO-specific proteases with preference for SUMO-2 or SUMO-3". J. Biol. Chem. 281 (23): 15869–77. doi:10.1074/jbc.M511658200. PMID 16608850.
- Olsen JV, Blagoev B, Gnad F, et al. (2006). "Global, in vivo, and site-specific phosphorylation dynamics in signaling networks". Cell. 127 (3): 635–48. doi:10.1016/j.cell.2006.09.026. PMID 17081983.
- Yun C, Wang Y, Mukhopadhyay D, et al. (2008). "Nucleolar protein B23/nucleophosmin regulates the vertebrate SUMO pathway through SENP3 and SENP5 proteases". J. Cell Biol. 183 (4): 589–95. doi:10.1083/jcb.200807185. PMC 2582899. PMID 19015314.
- Haindl M, Harasim T, Eick D, Muller S (March 2008). "The nucleolar SUMO-specific protease SENP3 reverses SUMO modification of nucleophosmin and is required for rRNA processing". EMBO Rep. 9 (3): 273–9. doi:10.1038/embor.2008.3. PMC 2267381. PMID 18259216.
- Kuo ML, den Besten W, Thomas MC, et al. (2008). "Arf-induced turnover of the nucleolar nucleophosmin-associated SUMO-2/3 protease Senp3". Cell Cycle. 7 (21): 3378–87. doi:10.4161/cc.7.21.6930. PMID 18948745. | https://www.wikidoc.org/index.php/SENP3 | |
7d08f26cc1c0d3a0f3cb0339e1e8b7654718ccb1 | wikidoc | SEP15 | SEP15
15 kDa selenoprotein is a protein that in humans is encoded by the SEP15 gene. Two alternatively spliced transcript variants encoding distinct isoforms have been found for this gene.
# Function
This gene encodes a selenoprotein, which contains a selenocysteine (Sec) residue at its active site. The selenocysteine is encoded by the UGA codon that normally signals translation termination. The 3' UTR of selenoprotein genes have a common stem-loop structure, the sec insertion sequence (SECIS), that is necessary for the recognition of UGA as a Sec codon rather than as a stop signal. Studies in mouse suggest that this selenoprotein may have redox function and may be involved in the quality control of protein folding.
# Clinical significance
This gene is localized on chromosome 1p31, a genetic locus commonly mutated or deleted in human cancers.
# Protein domain
The protein this gene encodes for is often called Sep15 however in the case of mice, it is named SelM. This protein is an selenoprotein only found in eukaryotes. This domain has a thioredoxin-like domain and a surface accessible active site redox motif. This suggests that they function as thiol-disulfide isomerases involved in disulfide bond formation in the endoplasmic reticulum.
## Function
Recent studies have shown in mice, where the SEP15 gene has been silenced the mice subsequently became deficient in SEP15 and were able to inhibit the development of colorectal cancer.
## Structure
The particular structure has an alpha/beta central domain which is actually made up of three alpha helices and a mixed parallel/anti-parallel four-stranded beta-sheet. | SEP15
15 kDa selenoprotein is a protein that in humans is encoded by the SEP15 gene.[1] Two alternatively spliced transcript variants encoding distinct isoforms have been found for this gene.
# Function
This gene encodes a selenoprotein, which contains a selenocysteine (Sec) residue at its active site. The selenocysteine is encoded by the UGA codon that normally signals translation termination. The 3' UTR of selenoprotein genes have a common stem-loop structure, the sec insertion sequence (SECIS), that is necessary for the recognition of UGA as a Sec codon rather than as a stop signal. Studies in mouse suggest that this selenoprotein may have redox function and may be involved in the quality control of protein folding.[1]
# Clinical significance
This gene is localized on chromosome 1p31, a genetic locus commonly mutated or deleted in human cancers.[1]
# Protein domain
The protein this gene encodes for is often called Sep15 however in the case of mice, it is named SelM. This protein is an selenoprotein only found in eukaryotes. This domain has a thioredoxin-like domain and a surface accessible active site redox motif.[2] This suggests that they function as thiol-disulfide isomerases involved in disulfide bond formation in the endoplasmic reticulum.[2]
## Function
Recent studies have shown in mice, where the SEP15 gene has been silenced the mice subsequently became deficient in SEP15 and were able to inhibit the development of colorectal cancer.[3]
## Structure
The particular structure has an alpha/beta central domain which is actually made up of three alpha helices and a mixed parallel/anti-parallel four-stranded beta-sheet.[2] | https://www.wikidoc.org/index.php/SEP15 | |
043d855580ba1f6327eddac4d90623c5b57eaca5 | wikidoc | SEPN1 | SEPN1
Selenoprotein N is a protein that in humans is encoded by the SEPN1 gene.
# Function
This gene encodes a selenoprotein, which contains a selenocysteine (Sec) residue at its active site. The selenocysteine is encoded by the UGA codon that normally signals translation termination. The 3' UTR of selenoprotein genes have a common stem-loop structure, the sec insertion sequence (SECIS), that is necessary for the recognition of UGA as a Sec codon rather than as a stop signal. Mutations in this gene cause the classical phenotype of multiminicore disease and congenital muscular dystrophy with spinal rigidity and restrictive respiratory syndrome. Two alternatively spliced transcript variants encoding distinct isoforms have been found for this gene.
# Model organisms
Model organisms have been used in the study of SEPN1 function. A conditional knockout mouse line, called Sepn1tm1a(KOMP)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty five tests were carried out on homozygous mutant mice and one significant abnormality was observed: than animals displayed vertebral fusion. | SEPN1
Selenoprotein N is a protein that in humans is encoded by the SEPN1 gene.[1][2]
# Function
This gene encodes a selenoprotein, which contains a selenocysteine (Sec) residue at its active site. The selenocysteine is encoded by the UGA codon that normally signals translation termination. The 3' UTR of selenoprotein genes have a common stem-loop structure, the sec insertion sequence (SECIS), that is necessary for the recognition of UGA as a Sec codon rather than as a stop signal. Mutations in this gene cause the classical phenotype of multiminicore disease and congenital muscular dystrophy with spinal rigidity and restrictive respiratory syndrome. Two alternatively spliced transcript variants encoding distinct isoforms have been found for this gene.[2]
# Model organisms
Model organisms have been used in the study of SEPN1 function. A conditional knockout mouse line, called Sepn1tm1a(KOMP)Wtsi[8][9] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[10][11][12]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[6][13] Twenty five tests were carried out on homozygous mutant mice and one significant abnormality was observed: than animals displayed vertebral fusion.[6] | https://www.wikidoc.org/index.php/SEPN1 | |
523fbd833cd0d9adae44aed573f81dfd29143ad6 | wikidoc | SEPT6 | SEPT6
Septin-6 is a protein that in humans is encoded by the SEPT6 gene.
# Function
This gene is a member of the septin family of GTPases. Members of this family are required for cytokinesis. This gene encodes four transcript variants encoding three distinct isoforms. An additional transcript variant has been identified, but its biological validity has not been determined.
# Clinical significance
One version of pediatric acute myeloid leukemia is the result of a reciprocal translocation between chromosomes 11 and X, with the breakpoint associated with the genes encoding the mixed-lineage leukemia and septin 2 proteins.
# Interactions
SEPT6 has been shown to interact with SEPT2. | SEPT6
Septin-6 is a protein that in humans is encoded by the SEPT6 gene.[1][2][3]
# Function
This gene is a member of the septin family of GTPases. Members of this family are required for cytokinesis. This gene encodes four transcript variants encoding three distinct isoforms. An additional transcript variant has been identified, but its biological validity has not been determined.[3]
# Clinical significance
One version of pediatric acute myeloid leukemia is the result of a reciprocal translocation between chromosomes 11 and X, with the breakpoint associated with the genes encoding the mixed-lineage leukemia and septin 2 proteins.[3]
# Interactions
SEPT6 has been shown to interact with SEPT2.[4][5] | https://www.wikidoc.org/index.php/SEPT6 | |
a64a5665bf32d7dfcf87119b7df6574caf09bd34 | wikidoc | SEPT9 | SEPT9
Septin-9 is a protein that in humans is encoded by the SEPT9 gene.
# Interactions
SEPT9 has been shown to interact with SEPT2 and SEPT7.
# Function
Along with AHNAK, eIF4E and S100A11, SEPT9 has been shown to be essential for pseudopod protrusion, tumor cell migration and invasion.
# Clinical significance
The v2 region of the SEPT9 promoter has been shown to be methylated in colorectal cancer tissue compared with normal colonic mucosa. Using highly sensitive real time PCR assays, methylated SEPT9 was detected in the blood of colorectal cancer patients. This alternate methylation pattern in cancer samples is suggestive of an aberrant activation or repression of the gene compared to normal tissue samples.
Testing to detect methylated SEPT9 is not indicated as a first option for colorectal cancer screening. It is similar in specificity and sensitivity to the stool guaiac test or fecal immune tests, and those tests should be used in preference. In cases when the physician aggressively has recommended a colonoscopy and the patient has declined that and these other tests, then this test has advantages over patients having no screening at all. | SEPT9
Septin-9 is a protein that in humans is encoded by the SEPT9 gene.[1][2][3]
# Interactions
SEPT9 has been shown to interact with SEPT2[4] and SEPT7.[4]
# Function
Along with AHNAK, eIF4E and S100A11, SEPT9 has been shown to be essential for pseudopod protrusion, tumor cell migration and invasion.[5]
# Clinical significance
The v2 region of the SEPT9 promoter has been shown to be methylated in colorectal cancer tissue compared with normal colonic mucosa.[6] Using highly sensitive real time PCR assays, methylated SEPT9 was detected in the blood of colorectal cancer patients. This alternate methylation pattern in cancer samples is suggestive of an aberrant activation or repression of the gene compared to normal tissue samples.[7][8]
Testing to detect methylated SEPT9 is not indicated as a first option for colorectal cancer screening.[9] It is similar in specificity and sensitivity to the stool guaiac test or fecal immune tests, and those tests should be used in preference.[9] In cases when the physician aggressively has recommended a colonoscopy and the patient has declined that and these other tests, then this test has advantages over patients having no screening at all.[9] | https://www.wikidoc.org/index.php/SEPT9 | |
ae61e3ddba007d731939e2cdb5b6e390b6ab8d7f | wikidoc | SESN1 | SESN1
Sestrin 1, also known as p53-regulated protein PA26, is a protein that in humans is encoded by the SESN1 gene.
This gene encodes a member of the sestrin family. Sestrins are induced by the p53 tumor suppressor protein and play a role in the cellular response to DNA damage and oxidative stress.
The encoded protein mediates p53 inhibition of cell growth by activating AMP-activated protein kinase, which results in the inhibition of the mammalian target of rapamycin protein. The encoded protein also plays a critical role in antioxidant defense by regenerating overoxidized peroxiredoxins, and the expression of this gene is a potential marker for exposure to radiation. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. | SESN1
Sestrin 1, also known as p53-regulated protein PA26, is a protein that in humans is encoded by the SESN1 gene.
This gene encodes a member of the sestrin family. Sestrins are induced by the p53 tumor suppressor protein and play a role in the cellular response to DNA damage and oxidative stress.
The encoded protein mediates p53 inhibition of cell growth by activating AMP-activated protein kinase, which results in the inhibition of the mammalian target of rapamycin protein. The encoded protein also plays a critical role in antioxidant defense by regenerating overoxidized peroxiredoxins, and the expression of this gene is a potential marker for exposure to radiation. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene.[1][2][3] | https://www.wikidoc.org/index.php/SESN1 | |
9c5ac7e281a3a5dd5dc5463495ba7470a5c7009d | wikidoc | SESN2 | SESN2
Sestrin-2 also known as Hi95 is a protein that in humans is encoded by the SESN2 gene.
# Function
This gene encodes a member of the sestrin family of PA26-related proteins. The encoded protein may function in the regulation of cell growth and survival. This protein may be involved in cellular response to different stress conditions. The Sestrins constitute a family of evolutionarily-conserved stress-inducible proteins that suppress oxidative stress and regulate adenosine monophosphate-dependent protein kinase (AMPK)-mammalian target of rapamycin (mTOR) signaling. By virtue of these activities, the Sestrins serve as important regulators of metabolic homeostasis. Accordingly, inactivation of Sestrin genes in invertebrates resulted in diverse metabolic pathologies, including oxidative damage, fat accumulation, mitochondrial dysfunction and muscle degeneration that resemble accelerated tissue aging.
# Ligands
The NMDA receptor antagonist ketamine has been found to activate the mammalian target of rapamycin complex 1 (mTORC1) pathway in the medial prefrontal cortex (mPFC) of the brain as an essential downstream mechanism in the mediation of its rapid-acting antidepressant effects. NV-5138 is a ligand and modulator of sestrin2, a leucine amino acid sensor and upstream regulatory pathway of mTORC1, and is under development for the treatment of depression. The drug has been found to directly and selectively activate the mTORC1 pathway, including in the mPFC, and to produce rapid-acting antidepressant effects similar to those of ketamine. | SESN2
Sestrin-2 also known as Hi95 is a protein that in humans is encoded by the SESN2 gene.[1][2][3]
# Function
This gene encodes a member of the sestrin family of PA26-related proteins. The encoded protein may function in the regulation of cell growth and survival. This protein may be involved in cellular response to different stress conditions.[3][4] The Sestrins constitute a family of evolutionarily-conserved stress-inducible proteins that suppress oxidative stress and regulate adenosine monophosphate-dependent protein kinase (AMPK)-mammalian target of rapamycin (mTOR) signaling. By virtue of these activities, the Sestrins serve as important regulators of metabolic homeostasis. Accordingly, inactivation of Sestrin genes in invertebrates resulted in diverse metabolic pathologies, including oxidative damage, fat accumulation, mitochondrial dysfunction and muscle degeneration that resemble accelerated tissue aging.[3][5]
# Ligands
The NMDA receptor antagonist ketamine has been found to activate the mammalian target of rapamycin complex 1 (mTORC1) pathway in the medial prefrontal cortex (mPFC) of the brain as an essential downstream mechanism in the mediation of its rapid-acting antidepressant effects.[6] NV-5138 is a ligand and modulator of sestrin2, a leucine amino acid sensor and upstream regulatory pathway of mTORC1, and is under development for the treatment of depression.[6] The drug has been found to directly and selectively activate the mTORC1 pathway, including in the mPFC, and to produce rapid-acting antidepressant effects similar to those of ketamine.[6] | https://www.wikidoc.org/index.php/SESN2 | |
fd83e7d45cf3a0c2b0b0451e37ff1035d8cde273 | wikidoc | SETD2 | SETD2
SET domain containing 2 is an enzyme that in humans is encoded by the SETD2 gene.
# Function
SETD2 protein is a histone methyltransferase that is specific for lysine-36 of histone H3, and methylation of this residue is associated with active chromatin. This protein also contains a novel transcriptional activation domain and has been found associated with hyperphosphorylated RNA polymerase II.
# Clinical significance
The SETD2 gene is located on the short arm of chromosome 3 and has been shown to play a tumour suppressor role in human cancer.
# Interactions
SETD2 has been shown to interact with Huntingtin. Huntington's disease (HD), a neurodegenerative disorder characterized by loss of striatal neurons, is caused by an expansion of a polyglutamine tract in the HD protein huntingtin. SETD2 belongs to a class of huntingtin interacting proteins characterized by WW motifs. | SETD2
SET domain containing 2 is an enzyme that in humans is encoded by the SETD2 gene.[1][2][3]
# Function
SETD2 protein is a histone methyltransferase that is specific for lysine-36 of histone H3, and methylation of this residue is associated with active chromatin. This protein also contains a novel transcriptional activation domain and has been found associated with hyperphosphorylated RNA polymerase II.[3]
# Clinical significance
The SETD2 gene is located on the short arm of chromosome 3 and has been shown to play a tumour suppressor role in human cancer.[4]
# Interactions
SETD2 has been shown to interact with Huntingtin.[5] Huntington's disease (HD), a neurodegenerative disorder characterized by loss of striatal neurons, is caused by an expansion of a polyglutamine tract in the HD protein huntingtin. SETD2 belongs to a class of huntingtin interacting proteins characterized by WW motifs.[3] | https://www.wikidoc.org/index.php/SETD2 | |
4eb4f12eabe45bda4a6536de624838f38e75d130 | wikidoc | SF3B1 | SF3B1
Splicing factor 3B subunit 1 is a protein that in humans is encoded by the SF3B1 gene.
# Function
This gene encodes subunit 1 of the splicing factor 3b protein complex. Splicing factor 3b, together with splicing factor 3a and a 12S RNA unit, forms the U2 small nuclear ribonucleoproteins complex (U2 snRNP). The splicing factor 3b/3a complex binds pre-mRNA upstream of the intron's branch site in a sequence independent manner and may anchor the U2 snRNP to the pre-mRNA. Splicing factor 3b is also a component of the minor U12-type spliceosome. The carboxy-terminal two-thirds of subunit 1 have 22 non-identical, tandem HEAT repeats that form rod-like, helical structures. Alternative splicing results in multiple transcript variants encoding different isoforms.
# Interactions
SF3B1 has been shown to interact with:
- CDC5L,
- DDX42,
- PPP1R8,
- SF3B2,
- SF3B3,
- SF3B14,
# Clinical relevance
Mutations in this gene have been recurrently seen in cases of advanced chronic lymphocytic leukemia, myelodysplastic syndromes and breast cancer. SF3B1 mutations are found in 60%-80% of patients with refractory anemia with ring sideroblasts (RARS; which is a myelodysplastic syndrome) or RARS with thrombocytosis (RARS-T; which is a myelodysplastic syndrome/myeloproliferative neoplasm). There is also an emerging body of evidence to suggest implications of SF3B1 mutations being involved in orbital melanoma. | SF3B1
Splicing factor 3B subunit 1 is a protein that in humans is encoded by the SF3B1 gene.[1][2]
# Function
This gene encodes subunit 1 of the splicing factor 3b protein complex. Splicing factor 3b, together with splicing factor 3a and a 12S RNA unit, forms the U2 small nuclear ribonucleoproteins complex (U2 snRNP). The splicing factor 3b/3a complex binds pre-mRNA upstream of the intron's branch site in a sequence independent manner and may anchor the U2 snRNP to the pre-mRNA. Splicing factor 3b is also a component of the minor U12-type spliceosome. The carboxy-terminal two-thirds of subunit 1 have 22 non-identical, tandem HEAT repeats that form rod-like, helical structures. Alternative splicing results in multiple transcript variants encoding different isoforms.[2]
# Interactions
SF3B1 has been shown to interact with:
- CDC5L,[3]
- DDX42,[4]
- PPP1R8,[5]
- SF3B2,[4][6]
- SF3B3,[4][6]
- SF3B14,[4][7]
# Clinical relevance
Mutations in this gene have been recurrently seen in cases of advanced chronic lymphocytic leukemia,[8] myelodysplastic syndromes[9] and breast cancer.[10] SF3B1 mutations are found in 60%-80% of patients with refractory anemia with ring sideroblasts (RARS; which is a myelodysplastic syndrome) or RARS with thrombocytosis (RARS-T; which is a myelodysplastic syndrome/myeloproliferative neoplasm). There is also an emerging body of evidence to suggest implications of SF3B1 mutations being involved in orbital melanoma. | https://www.wikidoc.org/index.php/SF3B1 | |
9c75602b42574d67ed17d53af1a7d6a71ade53bb | wikidoc | SF3B2 | SF3B2
Splicing factor 3B subunit 2 is a protein that in humans is encoded by the SF3B2 gene.
# Function
This gene encodes subunit 2 of the splicing factor 3b protein complex. Splicing factor 3b, together with splicing factor 3a and a 12S RNA unit, forms the U2 small nuclear ribonucleoproteins complex (U2 snRNP). The splicing factor 3b/3a complex binds pre-mRNA upstream of the intron's branch site in a sequence-independent manner and may anchor the U2 snRNP to the pre-mRNA. Splicing factor 3b is also a component of the minor U12-type spliceosome. Subunit 2 associates with pre-mRNA upstream of the branch site at the anchoring site. Subunit 2 also interacts directly with subunit 4 of the splicing factor 3b complex. Subunit 2 is a highly hydrophilic protein with a proline-rich N-terminus and a glutamate-rich stretch in the C-terminus.
# Interactions
SF3B2 has been shown to interact with SF3B4, RBM7, SF3B1 and CDC5L. | SF3B2
Splicing factor 3B subunit 2 is a protein that in humans is encoded by the SF3B2 gene.[1][2]
# Function
This gene encodes subunit 2 of the splicing factor 3b protein complex. Splicing factor 3b, together with splicing factor 3a and a 12S RNA unit, forms the U2 small nuclear ribonucleoproteins complex (U2 snRNP). The splicing factor 3b/3a complex binds pre-mRNA upstream of the intron's branch site in a sequence-independent manner and may anchor the U2 snRNP to the pre-mRNA. Splicing factor 3b is also a component of the minor U12-type spliceosome. Subunit 2 associates with pre-mRNA upstream of the branch site at the anchoring site. Subunit 2 also interacts directly with subunit 4 of the splicing factor 3b complex. Subunit 2 is a highly hydrophilic protein with a proline-rich N-terminus and a glutamate-rich stretch in the C-terminus.[2]
# Interactions
SF3B2 has been shown to interact with SF3B4,[3][4] RBM7,[5] SF3B1[6][7] and CDC5L.[8] | https://www.wikidoc.org/index.php/SF3B2 | |
4cbebb207d5b6437478f0e11aa58c72535cde507 | wikidoc | SF3B3 | SF3B3
Splicing factor 3B subunit 3 is a protein that in humans is encoded by the SF3B3 gene.
This gene encodes subunit 3 of the splicing factor 3b protein complex. Splicing factor 3b, together with splicing factor 3a and a 12S RNA unit, forms the U2 small nuclear ribonucleoproteins complex (U2 snRNP). The splicing factor 3b/3a complex binds pre-mRNA upstream of the intron's branch site in a sequence independent manner and may anchor the U2 snRNP to the pre-mRNA. Splicing factor 3b is also a component of the minor U12-type spliceosome. Subunit 3 has also been identified as a component of the STAGA (SPT3-TAF(II)31-GCN5L acetylase) transcription coactivator-HAT (histone acetyltransferase) complex, and the TFTC (TATA-binding-protein-free TAF(II)-containing complex). These complexes may function in chromatin modification, transcription, splicing, and DNA repair.
# Interactions
SF3B3 has been shown to interact with SF3B1, Transcription initiation protein SPT3 homolog and TAF9. | SF3B3
Splicing factor 3B subunit 3 is a protein that in humans is encoded by the SF3B3 gene.[1][2]
This gene encodes subunit 3 of the splicing factor 3b protein complex. Splicing factor 3b, together with splicing factor 3a and a 12S RNA unit, forms the U2 small nuclear ribonucleoproteins complex (U2 snRNP). The splicing factor 3b/3a complex binds pre-mRNA upstream of the intron's branch site in a sequence independent manner and may anchor the U2 snRNP to the pre-mRNA. Splicing factor 3b is also a component of the minor U12-type spliceosome. Subunit 3 has also been identified as a component of the STAGA (SPT3-TAF(II)31-GCN5L acetylase) transcription coactivator-HAT (histone acetyltransferase) complex, and the TFTC (TATA-binding-protein-free TAF(II)-containing complex). These complexes may function in chromatin modification, transcription, splicing, and DNA repair.[2]
# Interactions
SF3B3 has been shown to interact with SF3B1,[1][3] Transcription initiation protein SPT3 homolog[4] and TAF9.[4] | https://www.wikidoc.org/index.php/SF3B3 | |
623e8b6a80c7afd26980518a86c8a9f560d4a35f | wikidoc | SF3B4 | SF3B4
Splicing factor 3B subunit 4 is a protein that in humans is encoded by the SF3B4 gene.
# Function
This gene encodes one of four subunits of the splicing factor 3B. The protein encoded by this gene cross-links to a region in the pre-mRNA immediately upstream of the branchpoint sequence in pre-mRNA in the prespliceosomal complex A. It also may be involved in the assembly of the B, C and E spliceosomal complexes. In addition to RNA-binding activity, this protein interacts directly and highly specifically with subunit 2 of the splicing factor 3B. This protein contains two N-terminal RNA-recognition motifs (RRMs), consistent with the observation that it binds directly to pre-mRNA.
# Disease associations
In 2012, Canadian researchers belonging to the FORGE (Finding of Rare disease GEnes) consortium identified new dominant mutations in SF3B4 as the cause of Nager syndrome, a rare type of mandibulofacial dysostosis with associated limb malformations.
# Interactions
SF3B4 has been shown to interact with CDC5L, BMPR1A and SF3B2. | SF3B4
Splicing factor 3B subunit 4 is a protein that in humans is encoded by the SF3B4 gene.[1][2]
# Function
This gene encodes one of four subunits of the splicing factor 3B. The protein encoded by this gene cross-links to a region in the pre-mRNA immediately upstream of the branchpoint sequence in pre-mRNA in the prespliceosomal complex A. It also may be involved in the assembly of the B, C and E spliceosomal complexes. In addition to RNA-binding activity, this protein interacts directly and highly specifically with subunit 2 of the splicing factor 3B. This protein contains two N-terminal RNA-recognition motifs (RRMs), consistent with the observation that it binds directly to pre-mRNA.[2]
# Disease associations
In 2012, Canadian researchers belonging to the FORGE (Finding of Rare disease GEnes) consortium identified new dominant mutations in SF3B4 as the cause of Nager syndrome, a rare type of mandibulofacial dysostosis with associated limb malformations.[3]
# Interactions
SF3B4 has been shown to interact with CDC5L,[4] BMPR1A[5] and SF3B2.[1][6] | https://www.wikidoc.org/index.php/SF3B4 | |
7feefbdabd696717af94a97d7dd87798879aed12 | wikidoc | SFRP4 | SFRP4
Secreted frizzled-related protein 4 is a protein that in humans is encoded by the SFRP4 gene.
# Function
Secreted frizzled-related protein 4 (SFRP4) is a member of the SFRP family that contains a cysteine-rich domain homologous to the putative Wnt-binding site of Frizzled proteins. SFRPs act as soluble modulators of Wnt signaling. The expression of SFRP4 in ventricular myocardium correlates with apoptosis related gene expression.
SFRP4 is a hub gene in a Type 2 Diabetes-associated gene coexpression module in human islets, and reduces glucose-induced insulin secretion through decreased β-cell exocytosis. Expression and release of SFRP4 from islets is enhanced by interleukin-1β. SFRP4 is elevated in serum several years before clinical diagnosis of Type 2 Diabetes. Individuals who have above-average levels of SFRP4 in the blood are five times more likely to develop diabetes in the next few years than those with below-average levels. | SFRP4
Secreted frizzled-related protein 4 is a protein that in humans is encoded by the SFRP4 gene.[1][2]
# Function
Secreted frizzled-related protein 4 (SFRP4) is a member of the SFRP family that contains a cysteine-rich domain homologous to the putative Wnt-binding site of Frizzled proteins. SFRPs act as soluble modulators of Wnt signaling. The expression of SFRP4 in ventricular myocardium correlates with apoptosis related gene expression.[2]
SFRP4 is a hub gene in a Type 2 Diabetes-associated gene coexpression module in human islets, and reduces glucose-induced insulin secretion through decreased β-cell exocytosis. Expression and release of SFRP4 from islets is enhanced by interleukin-1β. SFRP4 is elevated in serum several years before clinical diagnosis of Type 2 Diabetes. Individuals who have above-average levels of SFRP4 in the blood are five times more likely to develop diabetes in the next few years than those with below-average levels.[3] | https://www.wikidoc.org/index.php/SFRP4 | |
414e9746888593c75487494454e4dd765d10ebfa | wikidoc | SFRS7 | SFRS7
Serine/arginine-rich splicing factor 7 (SRSF7) also known as splicing factor, arginine/serine-rich 7 (SFRS7) or splicing factor 9G8 is a protein that in humans is encoded by the SRSF7 gene.
# Function
The protein encoded by this gene is a member of the serine/arginine (SR)-rich family of pre-mRNA splicing factors, which constitute part of the spliceosome. Each of these factors contains an RNA recognition motif (RRM) for binding RNA and an RS domain for binding other proteins. The RS domain is rich in serine and arginine residues and facilitates interaction between different SR splicing factors. In addition to being critical for mRNA splicing, the SR proteins have also been shown to be involved in mRNA export from the nucleus and in translation.
# Model organisms
Model organisms have been used in the study of SRSF7 function. A conditional knockout mouse line called Srsf7tm1a(EUCOMM)Wtsi was generated at the Wellcome Trust Sanger Institute. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Additional screens performed: - In-depth immunological phenotyping | SFRS7
Serine/arginine-rich splicing factor 7 (SRSF7) also known as splicing factor, arginine/serine-rich 7 (SFRS7) or splicing factor 9G8 is a protein that in humans is encoded by the SRSF7 gene.[1]
# Function
The protein encoded by this gene is a member of the serine/arginine (SR)-rich family of pre-mRNA splicing factors, which constitute part of the spliceosome. Each of these factors contains an RNA recognition motif (RRM) for binding RNA and an RS domain for binding other proteins. The RS domain is rich in serine and arginine residues and facilitates interaction between different SR splicing factors. In addition to being critical for mRNA splicing, the SR proteins have also been shown to be involved in mRNA export from the nucleus and in translation.[1]
# Model organisms
Model organisms have been used in the study of SRSF7 function. A conditional knockout mouse line called Srsf7tm1a(EUCOMM)Wtsi was generated at the Wellcome Trust Sanger Institute.[2] Male and female animals underwent a standardized phenotypic screen[3] to determine the effects of deletion.[4][5][6][7] Additional screens performed: - In-depth immunological phenotyping[8] | https://www.wikidoc.org/index.php/SFRS7 | |
1ebc11b23773546e4e713f6ecc45feb081c21c29 | wikidoc | SGLT2 | SGLT2
The sodium/glucose cotransporter 2 (SGLT2) is a protein that in humans is encoded by the SLC5A2 (solute carrier family 5 (sodium/glucose cotransporter)) gene.
# Function
SGLT2 is a member of the sodium glucose cotransporter family which are sodium-dependent glucose transport proteins. SGLT2 is the major cotransporter involved in glucose reabsorption in the kidney.
# SGLT2 inhibitors for diabetes
SGLT2 inhibitors are called gliflozins. They lead to a reduction in blood glucose levels. Therefore, SGLT2 inhibitors have potential use in the treatment of type II diabetes. Gliflozins enhance glycemic control as well as reduce body weight and systolic and diastolic blood pressure. They reduce some cardiovascular complications, especially but not exclusively among patients with established cardiovascular disease
The gliflozins canagliflozin, dapagliflozin, and empagliflozin may lead to euglycemic ketoacidosis. Other side effects of gliflozins include increased risk of (generally mild) genital infections, such as candidal vulvovaginitis.
# Clinical significance
Mutations in this gene are also associated with renal glucosuria.
# Model organisms
Model organisms have been used in the study of SLC5A2 function. A conditional knockout mouse line, called Slc5a2tm1a(KOMP)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty two tests were carried out on homozygous mutant mice and one significant abnormality was observed: males displayed increased drinking behaviour. | SGLT2
The sodium/glucose cotransporter 2 (SGLT2) is a protein that in humans is encoded by the SLC5A2 (solute carrier family 5 (sodium/glucose cotransporter)) gene.[1]
# Function
SGLT2 is a member of the sodium glucose cotransporter family which are sodium-dependent glucose transport proteins. SGLT2 is the major cotransporter involved in glucose reabsorption in the kidney.[2]
# SGLT2 inhibitors for diabetes
SGLT2 inhibitors are called gliflozins. They lead to a reduction in blood glucose levels. Therefore, SGLT2 inhibitors have potential use in the treatment of type II diabetes. Gliflozins enhance glycemic control as well as reduce body weight and systolic and diastolic blood pressure. They reduce some cardiovascular complications, especially but not exclusively among patients with established cardiovascular disease[3]
The gliflozins canagliflozin, dapagliflozin, and empagliflozin may lead to euglycemic ketoacidosis.[4] Other side effects of gliflozins include increased risk of (generally mild) genital infections, such as candidal vulvovaginitis.[5]
# Clinical significance
Mutations in this gene are also associated with renal glucosuria.[6]
# Model organisms
Model organisms have been used in the study of SLC5A2 function. A conditional knockout mouse line, called Slc5a2tm1a(KOMP)Wtsi[12][13] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[14][15][16]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[10][17] Twenty two tests were carried out on homozygous mutant mice and one significant abnormality was observed: males displayed increased drinking behaviour.[10] | https://www.wikidoc.org/index.php/SGLT2 | |
03655b7fef06c4d9b6269a6e6fb9cba74491f60c | wikidoc | SGMS1 | SGMS1
Phosphatidylcholine:ceramide cholinephosphotransferase 1 is an enzyme that in humans is encoded by the SGMS1 gene.
# Function
The protein encoded by this gene is predicted to be a five-pass transmembrane protein. This gene may be predominately expressed in brain.
# Model organisms
Model organisms have been used in the study of SGMS1 function. A conditional knockout mouse line called Sgms1tm1a(EUCOMM)Wtsi was generated at the Wellcome Trust Sanger Institute. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Additional screens performed: - In-depth immunological phenotyping | SGMS1
Phosphatidylcholine:ceramide cholinephosphotransferase 1 is an enzyme that in humans is encoded by the SGMS1 gene.[1][2][3]
# Function
The protein encoded by this gene is predicted to be a five-pass transmembrane protein. This gene may be predominately expressed in brain.[3]
# Model organisms
Model organisms have been used in the study of SGMS1 function. A conditional knockout mouse line called Sgms1tm1a(EUCOMM)Wtsi was generated at the Wellcome Trust Sanger Institute.[4] Male and female animals underwent a standardized phenotypic screen[5] to determine the effects of deletion.[6][7][8][9] Additional screens performed: - In-depth immunological phenotyping[10] | https://www.wikidoc.org/index.php/SGMS1 | |
8256f1a9a27647f57e1cc50241c75ca2346c03e4 | wikidoc | SGOL1 | SGOL1
Shugoshin-like 1 is a protein that in humans is encoded by the SGOL1 gene.
# Model organisms
Model organisms have been used in the study of SGOL1 function. A conditional knockout mouse line, called Sgol1tm1a(EUCOMM)Wtsi has been generated.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty six tests were carried out on mutant mice and three significant abnormalities were observed. No homozygous mutant embryos were identified during gestation, and thus none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice and a decreased regulatory T cell number was observed in male animals.
# Mechanisms
A physical mechanism that guarantees the accurate segregation of sister chromatids during mitosis arises from the ring shaped cohesin complex consisting of 4 subunits (SMC1A/B, SMC3, SCC1, and SA1/2 in humans). This complex encircles the two sister chromatids and resists the pulling force of microtubules. The characteristic X-shape chromosomes are formed due to the centromeric cohesin protected by Shugoshin-PP2A complex.
Kinetochore localization of Sgo1-PP2A is dependent upon phosphorylation on histone H2A of nucleosome, which is the important substrate of spindle checkpoint kinase BUB1. Centromeric cohesin and H2A-pT120 specify two distinct pools of Sgo1-PP2A at inner centromeres and kinetochores respectively, while the CDK1/cyclin B phosphorylation on Sgo1 is essential for Sgo1-PP2A to protect centromeric cohesin, not only for bringing PP2A to cohesin, but also physically shield out the negative regulator WAPAL from cohesin. | SGOL1
Shugoshin-like 1 is a protein that in humans is encoded by the SGOL1 gene.[1][2]
# Model organisms
Model organisms have been used in the study of SGOL1 function. A conditional knockout mouse line, called Sgol1tm1a(EUCOMM)Wtsi[8][9] has been generated.[10][11][12]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[6][13] Twenty six tests were carried out on mutant mice and three significant abnormalities were observed. No homozygous mutant embryos were identified during gestation, and thus none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice and a decreased regulatory T cell number was observed in male animals.[6]
# Mechanisms
A physical mechanism that guarantees the accurate segregation of sister chromatids during mitosis arises from the ring shaped cohesin complex consisting of 4 subunits (SMC1A/B, SMC3, SCC1, and SA1/2 in humans). This complex encircles the two sister chromatids and resists the pulling force of microtubules.[14] The characteristic X-shape chromosomes are formed due to the centromeric cohesin protected by Shugoshin-PP2A complex.[15]
Kinetochore localization of Sgo1-PP2A is dependent upon phosphorylation on histone H2A of nucleosome, which is the important substrate of spindle checkpoint kinase BUB1.[16] Centromeric cohesin and H2A-pT120 specify two distinct pools of Sgo1-PP2A at inner centromeres and kinetochores respectively,[17] while the CDK1/cyclin B phosphorylation on Sgo1 is essential for Sgo1-PP2A to protect centromeric cohesin, not only for bringing PP2A to cohesin,[18] but also physically shield out the negative regulator WAPAL from cohesin.[19] | https://www.wikidoc.org/index.php/SGOL1 | |
9ea0c3fb6789921ccc66ffc5f03ad9cbb335154b | wikidoc | SGOL2 | SGOL2
Shugoshin-like 2 (S. pombe), also known as SGOL2, is a protein which in humans is encoded by the SGOL2 gene.
# Function
Shugoshin-like 2 (SGOL2) is one of the two mammalian orthologs of the Shugoshin/Mei-S322 family of proteins that regulate sister chromatid cohesion by protecting the integrity of a multiprotein complex named cohesin. This protective system is essential for faithful chromosome segregation during mitosis and meiosis, which is the physical basis of Mendelian inheritance.
## Model organisms
Model organisms have been used in the study of SGOL2 function. A conditional knockout mouse line, called Sgol2tm1a(EUCOMM)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty two tests were carried out on mutant mice but no significant abnormalities were observed.
Using another genetically engineered mouse that lacks Sgol2 function, and siRNA experiments in oocytes, it has been shown that disruption of the mouse SGOL2 does not cause any alteration in sister chromatid cohesion in embryonic cultured fibroblasts and adult somatic tissues. Moreover, although these mutant mice also develop normally and survive to adulthood without any apparent alteration, both male and female Sgol2-deficient mice from this line are infertile. By different approaches it was demonstrated that SGOL2 is necessary for protecting centromeric cohesion during mammalian meiosis I. In vivo, the loss of SGOL2 promotes a premature release of the meiosis-specific REC8 cohesin complexes from anaphase I centromeres. This molecular alteration is manifested cytologically by the complete loss of centromere cohesion at metaphase II leading to single chromatids and physiologically with the formation of aneuploid gametes that give rise to infertility. | SGOL2
Shugoshin-like 2 (S. pombe), also known as SGOL2, is a protein which in humans is encoded by the SGOL2 gene.[1][2]
# Function
Shugoshin-like 2 (SGOL2) is one of the two mammalian orthologs of the Shugoshin/Mei-S322 family of proteins that regulate sister chromatid cohesion by protecting the integrity of a multiprotein complex named cohesin.[3] This protective system is essential for faithful chromosome segregation during mitosis and meiosis, which is the physical basis of Mendelian inheritance.
## Model organisms
Model organisms have been used in the study of SGOL2 function. A conditional knockout mouse line, called Sgol2tm1a(EUCOMM)Wtsi[8][9] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute.[10][11][12] Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[6][13] Twenty two tests were carried out on mutant mice but no significant abnormalities were observed.[6]
Using another genetically engineered mouse that lacks Sgol2 function, and siRNA experiments in oocytes, it has been shown that disruption of the mouse SGOL2 does not cause any alteration in sister chromatid cohesion in embryonic cultured fibroblasts and adult somatic tissues. Moreover, although these mutant mice also develop normally and survive to adulthood without any apparent alteration, both male and female Sgol2-deficient mice from this line are infertile.[14] By different approaches it was demonstrated that SGOL2 is necessary for protecting centromeric cohesion during mammalian meiosis I.[14] In vivo, the loss of SGOL2 promotes a premature release of the meiosis-specific REC8 cohesin complexes from anaphase I centromeres.[15] This molecular alteration is manifested cytologically by the complete loss of centromere cohesion at metaphase II leading to single chromatids and physiologically with the formation of aneuploid gametes that give rise to infertility. | https://www.wikidoc.org/index.php/SGOL2 | |
1dcaab100c877a78f68e654ae7aeebf75f3850f3 | wikidoc | SH2B2 | SH2B2
SH2B adapter protein 2 is a protein that in humans is encoded by the SH2B2 gene.
# Function
The protein encoded by this gene is expressed in B lymphocytes and contains pleckstrin homology and src homology 2 (SH2) domains. In Burkitt lymphoma cell lines, it is tyrosine phosphorylated in response to B cell receptor stimulation. Because it binds Shc independent of stimulation and Grb2 after stimulation, it appears to play a role in signal transduction from the receptor to Shc/Grb2.
# Interactions
SH2B2 has been shown to interact with TrkA and Cbl gene. | SH2B2
SH2B adapter protein 2 is a protein that in humans is encoded by the SH2B2 gene.[1][2]
# Function
The protein encoded by this gene is expressed in B lymphocytes and contains pleckstrin homology and src homology 2 (SH2) domains. In Burkitt lymphoma cell lines, it is tyrosine phosphorylated in response to B cell receptor stimulation. Because it binds Shc independent of stimulation and Grb2 after stimulation, it appears to play a role in signal transduction from the receptor to Shc/Grb2.[2]
# Interactions
SH2B2 has been shown to interact with TrkA[3] and Cbl gene.[4][5] | https://www.wikidoc.org/index.php/SH2B2 | |
ef7cfff3753ff43cde39cc718bfedff006c67fcb | wikidoc | SH2B3 | SH2B3
SH2B adapter protein 3 (SH2B3), also known as lymphocyte adapter protein (LNK), is a protein that in humans is encoded by the SH2B3 gene on chromosome 12.
SH2B adapter protein 3 is a protein that in humans is encoded by the SH2B3 gene on chromosome 12. It is ubiquitously expressed in many tissues and cell types. LNK functions as a regulator in signaling pathways relating to hematopoiesis, inflammation, and cell migration. As a result, it is involved in blood diseases, autoimmune disorders, and vascular disease. The SH2B3 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.
# Structure
## Gene
The SH2B3 gene resides on chromosome 12 at the band 12q24 and contains 12 exons.
## Protein
This protein belongs to the Src homology 2-B (SH2B) adapter family. LNK contains 3 functional domains: a C-terminal Src homology 2 (SH2) domain, a pleckstrin homology (PH) domain, and a dimerization domain. The SH2 domain spans approximately 100 amino acid residues and binds phosphotyrosine-containing proteins such as kinases. The PH domain spans approximately 120 amino acid residues and binds the phosphatidylinositol lipids found in the cell membrane. Thus, it is proposed to target the protein to the cell membrane, where LNK performs its regulatory function. The dimerization domain spans approximately 70 amino acid residues and contains a central phenylalanine zipper motif, which is formed by stacking of the aromatic side chains from 10 phenylalanine residues. This motif is responsible for facilitating the homo- or heterodimerization of SH2-B family proteins as a mechanism for regulating signal transduction. In addition to these domains, LNK possesses a proline-rich region that contains a minimal consensus sequence of Pro-X-X-Pro, which is recognized by the SH3 domain of another protein, as well as putative tyrosine phosphorylation motifs.
# Function
LNK is widely expressed in human tissues, with the highest expression in hematopoietic cells. LNK negatively controls the activation of several receptors activation, including stem cell factor receptor (c-kit), thrombopoietin receptor (MPL), erythropoietin receptor (EPOR), platelet-derived growth factor receptor (PDGFR), macrophage colony-stimulating factor receptor (c-Fms), and their related pathways. LNK is a negative regulator of signaling in endothelial cells, such as the TNF signaling pathway, especially in inflammation. LNK has been found to function as a negative regulator in lymphopoiesis, megakaryopoiesis, erythropoiesis as well as HSC expansion by moderating growth factor and cytokine receptor-mediated signaling. The overexpression of LNK led to the inhibition of anti-CD3 mediated NF-AT-Luc activation, indicating that LNK is involved in the mechanism of T cell-negative regulation. In addition to its role in progenitor cell growth and commitment, LNK appears to be involved in cell motility and cellular interactions. LNK modulates crosstalk between integrin- and cytokine-mediated signals, thus controlling thrombopoiesis. LNK facilitates integrin aIIbb3 phosphorylation and signaling in order to promote platelet cytoskeleton rearrangement and spreading, and thus stabilizes thrombosis formation.
# Interactions
SH2B3 has been shown to interact with Filamin.
# Clinical significance
In humans, genetic linkage analyses, genome-wide association studies of single nucleotide polymorphisms, copy number variation surveys, and mutation screenings found the human chromosomal 12q24 locus, with the SH2B3 gene at its core, to be associated with an exceptionally wide spectrum of disease susceptibilities. For example, hematopoietic traits of red and white blood cells (like erythrocytosis and myeloproliferative disease), autoimmune disorders, and vascular pathology have been reported. Moreover, co-expression of the interleukin-7 receptor together with LNK was carefully studied, and it was concluded that interleukin-7 receptor expression was significantly more highly expressed than LNK in B-cell acute leukemic lymphoma. This observation distinguished a novel subset of high-risk B-cell acute lymphoblastic lymphoma with a potential therapy targeting the interleukin-7 signaling pathway. Another study indicated that LNK can suppress the interleukin-7/JAK/STAT signaling pathway to restrict pre B-cell progenitor expansion and leukemia development, which provided a pathogenic mechanism and a potential therapeutic approach for B-cell acute lymphoblastic leukemia with SH2B3 gene mutations.
## Clinical marker
A multi-locus genetic risk score study based on a combination of 27 loci, including the SBH2B3 gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22). | SH2B3
SH2B adapter protein 3 (SH2B3), also known as lymphocyte adapter protein (LNK), is a protein that in humans is encoded by the SH2B3 gene on chromosome 12.[1][2]
SH2B adapter protein 3 is a protein that in humans is encoded by the SH2B3 gene on chromosome 12. It is ubiquitously expressed in many tissues and cell types.[3] LNK functions as a regulator in signaling pathways relating to hematopoiesis, inflammation, and cell migration.[4] As a result, it is involved in blood diseases, autoimmune disorders, and vascular disease.[5] The SH2B3 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.[6]
# Structure
## Gene
The SH2B3 gene resides on chromosome 12 at the band 12q24 and contains 12 exons.[2]
## Protein
This protein belongs to the Src homology 2-B (SH2B) adapter family.[4][7] LNK contains 3 functional domains: a C-terminal Src homology 2 (SH2) domain, a pleckstrin homology (PH) domain, and a dimerization domain. The SH2 domain spans approximately 100 amino acid residues and binds phosphotyrosine-containing proteins such as kinases. The PH domain spans approximately 120 amino acid residues and binds the phosphatidylinositol lipids found in the cell membrane. Thus, it is proposed to target the protein to the cell membrane, where LNK performs its regulatory function. The dimerization domain spans approximately 70 amino acid residues and contains a central phenylalanine zipper motif, which is formed by stacking of the aromatic side chains from 10 phenylalanine residues. This motif is responsible for facilitating the homo- or heterodimerization of SH2-B family proteins as a mechanism for regulating signal transduction. In addition to these domains, LNK possesses a proline-rich region that contains a minimal consensus sequence of Pro-X-X-Pro, which is recognized by the SH3 domain of another protein, as well as putative tyrosine phosphorylation motifs.[4]
# Function
LNK is widely expressed in human tissues, with the highest expression in hematopoietic cells. LNK negatively controls the activation of several receptors activation, including stem cell factor receptor (c-kit),[8] thrombopoietin receptor (MPL),[9] erythropoietin receptor (EPOR),[10] platelet-derived growth factor receptor (PDGFR),[11] macrophage colony-stimulating factor receptor (c-Fms),[12] and their related pathways. LNK is a negative regulator of signaling in endothelial cells, such as the TNF signaling pathway, especially in inflammation. LNK has been found to function as a negative regulator in lymphopoiesis, megakaryopoiesis, erythropoiesis as well as HSC expansion by moderating growth factor and cytokine receptor-mediated signaling.[4] The overexpression of LNK led to the inhibition of anti-CD3 mediated NF-AT-Luc activation, indicating that LNK is involved in the mechanism of T cell-negative regulation.[13] In addition to its role in progenitor cell growth and commitment, LNK appears to be involved in cell motility and cellular interactions. LNK modulates crosstalk between integrin- and cytokine-mediated signals, thus controlling thrombopoiesis.[14] LNK facilitates integrin aIIbb3 phosphorylation and signaling in order to promote platelet cytoskeleton rearrangement and spreading, and thus stabilizes thrombosis formation.[15]
# Interactions
SH2B3 has been shown to interact with Filamin.[16]
# Clinical significance
In humans, genetic linkage analyses, genome-wide association studies of single nucleotide polymorphisms, copy number variation surveys, and mutation screenings found the human chromosomal 12q24 locus, with the SH2B3 gene at its core, to be associated with an exceptionally wide spectrum of disease susceptibilities. For example, hematopoietic traits of red and white blood cells (like erythrocytosis and myeloproliferative disease), autoimmune disorders, and vascular pathology have been reported.[5] Moreover, co-expression of the interleukin-7 receptor together with LNK was carefully studied, and it was concluded that interleukin-7 receptor expression was significantly more highly expressed than LNK in B-cell acute leukemic lymphoma. This observation distinguished a novel subset of high-risk B-cell acute lymphoblastic lymphoma[17] with a potential therapy targeting the interleukin-7 signaling pathway. Another study indicated that LNK can suppress the interleukin-7/JAK/STAT signaling pathway to restrict pre B-cell progenitor expansion and leukemia development, which provided a pathogenic mechanism and a potential therapeutic approach for B-cell acute lymphoblastic leukemia with SH2B3 gene mutations.[18]
## Clinical marker
A multi-locus genetic risk score study based on a combination of 27 loci, including the SBH2B3 gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22).[6] | https://www.wikidoc.org/index.php/SH2B3 | |
02f308fee42bdd1719d7fac1bb814b915993eec0 | wikidoc | SHLD1 | SHLD1
SHLD1 or shieldin complex subunit 1 is a gene on chromosome 20. The C20orf196 gene encodes an mRNA that is 1,763 base pairs long, and a protein that is 205 amino acids long.
# Function
C20orf196 is involved in the DNA repair network. Gupta et al. identified C20orf196 as part of a vertebrate-specific protein complex called shieldin. Shieldin is recruited to double stranded breaks (DSB) to promote nonhomologous end joining-dependent repair (NHEJ), immunoglobulin class-switch recombination (CSR), and fusion of unprotected telomeres. Analysis indicates a sub-stoichiometric interaction or weaker interaction affinity of SHLD1 to the shieldin complex.
# Gene
## Locus
C20orf196 is located on the short arm of chromosome 20 at 20p12.3, from base pairs 5,750,286 to 5,864,407 on the direct strand. It contains 11 exons.
## Aliases
Its aliases are RINN3 and SHLD1.
# Expression
## mRNA
### Alternative Splicing
C20orf196 produces 9 different mRNAs, with 7 alternatively spliced variants and 2 unspliced forms. There are 3 probable alternative promoters, 3 non-overlapping alternative last exons, and 2 alternative polyadenylation sites. The mRNAs differ by the truncation of the 5' end, truncation of the 3' end, presence or absence of 2 cassette exons, and overlapping exons with different boundaries.
### Isoforms
C20orf196 has six splice isoforms.
## Promoter
The promoter region is within bases 5749286 to 5750555, totaling 1270 base pairs. The transcription start site is located within bases 5750382 and 5750409, totaling 28 base pairs.
## Expression
RNA-Seq analysis has shown ubiquitous expression of c20orf196 in 26 human tissues: adrenal, appendix, bone marrow, brain, colon, duodenum, endometrium, esophagus, fat, gall bladder, heart, kidney, liver, lung, lymph node, ovary, pancreas, placenta, prostate, salivary gland, skin, small intestine, spleen, stomach, testis, thyroid, and urinary bladder. The highest C20orf196 mRNA levels were found in the lymph node, tonsil, thyroid, adrenal gland, prostate, pharynx, parathyroid, connective tissue, and bone marrow.
C20orf196 was found to be expressed in soft tissue/muscle tissue tumors, lymphoma tumors, and pancreatic tumors. C20orf196 representation was biased toward the fetal developmental stage. EBI expression data showed high expression of C20orf196 in the diencephalon and cerebral cortex in the developing brain.
# Protein
## General Features
The most common transcript encodes a protein that is 205 amino acids long with a molecular mass of 23 kDa. It has a predicted isoelectric point of 4.72. It is predicted to have a half-life around 30 hours. C20orf196 contains 19 positive residues (9.3%), 32 negative residues (15.6%), and 46 hydrophobic residues (22.4%).
## Cellular Localization
C20orf196 is predicted to localize in the nucleus.
## Domains
C20orf196 contains one domain, DUF4521, which arose in Amniote. DUF4521 spans from amino acid 3 to 201. Several regions of this domain are conserved in c20orf196 orthologs found in mammals, amphibians, and fish. The proteins of this family are functionally uncharacterized.
## Post-Translational Modifications
There are many phosphorylation sites targeted by unspecified serine kinases. C20orf196 is predicted to have one SUMOylation site at amino acid 203 and one N-glycosylation site at amino acid 69. C20orf196 is predicted to have two ubiquitination sites at amino acids 84 and 139.
## Secondary Structure
Several modeling programs predicted a secondary structure containing alpha helix, beta sheet, and coil regions. CFSSP has predicted that C20orf196 secondary structure is 57.1% alpha helices, 48.8% beta strands, and 16.6% beta turns.
## Protein Interations
Several databases citing yeast two-hybrid screenings have found C20orf196 to interact with PRMT1, QARS, MAD2L2, and CUL3. C20orf196 functionally interacts with REV7, SHLD2, and SHLD3 in the shieldin complex within the DNA repair network.
# Homology and Evolution
## Orthologs
C20orf196 gene orthologs are found in species including mammals, birds, reptiles, and amphibians. C20orf196 has distant orthologs in bony fish and cartilaginous fish. There are no invertebrate orthologs. Orthologs are found in 163 organisms.
## Paralogs
There are no paralogs in humans.
## Rate of evolution
C20orf196 has a high protein sequence divergence rate. It is a fast evolving protein. It evolves faster than fibrinogen, as seen in the figure to the right.
# Phenotype
Genome-wide association studies have identified SNPs found in the C20orf196 gene that are associated with parental longevity, information processing speed, and breast carcinoma occurrence. | SHLD1
SHLD1 or shieldin complex subunit 1 is a gene on chromosome 20.[1] The C20orf196 gene encodes an mRNA that is 1,763 base pairs long, and a protein that is 205 amino acids long.[1]
# Function
C20orf196 is involved in the DNA repair network. Gupta et al. identified C20orf196 as part of a vertebrate-specific protein complex called shieldin.[2] Shieldin is recruited to double stranded breaks (DSB) to promote nonhomologous end joining-dependent repair (NHEJ), immunoglobulin class-switch recombination (CSR), and fusion of unprotected telomeres.[2] Analysis indicates a sub-stoichiometric interaction or weaker interaction affinity of SHLD1 to the shieldin complex.[2]
# Gene
## Locus
C20orf196 is located on the short arm of chromosome 20 at 20p12.3, from base pairs 5,750,286 to 5,864,407 on the direct strand.[1] It contains 11 exons.[3]
## Aliases
Its aliases are RINN3[2] and SHLD1.
# Expression
## mRNA
### Alternative Splicing
C20orf196 produces 9 different mRNAs, with 7 alternatively spliced variants and 2 unspliced forms.[3] There are 3 probable alternative promoters, 3 non-overlapping alternative last exons, and 2 alternative polyadenylation sites.[3] The mRNAs differ by the truncation of the 5' end, truncation of the 3' end, presence or absence of 2 cassette exons, and overlapping exons with different boundaries.[3]
### Isoforms
C20orf196 has six splice isoforms.[3]
## Promoter
The promoter region is within bases 5749286 to 5750555, totaling 1270 base pairs.[1] The transcription start site is located within bases 5750382 and 5750409, totaling 28 base pairs.[1]
## Expression
RNA-Seq analysis has shown ubiquitous expression of c20orf196 in 26 human tissues: adrenal, appendix, bone marrow, brain, colon, duodenum, endometrium, esophagus, fat, gall bladder, heart, kidney, liver, lung, lymph node, ovary, pancreas, placenta, prostate, salivary gland, skin, small intestine, spleen, stomach, testis, thyroid, and urinary bladder.[1] The highest C20orf196 mRNA levels were found in the lymph node, tonsil, thyroid, adrenal gland, prostate, pharynx, parathyroid, connective tissue, and bone marrow.[4]
C20orf196 was found to be expressed in soft tissue/muscle tissue tumors, lymphoma tumors, and pancreatic tumors.[5] C20orf196 representation was biased toward the fetal developmental stage.[5] EBI expression data showed high expression of C20orf196 in the diencephalon and cerebral cortex in the developing brain.[5]
# Protein
## General Features
The most common transcript encodes a protein that is 205 amino acids long with a molecular mass of 23 kDa.[6] It has a predicted isoelectric point of 4.72.[7] It is predicted to have a half-life around 30 hours.[8] C20orf196 contains 19 positive residues (9.3%), 32 negative residues (15.6%), and 46 hydrophobic residues (22.4%).[9]
## Cellular Localization
C20orf196 is predicted to localize in the nucleus.[3]
## Domains
C20orf196 contains one domain, DUF4521, which arose in Amniote.[1] DUF4521 spans from amino acid 3 to 201.[1] Several regions of this domain are conserved in c20orf196 orthologs found in mammals, amphibians, and fish. The proteins of this family are functionally uncharacterized.
## Post-Translational Modifications
There are many phosphorylation sites targeted by unspecified serine kinases.[10] C20orf196 is predicted to have one SUMOylation site at amino acid 203 and one N-glycosylation site at amino acid 69.[11][12] C20orf196 is predicted to have two ubiquitination sites at amino acids 84 and 139.[13]
## Secondary Structure
Several modeling programs predicted a secondary structure containing alpha helix, beta sheet, and coil regions.[14][15] CFSSP has predicted that C20orf196 secondary structure is 57.1% alpha helices, 48.8% beta strands, and 16.6% beta turns.[16]
## Protein Interations
Several databases citing yeast two-hybrid screenings have found C20orf196 to interact with PRMT1, QARS, MAD2L2, and CUL3.[17][18][19][20] C20orf196 functionally interacts with REV7, SHLD2, and SHLD3 in the shieldin complex within the DNA repair network.[2]
# Homology and Evolution
## Orthologs
C20orf196 gene orthologs are found in species including mammals, birds, reptiles, and amphibians.[2][21] C20orf196 has distant orthologs in bony fish and cartilaginous fish.[2][21] There are no invertebrate orthologs.[2] Orthologs are found in 163 organisms.[1]
## Paralogs
There are no paralogs in humans.[1]
## Rate of evolution
C20orf196 has a high protein sequence divergence rate. It is a fast evolving protein. It evolves faster than fibrinogen, as seen in the figure to the right.
# Phenotype
Genome-wide association studies have identified SNPs found in the C20orf196 gene that are associated with parental longevity, information processing speed, and breast carcinoma occurrence.[22] | https://www.wikidoc.org/index.php/SHLD1 | |
435fcbba9d3d81a696065751944dd390d1663459 | wikidoc | SHOX2 | SHOX2
Short stature homeobox 2, also known as homeobox protein Og12X or paired-related homeobox protein SHOT, is a protein that in humans is encoded by the SHOX2 gene.
# Function
SHOX2 is a member of the homeobox family of genes that encode proteins containing a 60-amino acid residue motif that represents a DNA-binding domain. Homeobox proteins have been characterized extensively as transcriptional regulators involved in pattern formation in both invertebrate and vertebrate species.
# Clinical significance
Several human genetic disorders are caused by aberrations in human homeobox genes. This locus represents a pseudoautosomal homeobox gene that is thought to be responsible for idiopathic short stature, and it is implicated in the short stature phenotype of Turner syndrome patients. This gene is considered to be a candidate gene for Cornelia de Lange Syndrome.
SHOX2 localises on chromosome 3, so it is an autosomal and not a pseudoautosomal homeobox (SHOX, which localises on the PAR1 region of chromosome X and Y, has a pseudoautosomal hereditability). | SHOX2
Short stature homeobox 2, also known as homeobox protein Og12X or paired-related homeobox protein SHOT, is a protein that in humans is encoded by the SHOX2 gene.[1][2][3]
# Function
SHOX2 is a member of the homeobox family of genes that encode proteins containing a 60-amino acid residue motif that represents a DNA-binding domain. Homeobox proteins have been characterized extensively as transcriptional regulators involved in pattern formation in both invertebrate and vertebrate species.[1]
# Clinical significance
Several human genetic disorders are caused by aberrations in human homeobox genes. This locus represents a pseudoautosomal homeobox gene that is thought to be responsible for idiopathic short stature, and it is implicated in the short stature phenotype of Turner syndrome patients. This gene is considered to be a candidate gene for Cornelia de Lange Syndrome.[1]
SHOX2 localises on chromosome 3, so it is an autosomal and not a pseudoautosomal homeobox (SHOX, which localises on the PAR1 region of chromosome X and Y, has a pseudoautosomal hereditability). | https://www.wikidoc.org/index.php/SHOX2 | |
29bd6daa666f6ee5f586cc29fdf23cd88b4b7087 | wikidoc | SIAH2 | SIAH2
E3 ubiquitin-protein ligase SIAH2 is an enzyme that in humans is encoded by the SIAH2 gene.
# Function
This gene encodes a protein that is a member of the seven in absentia homolog (SIAH) family. The protein is an E3 ligase and is involved in ubiquitination and proteasome-mediated degradation of specific proteins. The activity of this ubiquitin ligase has been implicated in regulating cellular response to hypoxia.
# Interactions
SIAH2 has been shown to interact with PEG10, Synaptophysin, PEG3 and VAV1. | SIAH2
E3 ubiquitin-protein ligase SIAH2 is an enzyme that in humans is encoded by the SIAH2 gene.[1][2]
# Function
This gene encodes a protein that is a member of the seven in absentia homolog (SIAH) family. The protein is an E3 ligase and is involved in ubiquitination and proteasome-mediated degradation of specific proteins. The activity of this ubiquitin ligase has been implicated in regulating cellular response to hypoxia.[2]
# Interactions
SIAH2 has been shown to interact with PEG10,[3] Synaptophysin,[4] PEG3[5] and VAV1.[6] | https://www.wikidoc.org/index.php/SIAH2 | |
533d87d9831451860ac473bdfdf589a10367ec02 | wikidoc | SIRT2 | SIRT2
NAD-dependent deacetylase sirtuin-2 is an enzyme that in humans is encoded by the SIRT2 gene. SIRT2 is an NAD+ (nicotinamide adenine dinucleotide)-dependent deacetylase. Studies of this protein have often been divergent, highlighting the dependence of pleiotropic effects of SIRT2 on cellular context. The natural polyphenol resveratrol is known to exert opposite actions on neural cells according to their normal or cancerous status. Similar to other sirtuin family members, SIRT2 displays a ubiquitous distribution. SIRT2 is expressed in a wide range of tissues and organs and has been detected particularly in metabolically relevant tissues, including the brain, muscle, liver, testes, pancreas, kidney, and adipose tissue of mice. Of note, SIRT2 expression is much higher in the brain than all other organs studied, particularly in the cortex, striatum, hippocampus, and spinal cord.
# Function
Studies suggest that the human sirtuins may function as intracellular regulatory proteins with mono-ADP-ribosyltransferase activity. Cytosolic functions of SIRT2 include the regulation of microtubule acetylation, control of myelination in the central and peripheral nervous system and gluconeogenesis. There is growing evidence for additional functions of SIRT2 in the nucleus. During the G2/M transition, nuclear SIRT2 is responsible for global deacetylation of H4K16, facilitating H4K20 methylation and subsequent chromatin compaction. In response to DNA damage, SIRT2 was also found to deacetylate H3K56 in vivo. Finally, SIRT2 negatively regulates the acetyltransferase activity of the transcriptional co-activator p300 via deacetylation of an automodification loop within its catalytic domain.
# Structure
## Gene
Human SIRT2 gene has 18 exons resides on chromosome 19 at q13. For SIRT2, four different human splice variants are deposited in the GenBank sequence database.
## Protein
SIRT2 gene encodes a member of the sirtuin family of proteins, homologs to the yeast Sir2 protein. Members of the sirtuin family are characterized by a sirtuin core domain and grouped into four classes. The protein encoded by this gene is included in class I of the sirtuin family. Several transcript variants are resulted from alternative splicing of this gene. Only transcript variants 1 and 2 have confirmed protein products of physiological relevance. A leucine-rich nuclear export signal (NES) within the N-terminal region of these two isoforms is identified. Since deletion of the NES led to nucleocytoplasmic distribution, it is suggested to mediate their cytosolic localization.
# Selective ligands
## Inhibitors
- Benzamide compound # 64
- (S)-2-Pentyl-6-chloro,8-bromo-chroman-4-one: IC50 of 1.5 μM, highly selective over SIRT2 and SIRT3
- 3′-Phenethyloxy-2-anilinobenzamide (33i): IC50 of 0.57 μM
# Model organisms
The functions of human sirtuins have not yet been determined; however, model organisms have been used in the study of SIRT2 function. Yeast sirtuin proteins are known to regulate epigenetic gene silencing and suppress recombination of rDNA.
A conditional knockout mouse line, called Sirt2tm1a(EUCOMM)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.
Twenty five tests were carried out on homozygous mutant adult mice, however no significant abnormalities were observed.
# Animal studies
## Metabolic actions
SIRT2 suppresses inflammatory responses in mice through p65 deacetylation and inhibition of NF-κB activity. SIRT2 is responsible for the deacetylation and activation of G6PD, stimulating pentose phosphate pathway to supply cytosolic NADPH to counteract oxidative damage and protect mouse erythrocytes.
## Neurodegeneration
Several studies in cell and invertebrate models of Parkinson's disease (PD) and Huntington's disease (HD) suggested potential neuroprotective effects of SIRT2 inhibition, in striking contrast with other sirtuin family members. In addition, recent evidence shows that inhibition of SIRT2 protects against MPTP-induced neuronal loss in vivo.
# Clinical significance
## Metabolic actions
Several SIRT2 deacetylation targets play important roles in metabolic homeostasis. SIRT2 inhibits adipogenesis by deacetylating FOXO1 and thus may protect against insulin resistance. SIRT2 sensitizes cells to the action of insulin by physically interacting with and activating Akt and downstream targets. SIRT2 mediates mitochondrial biogenesis by deacetylating PGC-1α, upregulates antioxidant enzyme expression by deacetylating FOXO3a, and thereby reduces ROS levels.
## Cell cycle regulation
Although preferentially cytosolic, SIRT2 transiently shuttles to the nucleus during the G2/M transition of the cell cycle, where it has a strong preference for histone H4 lysine 16 (H4K16Ac), thereby regulating chromosomal condensation during mitosis. During the cell cycle, SIRT2 associates with several mitotic structures including the centrosome, mitotic spindle, and midbody, presumably to ensure normal cell division. Finally, cells with SIRT2 overexpression exhibit marked prolongation of the cell cycle.
## Tumorigenesis
Mounting evidence implies a role for SIRT2 in tumorigenesis. SIRT2 may suppress or promote tumor growth in a context-dependent manner. SIRT2 has been proposed to act as a tumor suppressor by preventing chromosomal instability during mitosis. SIRT2-specific inhibitors exhibits broad anticancer activity.
# Interactions
SIRT2 has been shown to interact with:
- α-tubulin,
- TUG,
- β-catenin,
- PGAM2,
- TIAM1,
- ApoE4,
- p53,
- PEPCK,
- FOXO1,
- p300,
- 14-3-3 protein,
- G6PD, and
- CBP. | SIRT2
NAD-dependent deacetylase sirtuin-2 is an enzyme that in humans is encoded by the SIRT2 gene.[1][2][3] SIRT2 is an NAD+ (nicotinamide adenine dinucleotide)-dependent deacetylase. Studies of this protein have often been divergent, highlighting the dependence of pleiotropic effects of SIRT2 on cellular context. The natural polyphenol resveratrol is known to exert opposite actions on neural cells according to their normal or cancerous status.[4] Similar to other sirtuin family members, SIRT2 displays a ubiquitous distribution. SIRT2 is expressed in a wide range of tissues and organs and has been detected particularly in metabolically relevant tissues, including the brain, muscle, liver, testes, pancreas, kidney, and adipose tissue of mice. Of note, SIRT2 expression is much higher in the brain than all other organs studied, particularly in the cortex, striatum, hippocampus, and spinal cord.[5]
# Function
Studies suggest that the human sirtuins may function as intracellular regulatory proteins with mono-ADP-ribosyltransferase activity.[3] Cytosolic functions of SIRT2 include the regulation of microtubule acetylation, control of myelination in the central and peripheral nervous system[citation needed] and gluconeogenesis.[6] There is growing evidence for additional functions of SIRT2 in the nucleus. During the G2/M transition, nuclear SIRT2 is responsible for global deacetylation of H4K16, facilitating H4K20 methylation and subsequent chromatin compaction.[7] In response to DNA damage, SIRT2 was also found to deacetylate H3K56 in vivo.[8] Finally, SIRT2 negatively regulates the acetyltransferase activity of the transcriptional co-activator p300 via deacetylation of an automodification loop within its catalytic domain.[9]
# Structure
## Gene
Human SIRT2 gene has 18 exons resides on chromosome 19 at q13.[3] For SIRT2, four different human splice variants are deposited in the GenBank sequence database.[10]
## Protein
SIRT2 gene encodes a member of the sirtuin family of proteins, homologs to the yeast Sir2 protein. Members of the sirtuin family are characterized by a sirtuin core domain and grouped into four classes. The protein encoded by this gene is included in class I of the sirtuin family. Several transcript variants are resulted from alternative splicing of this gene.[3] Only transcript variants 1 and 2 have confirmed protein products of physiological relevance. A leucine-rich nuclear export signal (NES) within the N-terminal region of these two isoforms is identified.[10] Since deletion of the NES led to nucleocytoplasmic distribution, it is suggested to mediate their cytosolic localization.[11]
# Selective ligands
## Inhibitors
- Benzamide compound # 64[12]
- (S)-2-Pentyl-6-chloro,8-bromo-chroman-4-one: IC50 of 1.5 μM, highly selective over SIRT2 and SIRT3[13]
- 3′-Phenethyloxy-2-anilinobenzamide (33i): IC50 of 0.57 μM[14]
# Model organisms
The functions of human sirtuins have not yet been determined; however, model organisms have been used in the study of SIRT2 function. Yeast sirtuin proteins are known to regulate epigenetic gene silencing and suppress recombination of rDNA.
A conditional knockout mouse line, called Sirt2tm1a(EUCOMM)Wtsi[16][17] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute.[18][19][20] Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[15][21]
Twenty five tests were carried out on homozygous mutant adult mice, however no significant abnormalities were observed.[15]
# Animal studies
## Metabolic actions
SIRT2 suppresses inflammatory responses in mice through p65 deacetylation and inhibition of NF-κB activity.[22] SIRT2 is responsible for the deacetylation and activation of G6PD, stimulating pentose phosphate pathway to supply cytosolic NADPH to counteract oxidative damage and protect mouse erythrocytes.[23]
## Neurodegeneration
Several studies in cell and invertebrate models of Parkinson's disease (PD) and Huntington's disease (HD) suggested potential neuroprotective effects of SIRT2 inhibition, in striking contrast with other sirtuin family members.[24][25] In addition, recent evidence shows that inhibition of SIRT2 protects against MPTP-induced neuronal loss in vivo.[26]
# Clinical significance
## Metabolic actions
Several SIRT2 deacetylation targets play important roles in metabolic homeostasis. SIRT2 inhibits adipogenesis by deacetylating FOXO1 and thus may protect against insulin resistance. SIRT2 sensitizes cells to the action of insulin by physically interacting with and activating Akt and downstream targets. SIRT2 mediates mitochondrial biogenesis by deacetylating PGC-1α, upregulates antioxidant enzyme expression by deacetylating FOXO3a, and thereby reduces ROS levels.
## Cell cycle regulation
Although preferentially cytosolic, SIRT2 transiently shuttles to the nucleus during the G2/M transition of the cell cycle, where it has a strong preference for histone H4 lysine 16 (H4K16Ac),[27] thereby regulating chromosomal condensation during mitosis.[28] During the cell cycle, SIRT2 associates with several mitotic structures including the centrosome, mitotic spindle, and midbody, presumably to ensure normal cell division.[11] Finally, cells with SIRT2 overexpression exhibit marked prolongation of the cell cycle.[29]
## Tumorigenesis
Mounting evidence implies a role for SIRT2 in tumorigenesis. SIRT2 may suppress or promote tumor growth in a context-dependent manner. SIRT2 has been proposed to act as a tumor suppressor by preventing chromosomal instability during mitosis.[30] SIRT2-specific inhibitors exhibits broad anticancer activity.[31][32]
# Interactions
SIRT2 has been shown to interact with:
- α-tubulin,[33]
- TUG,[34]
- β-catenin,[35]
- PGAM2,[36]
- TIAM1,[37]
- ApoE4,[38]
- p53,[39]
- PEPCK,[40]
- FOXO1,[41]
- p300,[42]
- 14-3-3 protein,[43]
- G6PD,[23][32] and
- CBP.[44] | https://www.wikidoc.org/index.php/SIRT2 | |
6ca801b593ee4d29a3d9b7fadad24542a58a2349 | wikidoc | SIRT4 | SIRT4
Sirtuin 4, also known as SIRT4, is a protein which in humans is encoded by the SIRT4 gene.
# Function
This gene encodes a member of the sirtuin family of proteins which are homologs of the Sir2 gene in budding yeast. Members of the sirtuin family are characterized by a sirtuin core domain and grouped into four classes. The functions of human sirtuins have not yet been fully determined; however, yeast sirtuin proteins are known to regulate epigenetic gene silencing and suppress recombination of rDNA. Studies suggest that the human sirtuins may function as intracellular regulatory proteins with mono-ADP-ribosyltransferase activity. The protein encoded by this gene is included in class IV of the sirtuin family.
SIRT4 is a mitochondrial ADP-ribosyltransferase that inhibits mitochondrial glutamate dehydrogenase 1 activity, thereby downregulating insulin secretion in response to amino acids. It has been shown that SIRT4 regulates fatty acid oxidation and mitochondrial gene expression in liver and muscle cells. | SIRT4
Sirtuin 4, also known as SIRT4, is a protein which in humans is encoded by the SIRT4 gene.[1][2]
# Function
This gene encodes a member of the sirtuin family of proteins which are homologs of the Sir2 gene in budding yeast. Members of the sirtuin family are characterized by a sirtuin core domain and grouped into four classes. The functions of human sirtuins have not yet been fully determined; however, yeast sirtuin proteins are known to regulate epigenetic gene silencing and suppress recombination of rDNA.[3] Studies suggest that the human sirtuins may function as intracellular regulatory proteins with mono-ADP-ribosyltransferase activity.[1][3] The protein encoded by this gene is included in class IV of the sirtuin family.[2]
SIRT4 is a mitochondrial ADP-ribosyltransferase that inhibits mitochondrial glutamate dehydrogenase 1 activity, thereby downregulating insulin secretion in response to amino acids.[4] It has been shown that SIRT4 regulates fatty acid oxidation and mitochondrial gene expression in liver and muscle cells.[5] | https://www.wikidoc.org/index.php/SIRT4 | |
dd11ad84992131e32ed471dd9cdc3f2128d8ae7f | wikidoc | SIRT5 | SIRT5
Sirtuin (silent mating type information regulation 2 homolog) 5 (S. cerevisiae), also known as SIRT5 is a protein which in humans in encoded by the SIRT5 gene and in other species by the orthologous Sirt5 gene.
This gene encodes a member of the sirtuin family of proteins, homologs to the yeast Sir2 protein. Members of the sirtuin family are characterized by a sirtuin core domain and belong to the class III of the superfamily, and are dependent on NAD+ as co-factor of enzymatic activities. SIRT5 is one of the three sirtuins localized primarily to the mitochondrion.
# Structure
Alternative splicing of this gene results in two transcript variants. The protein structure of SIRT5 has been resolved and shows high degrees of structural conservation with other sirtuins, such as the ancestral yeast protein and human SIRT2.
# Function
SIRT5 has been found to exhibit enzymatic activities as a deacetylase, desuccinylase, and demalonylase, capable of removing acetyl, succinyl, and malonyl groups from the lysine residues of proteins. SIRT5 deacetylases and regulates carbamoyl phosphate synthetase (CPS1), the rate-limiting and initiating step of the urea cycle in liver mitochondria. Deacetylation of CPS1 stimulates its enzymatic activity. Mice with deletion of SIRT5 show elevated ammonia levels after a prolonged fast, whereas in contrast, mice overexpressing SIRT5 show increased CPS1 activity, suggesting one of the functions of SIRT5 may be to regulate the urea cycle. SIRT5 also interacts with and deacetylates cytochrome c. Large-scale profiling studies of SIRT5 deacetylase activity have uncovered over 700 protein substrates, including proteins localized to the mitochondria, the cytosol and other sub cellular localization. The identities of SIRT5 desuccinylation substrates suggest that SIRT5-mediated desuccinylation may be involved in energy metabolism.
The physiological consequences of SIRT5 molecular functions in human is under investigation but may involved regulations of mitochondrial metabolism.
# Interactions
NAD+
Cytochrome c
Carbamoyl phosphate synthetase (CPS1) | SIRT5
Sirtuin (silent mating type information regulation 2 homolog) 5 (S. cerevisiae), also known as SIRT5 is a protein which in humans in encoded by the SIRT5 gene and in other species by the orthologous Sirt5 gene.[1]
This gene encodes a member of the sirtuin family of proteins, homologs to the yeast Sir2 protein. Members of the sirtuin family are characterized by a sirtuin core domain and belong to the class III of the [histone deacetylase] superfamily, and are dependent on NAD+ as co-factor of enzymatic activities. SIRT5 is one of the three sirtuins localized primarily to the mitochondrion.
# Structure
Alternative splicing of this gene results in two transcript variants.[1] The protein structure of SIRT5 has been resolved and shows high degrees of structural conservation with other sirtuins, such as the ancestral yeast protein and human SIRT2.
# Function
SIRT5 has been found to exhibit enzymatic activities as a deacetylase, desuccinylase, and demalonylase, capable of removing acetyl, succinyl, and malonyl groups from the lysine residues of proteins.[2] SIRT5 deacetylases and regulates carbamoyl phosphate synthetase (CPS1), the rate-limiting and initiating step of the urea cycle in liver mitochondria. Deacetylation of CPS1 stimulates its enzymatic activity. Mice with deletion of SIRT5 show elevated ammonia levels after a prolonged fast, whereas in contrast, mice overexpressing SIRT5 show increased CPS1 activity, suggesting one of the functions of SIRT5 may be to regulate the urea cycle.[3] SIRT5 also interacts with and deacetylates cytochrome c.[4] Large-scale profiling studies of SIRT5 deacetylase activity have uncovered over 700 protein substrates, including proteins localized to the mitochondria, the cytosol and other sub cellular localization. The identities of SIRT5 desuccinylation substrates suggest that SIRT5-mediated desuccinylation may be involved in energy metabolism.[5]
The physiological consequences of SIRT5 molecular functions in human is under investigation but may involved regulations of mitochondrial metabolism.[6]
# Interactions
NAD+
Cytochrome c [7]
Carbamoyl phosphate synthetase (CPS1) | https://www.wikidoc.org/index.php/SIRT5 | |
dc69934f000e3e080f99c395e7790baa7ad9a6ff | wikidoc | SIRT6 | SIRT6
Sirtuin-6 (SIRT6) is a stress responsive protein deacetylase and mono-ADP ribosyltransferase enzyme encoded by the SIRT6 gene. SIRT6 functions in multiple molecular pathways related to aging, including DNA repair, telomere maintenance, glycolysis and inflammation.
# Function
Studies in mice have revealed that Sirt6 is essential for post-natal development and survival. Sirt6 knock-out mice, in which the gene encoding Sirt6 has been disrupted, exhibit a severe progeria, or premature aging syndrome, characterized by spinal curvature, greying of the fur, lymphopenia and low levels of blood glucose. The lifespan of Sirt6 knock-out mice is typically one to three months, dependent upon the strain in which the Sirt6 gene has been deleted. By contrast, wild type mice, which retain expression of Sirt6, exhibit a maximum lifespan of two to four years.
Mice which have been genetically engineered to overexpress, or produce more, Sirt6 protein exhibit an extended maximum lifespan. This lifespan extension, of about 15-16 percent, is observed only in male mice.
Reciprocal regulation between SIRT6 and miRNA-122 controls liver metabolism and Predicts Hepatocarcinoma prognosis by study of Haim Cohen's lab with mice. they found that SIRT6 and miR-122 negatively regulate each other's expression. The study found SIRT6 was shown to act as a tumor suppressor that blocks the Warburg effect in cancer cells.
# DNA repair
SIRT6 is a chromatin-associated protein that is required for normal base excision repair of DNA damage in mammalian cells. Deficiency of SIRT6 in mice leads to abnormalities that overlap with aging-associated degenerative processes.
SIRT6 also promotes the repair of DNA double-strand breaks by the process of non-homologous end joining. SIRT6 stabilizes the repair protein DNA-PKcs (DNA-dependent protein kinase catalytic subunit) at chromatin sites of damage.
As normal human fibroblasts replicate and progress towards replicative senescence the capability to undergo homologous recombinational repair (HRR) declines. However, over-expression of SIRT6 in “middle-aged” and pre-senescent cells strongly stimulates HRR. This effect depends on the mono-ADP ribosylation activity of poly(ADP-ribose) polymerase (PARP1). SIRT6 also rescues the decline in base excision repair of aged human fibroblasts in a PARP1 dependent manner. These findings suggest that SIRT6 expression may slow the aging process by facilitating DNA repair (see DNA damage theory of aging).
# Clinical relevance
The medical and therapeutic relevance of SIRT6 in humans remains unclear. SIRT6 may be an attractive drug target for pharmocological activation in several diseases. Because SIRT6 attenuates glycolysis and inflammation, the gene is of medical interest in the context of several diseases, including diabetes and arthritis. Additionally, SIRT6 may be relevant in the context of cancer. Several studies have indicated that SIRT6 is selectively inactivated during oncogenesis in a variety of tumor types; a separate study demonstrated that SIRT6 overexpression was selectively cytotoxic to cancer cells. Neurodegenerative diseases in seniors (including Alzheimer's) appear concurrently with low levels of SIRT6.
# Activators
Sirt6 deacetylation activity can be stimulated by high concentrations (several hundred micromolar) of fatty acids, and more potently by a first series of synthetic activators based on a pyrroloquinoxaline scaffold. Crystal structures of Sirt6/activator complexes show that the compounds exploit a Sirt6-specific pocket in the enzyme's substrate acyl binding channel. | SIRT6
Sirtuin-6 (SIRT6) is a stress responsive protein deacetylase and mono-ADP ribosyltransferase enzyme encoded by the SIRT6 gene.[1][2] SIRT6 functions in multiple molecular pathways related to aging, including DNA repair, telomere maintenance, glycolysis and inflammation.[1]
# Function
Studies in mice have revealed that Sirt6 is essential for post-natal development and survival. Sirt6 knock-out mice, in which the gene encoding Sirt6 has been disrupted, exhibit a severe progeria, or premature aging syndrome, characterized by spinal curvature, greying of the fur, lymphopenia and low levels of blood glucose.[3] The lifespan of Sirt6 knock-out mice is typically one to three months, dependent upon the strain in which the Sirt6 gene has been deleted. By contrast, wild type mice, which retain expression of Sirt6, exhibit a maximum lifespan of two to four years.[3]
Mice which have been genetically engineered to overexpress, or produce more, Sirt6 protein exhibit an extended maximum lifespan. This lifespan extension, of about 15-16 percent, is observed only in male mice.[4]
Reciprocal regulation between SIRT6 and miRNA-122 controls liver metabolism and Predicts Hepatocarcinoma prognosis by study of Haim Cohen's lab with mice. they found that SIRT6 and miR-122 negatively regulate each other's expression. The study found SIRT6 was shown to act as a tumor suppressor that blocks the Warburg effect in cancer cells.[5]
# DNA repair
SIRT6 is a chromatin-associated protein that is required for normal base excision repair of DNA damage in mammalian cells.[6] Deficiency of SIRT6 in mice leads to abnormalities that overlap with aging-associated degenerative processes.[6]
SIRT6 also promotes the repair of DNA double-strand breaks by the process of non-homologous end joining. SIRT6 stabilizes the repair protein DNA-PKcs (DNA-dependent protein kinase catalytic subunit) at chromatin sites of damage.[7]
As normal human fibroblasts replicate and progress towards replicative senescence the capability to undergo homologous recombinational repair (HRR) declines.[8] However, over-expression of SIRT6 in “middle-aged” and pre-senescent cells strongly stimulates HRR.[8] This effect depends on the mono-ADP ribosylation activity of poly(ADP-ribose) polymerase (PARP1). SIRT6 also rescues the decline in base excision repair of aged human fibroblasts in a PARP1 dependent manner.[9] These findings suggest that SIRT6 expression may slow the aging process by facilitating DNA repair (see DNA damage theory of aging).
# Clinical relevance
The medical and therapeutic relevance of SIRT6 in humans remains unclear. SIRT6 may be an attractive drug target for pharmocological activation in several diseases.[10] Because SIRT6 attenuates glycolysis and inflammation, the gene is of medical interest in the context of several diseases, including diabetes and arthritis.[11] Additionally, SIRT6 may be relevant in the context of cancer. Several studies have indicated that SIRT6 is selectively inactivated during oncogenesis in a variety of tumor types; a separate study demonstrated that SIRT6 overexpression was selectively cytotoxic to cancer cells.[12] Neurodegenerative diseases in seniors (including Alzheimer's) appear concurrently with low levels of SIRT6.[13]
# Activators
Sirt6 deacetylation activity can be stimulated by high concentrations (several hundred micromolar) of fatty acids,[14] and more potently by a first series of synthetic activators based on a pyrrolo[1,2-a]quinoxaline scaffold.[15] Crystal structures of Sirt6/activator complexes show that the compounds exploit a Sirt6-specific pocket in the enzyme's substrate acyl binding channel.[15] | https://www.wikidoc.org/index.php/SIRT6 | |
bb7286432576d5cd45f463e5b0cead8fbe39a1ba | wikidoc | SIRT7 | SIRT7
NAD-dependent deacetylase sirtuin-7 is an enzyme that in humans is encoded by the SIRT7 gene.
# Function
This gene encodes a member of the sirtuin family of proteins, homologs to the yeast Sir2 protein. Members of the sirtuin family are characterized by a sirtuin core domain and grouped into four classes. The functions of human sirtuins have not yet been determined; however, yeast sirtuin proteins are known to regulate epigenetic gene silencing and suppress recombination of rDNA. Studies suggest that the human sirtuins may function as intracellular regulatory proteins with mono-ADP-ribosyltransferase activity. The protein encoded by this gene is included in class IV of the sirtuin family.
In humans cells, SIRT7 has only been shown to interact with two other molecules: RNA polymerase I (RNA Pol I) and upstream binding factor (UBF). SIRT7 is localized to the nucleolus and interacts with RNA Pol I. Chromatin immunoprecipitation studies demonstrate that SIRT7 localizes to rDNA, and coimmunoprecipitation shows that SIRT7 binds RNA Pol I. In addition SIRT7 interacts with UBF, a major component of the RNA Pol I initiation complex. It is not known whether or not SIRT7 is modifying RNA Pol I and/or UBF, and if so, what those modifications are.
SIRT7 is expressed more in metabolically active tissues, such as liver and spleen, and less in non-proliferating tissues, such as heart and brain. Furthermore, it has been shown that SIRT7 is necessary for rDNA transcription. Knock down of SIRT7 in HEK293 cells resulted in decreased rRNA levels. This same study found that this SIRT3 knockdown decreased the amount of RNA Pol I associated with rDNA, suggesting that SIRT7 may be required for rDNA transcription. Knock down SIRT7 led to reduced RNA Pol I levels, but RNA Pol I mRNA levels did not change. This suggests that SIRT7 plays a crucial role in connecting the function of chromatin remodeling complexes to RNA Pol I machinery during transcription.
SIRT7 may help attenuate DNA damage and thereby promoting cellular survival under conditions of genomic stress.
## DNA repair
Depletion of SIRT7 results in impaired repair of DNA double-strand breaks (DSBs) by the process of non-homologous end joining (NHDJ). DSBs are one of the most significant types of DNA damage leading to genome instability. SIRT7 is recruited to DSBs where it specifically deacylates histone H3 at lysine 18. This affects the focal accumulation of the DNA damage response factor 53BP1, a protein that promotes NHEJ by protecting DNA from end resection.
## Accelerated aging
Sirt7 mutant mice show phenotypic and molecular features of accelerated aging. These features include premature curvature of the spine, reduced weight and fat content, compromised hematopoietic stem cell function and leukopenia, and multiple organ disfunction.
# Clinical relevance
This gene has been found to be involved in maintenance of oncogenic transformation. | SIRT7
NAD-dependent deacetylase sirtuin-7 is an enzyme that in humans is encoded by the SIRT7 gene.[1][2][3]
# Function
This gene encodes a member of the sirtuin family of proteins, homologs to the yeast Sir2 protein. Members of the sirtuin family are characterized by a sirtuin core domain and grouped into four classes. The functions of human sirtuins have not yet been determined; however, yeast sirtuin proteins are known to regulate epigenetic gene silencing and suppress recombination of rDNA. Studies suggest that the human sirtuins may function as intracellular regulatory proteins with mono-ADP-ribosyltransferase activity. The protein encoded by this gene is included in class IV of the sirtuin family.[3]
In humans cells, SIRT7 has only been shown to interact with two other molecules: RNA polymerase I (RNA Pol I) and upstream binding factor (UBF).[2] SIRT7 is localized to the nucleolus and interacts with RNA Pol I. Chromatin immunoprecipitation studies demonstrate that SIRT7 localizes to rDNA, and coimmunoprecipitation shows that SIRT7 binds RNA Pol I. In addition SIRT7 interacts with UBF, a major component of the RNA Pol I initiation complex.[4] It is not known whether or not SIRT7 is modifying RNA Pol I and/or UBF, and if so, what those modifications are.
SIRT7 is expressed more in metabolically active tissues, such as liver and spleen, and less in non-proliferating tissues, such as heart and brain.[2] Furthermore, it has been shown that SIRT7 is necessary for rDNA transcription. Knock down of SIRT7 in HEK293 cells resulted in decreased rRNA levels. This same study found that this SIRT3 knockdown decreased the amount of RNA Pol I associated with rDNA, suggesting that SIRT7 may be required for rDNA transcription. Knock down SIRT7 led to reduced RNA Pol I levels, but RNA Pol I mRNA levels did not change. This suggests that SIRT7 plays a crucial role in connecting the function of chromatin remodeling complexes to RNA Pol I machinery during transcription.[5]
SIRT7 may help attenuate DNA damage and thereby promoting cellular survival under conditions of genomic stress.[6]
## DNA repair
Depletion of SIRT7 results in impaired repair of DNA double-strand breaks (DSBs) by the process of non-homologous end joining (NHDJ).[7] DSBs are one of the most significant types of DNA damage leading to genome instability. SIRT7 is recruited to DSBs where it specifically deacylates histone H3 at lysine 18. This affects the focal accumulation of the DNA damage response factor 53BP1, a protein that promotes NHEJ by protecting DNA from end resection.[7][8]
## Accelerated aging
Sirt7 mutant mice show phenotypic and molecular features of accelerated aging.[7] These features include premature curvature of the spine, reduced weight and fat content, compromised hematopoietic stem cell function and leukopenia, and multiple organ disfunction.[7][8]
# Clinical relevance
This gene has been found to be involved in maintenance of oncogenic transformation.[9] | https://www.wikidoc.org/index.php/SIRT7 | |
661c90a3221ee59146a676fbe58ca404c9ff224d | wikidoc | SIVA1 | SIVA1
Apoptosis regulatory protein Siva is a protein that in humans is encoded by the SIVA1 gene.
This gene encodes a protein with an important role in the apoptotic (programmed cell death) pathway induced by the CD27 antigen, a member of the tumor necrosis factor receptor (TFNR) superfamily. The CD27 antigen cytoplasmic tail binds to the N-terminus of this protein. Two alternatively spliced transcript variants encoding distinct proteins have been described.
# Interactions
SIVA1 has been shown to interact with CD27.
# Siva (protein)
Siva protein is a zinc-containing intracellular ligand of the CD4 receptor that promotes HIV-1 envelope-induced apoptosis in T-lymphoid cells. Recent research has demonstrated that Siva is a direct transcriptional target for the tumor-suppressors p53 and E2F1. | SIVA1
Apoptosis regulatory protein Siva is a protein that in humans is encoded by the SIVA1 gene.[1][2]
This gene encodes a protein with an important role in the apoptotic (programmed cell death) pathway induced by the CD27 antigen, a member of the tumor necrosis factor receptor (TFNR) superfamily. The CD27 antigen cytoplasmic tail binds to the N-terminus of this protein. Two alternatively spliced transcript variants encoding distinct proteins have been described.[2]
# Interactions
SIVA1 has been shown to interact with CD27.[1]
# Siva (protein)
Siva protein is a zinc-containing intracellular ligand of the CD4 receptor that promotes HIV-1 envelope-induced apoptosis in T-lymphoid cells. Recent research has demonstrated that Siva is a direct transcriptional target for the tumor-suppressors p53 and E2F1. [3] | https://www.wikidoc.org/index.php/SIVA1 | |
bcfd3439bb6f2810a4e26ddd2e8294f3e7601a5b | wikidoc | SKAP1 | SKAP1
Src kinase-associated phosphoprotein 1 is an adapter protein that in humans is encoded by the SKAP1 gene.
This gene encodes a T cell adapter protein, a class of intracellular molecules with modular domains capable of recruiting additional proteins but that exhibit no intrinsic enzymatic activity. The encoded protein contains a unique N-terminal region followed by a PH domain and C-terminal SH3 domain. Along with the adhesion and degranulation-promoting adapter protein, the encoded protein plays a critical role in inside-out signaling by coupling T-cell antigen receptor stimulation to the activation of integrins.
The demonstration that SKAP1 regulates LFA-1 adhesion was made by retroviral infection and by the SKAP1 deficient mouse. Additional work has implicated SKAP1 in binding to the exchange factor RasGRP1 and in regulating ERK activation in T-cells.
# Interactions
SKAP1 has been shown to interact with FYN, PTPRC and FYB. | SKAP1
Src kinase-associated phosphoprotein 1 is an adapter protein that in humans is encoded by the SKAP1 gene.[1][2]
This gene encodes a T cell adapter protein, a class of intracellular molecules with modular domains capable of recruiting additional proteins but that exhibit no intrinsic enzymatic activity. The encoded protein contains a unique N-terminal region followed by a PH domain and C-terminal SH3 domain. Along with the adhesion and degranulation-promoting adapter protein, the encoded protein plays a critical role in inside-out signaling by coupling T-cell antigen receptor stimulation to the activation of integrins.[2]
The demonstration that SKAP1 regulates LFA-1 adhesion was made by retroviral infection [3] and by the SKAP1 deficient mouse.[4] Additional work has implicated SKAP1 in binding to the exchange factor RasGRP1 and in regulating ERK activation in T-cells.[5][6]
# Interactions
SKAP1 has been shown to interact with FYN,[1][7][8] PTPRC[9] and FYB.[8][10] | https://www.wikidoc.org/index.php/SKAP1 | |
0ee80c85e5cea6b6b9905387ed25fe5898c89948 | wikidoc | SMC1A | SMC1A
Structural maintenance of chromosomes protein 1A is a protein that in humans is encoded by the SMC1A gene.
# Function
Proper cohesion of sister chromatids is a prerequisite for the correct segregation of chromosomes during cell division. The cohesin multiprotein complex is required for sister chromatid cohesion. This complex is composed partly of two structural maintenance of chromosomes (SMC) proteins, SMC3 and either SMC1L2 or the protein encoded by this gene. Most of the cohesin complexes dissociate from the chromosomes before mitosis, although those complexes at the kinetochore remain. Therefore, the encoded protein is thought to be an important part of functional kinetochores. In addition, this protein interacts with BRCA1 and is phosphorylated by ATM, indicating a potential role for this protein in DNA repair. This gene, which belongs to the SMC gene family, is located in an area of the X-chromosome that escapes X inactivation.
# Interactions
SMC1A has been shown to interact with SMC3 and Ataxia telangiectasia mutated. | SMC1A
Structural maintenance of chromosomes protein 1A is a protein that in humans is encoded by the SMC1A gene.[1][2]
# Function
Proper cohesion of sister chromatids is a prerequisite for the correct segregation of chromosomes during cell division. The cohesin multiprotein complex is required for sister chromatid cohesion. This complex is composed partly of two structural maintenance of chromosomes (SMC) proteins, SMC3 and either SMC1L2 or the protein encoded by this gene. Most of the cohesin complexes dissociate from the chromosomes before mitosis, although those complexes at the kinetochore remain. Therefore, the encoded protein is thought to be an important part of functional kinetochores. In addition, this protein interacts with BRCA1 and is phosphorylated by ATM, indicating a potential role for this protein in DNA repair. This gene, which belongs to the SMC gene family, is located in an area of the X-chromosome that escapes X inactivation.[2]
# Interactions
SMC1A has been shown to interact with SMC3[3][4][5][6] and Ataxia telangiectasia mutated.[3] | https://www.wikidoc.org/index.php/SMC1A | |
f407f72bae0856d06e06154d2a14f5096c48115a | wikidoc | SMCO4 | SMCO4
SMCO4 (Single-pass membrane protein with coiled-coil domains 4) is a human gene that encodes the FN5 protein. The FN5 protein is a single-pass transmembrane protein, which means that one end of the protein will remain in the cytoplasm, while the other end of the protein is exposed to the interior of the cell.
# Gene Properties
The SMCO4 gene is located on chromosome 11, with specific chromosomal coordinates of 11q13.3-q23.3 in Homo sapiens. SMCO4 has two common aliases: C11orf75 (Chromosome 11 Open Reading Frame 75) and FN5.
# mRNA features
SMCO4 has 7 isoforms in Homo sapiens. The SMCO4 isoform 1 has 9 exons, while the rest of the isoforms have varying amounts of rxons. These isoforms are listed in the table below, with their accession numbers for reference.
# Protein
MRQLKGKPKKETSKDKKERKQAMQEARQQITTVVLPTLAVVVLLIVVFVYVATRPTITE
The protein that is encoded by SMCO4 is rich in phosphorylable amino acids and has a high pH. There are no predicted protein repeats. There is evidence that the protein is present in the outer membrane of the mitochondria. The absence of an N-terminal signal peptide shows that the protein does not have the ability to leave the organelle it is in, which correlates with the knowledge that it is a transmembrane protein.
## Structure
The structure of the FN5 protein is not yet known, but the protein qualities are useful in predicting the protein's structure. There is no evidence that the protein would take on any Beta-turns; its secondary structure would be composed of only alpha-helixes. There are two separate helixes: the transmembrane helix and the alpha helix.
# Expression
## Expression Analysis
SMCO4 expression in humans was predicted to be highest in the salivary glands. Overall, there was RNA tissue expression shown in 37 human tissues and expression of the protein in 71 cell types.
## Regulation of Expression
SMCO4 is not ubiquitously expressed throughout humans. There is evidence that the expression of SMCO4 is easily manipulated by many different factors, making constant expression unlikely. One example of this expression regulation comes from an experiment that showed increased SMCO4 expression in the presence of Gamma-tocotrienol.
# Predicted Interactions
SMCO4 is predicted to interact with the following proteins:
# Conservation
Two microRNAs, miR-124-3p.1 and miR-183-5p.1, are thought to be highly conserved throughout variety of vertebrates. TheseicroRio RNAs are both neuronal in nature.
## Orthologs
Orthologs of SMCO4 were found in a variety of species, including mammals, birds, reptiles, amphibians, insects and parasites. The primates were consistently found to have the highest sequence identity with the human SMCO4 sequence, followed closely by an extinct fish species called Latimeria chalumnae. There was no evidence of SMCO4 presence in yeast species. | SMCO4
SMCO4 (Single-pass membrane protein with coiled-coil domains 4) is a human gene that encodes the FN5 protein. The FN5 protein is a single-pass transmembrane protein, which means that one end of the protein will remain in the cytoplasm, while the other end of the protein is exposed to the interior of the cell.
# Gene Properties
The SMCO4 gene is located on chromosome 11, with specific chromosomal coordinates of 11q13.3-q23.3 in Homo sapiens.[1] SMCO4 has two common aliases: C11orf75 (Chromosome 11 Open Reading Frame 75) and FN5.[2]
# mRNA features
SMCO4 has 7 isoforms in Homo sapiens.[3] The SMCO4 isoform 1 has 9 exons, while the rest of the isoforms have varying amounts of rxons. These isoforms are listed in the table below, with their accession numbers for reference.
# Protein
MRQLKGKPKKETSKDKKERKQAMQEARQQITTVVLPTLAVVVLLIVVFVYVATRPTITE
The protein that is encoded by SMCO4 is rich in phosphorylable amino acids and has a high pH. There are no predicted protein repeats. There is evidence that the protein is present in the outer membrane of the mitochondria.[5] The absence of an N-terminal signal peptide shows that the protein does not have the ability to leave the organelle it is in, which correlates with the knowledge that it is a transmembrane protein.
## Structure
The structure of the FN5 protein is not yet known, but the protein qualities are useful in predicting the protein's structure. There is no evidence that the protein would take on any Beta-turns; its secondary structure would be composed of only alpha-helixes. There are two separate helixes: the transmembrane helix and the alpha helix.
# Expression
## Expression Analysis
SMCO4 expression in humans was predicted to be highest in the salivary glands.[6][7] Overall, there was RNA tissue expression shown in 37 human tissues and expression of the protein in 71 cell types.[7]
## Regulation of Expression
SMCO4 is not ubiquitously expressed throughout humans. There is evidence that the expression of SMCO4 is easily manipulated by many different factors, making constant expression unlikely. One example of this expression regulation comes from an experiment that showed increased SMCO4 expression in the presence of Gamma-tocotrienol.[8][9]
# Predicted Interactions
SMCO4 is predicted to interact with the following proteins:[10]
# Conservation
Two microRNAs, miR-124-3p.1 and miR-183-5p.1, are thought to be highly conserved throughout variety of vertebrates. TheseicroRio RNAs are both neuronal in nature.[11]
## Orthologs
Orthologs of SMCO4 were found in a variety of species, including mammals, birds, reptiles, amphibians, insects and parasites. The primates were consistently found to have the highest sequence identity with the human SMCO4 sequence, followed closely by an extinct fish species called Latimeria chalumnae. There was no evidence of SMCO4 presence in yeast species. | https://www.wikidoc.org/index.php/SMCO4 | |
e3a07e4bf84f6d3bf6d283756f5c9d518a6d0ea4 | wikidoc | SMOC2 | SMOC2
SPARC-related modular calcium-binding protein 2 is a protein that in humans is encoded by the SMOC2 gene.
# Clinical relevance
This gene has been shown mutated in clinical cases of major dental developmental defects.
Brachycephalic dogs show a shortening of the snout along with a widening of the hard palate. This skull form is highly associated with disorders of breathing and of the eyes. Brachycephaly in dogs is correlated to a retrotransposon induced missplicing the SMOC2 gene. | SMOC2
SPARC-related modular calcium-binding protein 2 is a protein that in humans is encoded by the SMOC2 gene.[1][2]
# Clinical relevance
This gene has been shown mutated in clinical cases of major dental developmental defects.[3]
Brachycephalic dogs show a shortening of the snout along with a widening of the hard palate. This skull form is highly associated with disorders of breathing and of the eyes. Brachycephaly in dogs is correlated to a retrotransposon induced missplicing the SMOC2 gene.[4] | https://www.wikidoc.org/index.php/SMOC2 | |
d5661ccb113694f24925b7c0f8ca3246e8751cb8 | wikidoc | SMYD3 | SMYD3
SET and MYND domain-containing protein 3 is a protein that in humans is encoded by the SMYD3 gene.
# Function
SMYD3 is a histone methyltransferase that plays a role in transcriptional regulation as a member of an RNA polymerase complex.
# Model organisms
Model organisms have been used in the study of SMYD3 function. A conditional knockout mouse line, called Smyd3tm2a(KOMP)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty three tests were carried out on homozygous mutant adult mice, however no significant abnormalities were observed.
# Interactions
SMYD3 has been shown to interact with Heat shock protein 90kDa alpha (cytosolic), member A1 and POLR2A.
SMYD3 trimethylates a lysine residue on MAP3K2, which causes crosstalk into the MAP kinase signaling pathway in Ras-driven cancers. | SMYD3
SET and MYND domain-containing protein 3 is a protein that in humans is encoded by the SMYD3 gene.[1]
# Function
SMYD3 is a histone methyltransferase that plays a role in transcriptional regulation as a member of an RNA polymerase complex.[1]
# Model organisms
Model organisms have been used in the study of SMYD3 function. A conditional knockout mouse line, called Smyd3tm2a(KOMP)Wtsi[6][7] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute.[8][9][10]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[4][11] Twenty three tests were carried out on homozygous mutant adult mice, however no significant abnormalities were observed.[4]
# Interactions
SMYD3 has been shown to interact with Heat shock protein 90kDa alpha (cytosolic), member A1[12] and POLR2A.[12]
SMYD3 trimethylates a lysine residue on MAP3K2, which causes crosstalk into the MAP kinase signaling pathway in Ras-driven cancers.[13] | https://www.wikidoc.org/index.php/SMYD3 | |
e5670a7341faa8f36b4c6d053504690c15cfde3c | wikidoc | SMYD4 | SMYD4
SET and MYND domain-containing protein 4 is a protein that in humans is encoded by the SMYD4 gene.
# Model organisms
Model organisms have been used in the study of SMYD4 function. A conditional knockout mouse line, called Smyd4tm1a(EUCOMM)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty six tests were carried out on homozygous mutant adult mice, however no significant abnormalities were observed. | SMYD4
SET and MYND domain-containing protein 4 is a protein that in humans is encoded by the SMYD4 gene.[1][2]
# Model organisms
Model organisms have been used in the study of SMYD4 function. A conditional knockout mouse line, called Smyd4tm1a(EUCOMM)Wtsi[7][8] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute.[9][10][11]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[5][12] Twenty six tests were carried out on homozygous mutant adult mice, however no significant abnormalities were observed.[5] | https://www.wikidoc.org/index.php/SMYD4 | |
08affc0d6c2e97ee9e3acbf5821f7a5239a39c25 | wikidoc | SNAI1 | SNAI1
Zinc finger protein SNAI1 (sometimes referred to as Snail) is a protein that in humans is encoded by the SNAI1 gene. Snail is a family of transcription factors that promote the repression of the adhesion molecule E-cadherin to regulate epithelial to mesenchymal transition (EMT) during embryonic development.
# Function
The Drosophila embryonic protein SNAI1, commonly known as Snail, is a zinc finger transcriptional repressor which downregulates the expression of ectodermal genes within the mesoderm. The nuclear protein encoded by this gene is structurally similar to the Drosophila snail protein, and is also thought to be critical for mesoderm formation in the developing embryo. At least two variants of a similar processed pseudogene have been found on chromosome 2. SNAI1 zinc-fingers (ZF) binds to E-box, an E-cadherin promoter region, and represses the expression of the adhesion molecule, which induces the tightly bound epithelial cells to break loose from each other and migrate into the developing embryo to become mesenchymal cells. This process allows for the formation of the mesodermal layer in the developing embryo. Though SNAI1 is shown to repress expression of E-cadherin in epithelial cells, studies have shown homozygous mutant embryos are still able to form a mesodermal layer. However, the mesodermal layer present shows characteristics of epithelial cells and not mesenchymal cells (the mutant mesoderm cells exhibited a polarized state). Other studies show that mutation of specific ZFs contribute to a decrease in SNAI1 E-cadherin repression.
SNAI1 and other epithelial-mesenchymal transition (EMT) genes are regulated by several genes and molecules including Wnt and prostaglandins. Wnt3a is a master regulator of paraxial presomatic mesoderm cells (PSM) which differentiate into the musculoskeleton of the trunk and tail. Other genes, most of which act downstream of Wnt include Msx1, Pax3, and Mesogenin 1 (Msgn1). Msgn1 activates SNAI1 by binding to its enhancer and activating SNAI1 to induce EMT. MSGN1 also regulates many of the same genes as SNAI1 to ensure EMT activation, granting the system redundancy. This suggests that Msgn1 and SNAI1 act together through a feed forward mechanism. When Msgn1 is deleted, the mesodermal progenitors do not move from the primitive streak (PS) but still show mesenchymal morphology. This suggests that the Msgn1/SNAI1 axis mostly functions to drive cell movement. Prostaglandin E2 (PE2), an important hormone in homeostasis and maintaining normal fertility and pregnancy, stabilizes SNAI1 post-transcriptionally and, therefore, also plays a role in embryogenesis. When the prostaglandin signaling pathway is compromised, SNAI1 transcriptional repressor activity decreases, increasing E-cadherin protein levels during gastrulation. However, this does not prevent gastrulation from occurring.
# Clinical significance
Snail gene may show a role in recurrence of breast cancer by downregulating E-cadherin and inducing an epithelial to mesenchymal transition. The process of EMT is also noted as an important and noteworthy process in tumor growth, through the invasion and metastasis of tumor cells due to repression of E-cadherin adhesion molecules. Through knockout models, one study has shown the importance of SNAI1 in the growth of breast cancer cells. Knockout models showed significant reduction in cancer invasiveness and therefore can be used as a therapeutic measure for the treatment of breast cancer before chemotherapy treatment.
# Interactions
SNAI1 has been shown to interact with CTDSPL, CTDSP1 and CTDSP2. | SNAI1
Zinc finger protein SNAI1 (sometimes referred to as Snail) is a protein that in humans is encoded by the SNAI1 gene.[1][2] Snail is a family of transcription factors that promote the repression of the adhesion molecule E-cadherin to regulate epithelial to mesenchymal transition (EMT) during embryonic development.
# Function
The Drosophila embryonic protein SNAI1, commonly known as Snail, is a zinc finger transcriptional repressor which downregulates the expression of ectodermal genes within the mesoderm. The nuclear protein encoded by this gene is structurally similar to the Drosophila snail protein, and is also thought to be critical for mesoderm formation in the developing embryo. At least two variants of a similar processed pseudogene have been found on chromosome 2.[2] SNAI1 zinc-fingers (ZF) binds to E-box, an E-cadherin promoter region,[3] and represses the expression of the adhesion molecule, which induces the tightly bound epithelial cells to break loose from each other and migrate into the developing embryo to become mesenchymal cells. This process allows for the formation of the mesodermal layer in the developing embryo. Though SNAI1 is shown to repress expression of E-cadherin in epithelial cells, studies have shown homozygous mutant embryos are still able to form a mesodermal layer.[4] However, the mesodermal layer present shows characteristics of epithelial cells and not mesenchymal cells (the mutant mesoderm cells exhibited a polarized state). Other studies show that mutation of specific ZFs contribute to a decrease in SNAI1 E-cadherin repression.[3]
SNAI1 and other epithelial-mesenchymal transition (EMT) genes are regulated by several genes and molecules including Wnt and prostaglandins. Wnt3a is a master regulator of paraxial presomatic mesoderm cells (PSM) which differentiate into the musculoskeleton of the trunk and tail. Other genes, most of which act downstream of Wnt include Msx1, Pax3, and Mesogenin 1 (Msgn1). Msgn1 activates SNAI1 by binding to its enhancer and activating SNAI1 to induce EMT. MSGN1 also regulates many of the same genes as SNAI1 to ensure EMT activation, granting the system redundancy. This suggests that Msgn1 and SNAI1 act together through a feed forward mechanism. When Msgn1 is deleted, the mesodermal progenitors do not move from the primitive streak (PS) but still show mesenchymal morphology. This suggests that the Msgn1/SNAI1 axis mostly functions to drive cell movement. [5] Prostaglandin E2 (PE2), an important hormone in homeostasis and maintaining normal fertility and pregnancy, stabilizes SNAI1 post-transcriptionally and, therefore, also plays a role in embryogenesis. When the prostaglandin signaling pathway is compromised, SNAI1 transcriptional repressor activity decreases, increasing E-cadherin protein levels during gastrulation. However, this does not prevent gastrulation from occurring. [6]
# Clinical significance
Snail gene may show a role in recurrence of breast cancer by downregulating E-cadherin and inducing an epithelial to mesenchymal transition.[7] The process of EMT is also noted as an important and noteworthy process in tumor growth, through the invasion and metastasis of tumor cells due to repression of E-cadherin adhesion molecules. Through knockout models, one study has shown the importance of SNAI1 in the growth of breast cancer cells.[8] Knockout models showed significant reduction in cancer invasiveness and therefore can be used as a therapeutic measure for the treatment of breast cancer before chemotherapy treatment.[8]
# Interactions
SNAI1 has been shown to interact with CTDSPL,[9] CTDSP1[9] and CTDSP2.[9] | https://www.wikidoc.org/index.php/SNAI1 | |
9c2185fad9be430a9d019a650724c5f256b5647d | wikidoc | SNAI2 | SNAI2
Zinc finger protein SNAI2 is a protein that in humans is encoded by the SNAI2 gene.
# Function
This gene encodes a member of the Snail superfamily of C2H2-type zinc finger transcription factors. The encoded protein acts as a transcriptional repressor that binds to E-box motifs and is also likely to repress E-cadherin transcription in breast carcinoma. This protein is involved in epithelial-mesenchymal transitions and has antiapoptotic activity. It regulates differentiation and migration of neural crest cells along with other genes (e.g. FOXD3, SOX9 and SOX10, BMPs) in embryonic life. Mutations in this gene may be associated with sporadic cases of neural tube defects.
# Function
The human embryonic protein SNAI2, commonly known as SLUG, is a zinc finger transcriptional repressor which downregulates expression of E-cadherin in premigratory neural crest cells; thus, SNAI2 induces tightly bound epithelial cells to break into a loose mesenchymal phenotype, allowing gastrulation of mesoderm in the developing embryo. Structurally similar to anti-apoptotic Ces-1 in C. elegans, SLUG is a negative regulator of productive cell death in the developing embryo and adults.
# Clinical significance
Widely expressed in human tissues, SLUG is most notably absent in peripheral blood leukocytes, adult liver, and both fetal and adult brain tissues. SLUG plays a role in breast carcinoma as well as leukemia by downregulation of E-cadherin, which supports mesenchymal phenotype by shifting expression from a Type I to Type II cadherin profile. Maintenance of mesenchymal phenotype enables metastasis of tumor cells, though SLUG is expressed in carcinomas regardless to invasiveness. A knockout model using chick embryos has also showed inhibition of mesodermal and neural crest delamination; chick embryo Slug gain of function appears to increase neural crest production. Mutations in Slug are associated with loss of pregnancy during gastrulation in some animals.
# Interactions
BMPs precede expression of SLUG, and are suspected as the immediate upstream inducers of gene expression. | SNAI2
Zinc finger protein SNAI2 is a protein that in humans is encoded by the SNAI2 gene.[1][2][3]
# Function
This gene encodes a member of the Snail superfamily of C2H2-type zinc finger transcription factors. The encoded protein acts as a transcriptional repressor that binds to E-box motifs and is also likely to repress E-cadherin transcription in breast carcinoma. This protein is involved in epithelial-mesenchymal transitions and has antiapoptotic activity. It regulates differentiation and migration of neural crest cells along with other genes (e.g. FOXD3, SOX9 and SOX10, BMPs) in embryonic life. Mutations in this gene may be associated with sporadic cases of neural tube defects.[3]
# Function
The human embryonic protein SNAI2, commonly known as SLUG, is a zinc finger transcriptional repressor which downregulates expression of E-cadherin in premigratory neural crest cells; thus, SNAI2 induces tightly bound epithelial cells to break into a loose mesenchymal phenotype, allowing gastrulation of mesoderm in the developing embryo.[4][5] Structurally similar to anti-apoptotic Ces-1 in C. elegans, SLUG is a negative regulator of productive cell death in the developing embryo and adults.[4][6]
# Clinical significance
Widely expressed in human tissues, SLUG is most notably absent in peripheral blood leukocytes, adult liver, and both fetal and adult brain tissues.[6] SLUG plays a role in breast carcinoma as well as leukemia by downregulation of E-cadherin, which supports mesenchymal phenotype by shifting expression from a Type I to Type II cadherin profile.[6][7] Maintenance of mesenchymal phenotype enables metastasis of tumor cells, though SLUG is expressed in carcinomas regardless to invasiveness.[4][5][6] A knockout model using chick embryos has also showed inhibition of mesodermal and neural crest delamination; chick embryo Slug gain of function appears to increase neural crest production.[4] Mutations in Slug are associated with loss of pregnancy during gastrulation in some animals.[4]
# Interactions
BMPs precede expression of SLUG, and are suspected as the immediate upstream inducers of gene expression.[5][8] | https://www.wikidoc.org/index.php/SNAI2 | |
61a0e7395466d71a5c952f613c75c0fddaa23a94 | wikidoc | SNX17 | SNX17
Sorting nexin-17 is a protein that in humans is encoded by the SNX17 gene.
# Function
This gene encodes a member of the sorting nexin family. Members of this family contain a phox (PX) domain, which is a phosphoinositide binding domain, and are involved in intracellular trafficking. This protein does not contain a coiled coil region, like some family members, but contains a B41 domain. This protein interacts with the cytoplasmic domain of P-selectin, and may function in the intracellular trafficking of P-selectin.
# Interactions
SNX17 has been shown to interact with Low density lipoprotein receptor-related protein 8 | SNX17
Sorting nexin-17 is a protein that in humans is encoded by the SNX17 gene.[1][2][3]
# Function
This gene encodes a member of the sorting nexin family. Members of this family contain a phox (PX) domain, which is a phosphoinositide binding domain, and are involved in intracellular trafficking. This protein does not contain a coiled coil region, like some family members, but contains a B41 domain. This protein interacts with the cytoplasmic domain of P-selectin, and may function in the intracellular trafficking of P-selectin.[3]
# Interactions
SNX17 has been shown to interact with Low density lipoprotein receptor-related protein 8[1] | https://www.wikidoc.org/index.php/SNX17 | |
fce1b82ba83b923360457a128794300de5c36ce5 | wikidoc | SOAT1 | SOAT1
Sterol O-acyltransferase (acyl-Coenzyme A: cholesterol acyltransferase) 1, also known as SOAT1, is an enzyme that in humans is encoded by the SOAT1 gene.
# Function
Acyl-coenzyme A:cholesterol acyltransferase (EC 2.3.1.26) is an intracellular protein located in the endoplasmic reticulum that forms cholesterol esters from cholesterol. Accumulation of cholesterol esters as cytoplasmic lipid droplets within macrophages and smooth muscle cells is a characteristic feature of the early stages of atherosclerotic plaques (Cadigan et al., 1988).
# Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.
- ↑ The interactive pathway map can be edited at WikiPathways: "Statin_Pathway_WP430"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} | SOAT1
Sterol O-acyltransferase (acyl-Coenzyme A: cholesterol acyltransferase) 1, also known as SOAT1, is an enzyme that in humans is encoded by the SOAT1 gene.[1]
# Function
Acyl-coenzyme A:cholesterol acyltransferase (EC 2.3.1.26) is an intracellular protein located in the endoplasmic reticulum that forms cholesterol esters from cholesterol. Accumulation of cholesterol esters as cytoplasmic lipid droplets within macrophages and smooth muscle cells is a characteristic feature of the early stages of atherosclerotic plaques (Cadigan et al., 1988).[1]
# Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles. [§ 1]
- ↑ The interactive pathway map can be edited at WikiPathways: "Statin_Pathway_WP430"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} | https://www.wikidoc.org/index.php/SOAT1 | |
af8044da2d2c9364986551e0f7d317f0a1d92c32 | wikidoc | SOCS2 | SOCS2
Suppressor of cytokine signaling 2 is a protein that in humans is encoded by the SOCS2 gene.
This gene encodes a member of the STAT-induced STAT inhibitor (SSI), also known as suppressor of cytokine signalling (SOCS), family. SSI family members are cytokine-inducible negative regulators of cytokine signaling. The expression of this gene can be induced by a subset of cytokines, including erythropoietin, GM-CSF, IL10 and interferon-gamma (IFN-gamma). The protein encoded by this gene is found to interact with the cytoplasmic domain of insulin-like growth factor 1 receptor (IGF1R), and thus is thought to be involved in the regulation of IGF1R mediated cell signaling. Knockout studies in mice also suggested a regulatory role of this gene in IGF-1 related growth control.
# Interactions
SOCS2 has been shown to interact with insulin-like growth factor 1 receptor and erythropoietin receptor. | SOCS2
Suppressor of cytokine signaling 2 is a protein that in humans is encoded by the SOCS2 gene.[1][2][3]
This gene encodes a member of the STAT-induced STAT inhibitor (SSI), also known as suppressor of cytokine signalling (SOCS), family. SSI family members are cytokine-inducible negative regulators of cytokine signaling. The expression of this gene can be induced by a subset of cytokines, including erythropoietin, GM-CSF, IL10 and interferon-gamma (IFN-gamma). The protein encoded by this gene is found to interact with the cytoplasmic domain of insulin-like growth factor 1 receptor (IGF1R), and thus is thought to be involved in the regulation of IGF1R mediated cell signaling.[4] Knockout studies in mice also suggested a regulatory role of this gene in IGF-1 related growth control.[3][5]
# Interactions
SOCS2 has been shown to interact with insulin-like growth factor 1 receptor[4] and erythropoietin receptor.[6] | https://www.wikidoc.org/index.php/SOCS2 | |
b2cebf40f1427cc89e45cf9515dc10fe503e7330 | wikidoc | SOCS3 | SOCS3
Suppressor of cytokine signaling 3 (SOCS3 or SOCS-3) is a protein that in humans is encoded by the SOCS3 gene.
This gene encodes a member of the STAT-induced STAT inhibitor (SSI), also known as suppressor of cytokine signaling (SOCS), family. SSI family members are cytokine-inducible negative regulators of cytokine signaling.
# Function
The expression of SOCS3 gene is induced by various cytokines, including IL6, IL10, and interferon (IFN)-gamma.
For signaling of IL-6, Epo, GCSF and Leptin, binding of SOCS3 to the respective cytokine receptor has been found to be crucial for the inhibitory function of SOCS3.
Overexpression of SOCS3 inhibits insulin signaling in adipose tissue and the liver, but not in muscle. But deletion of SOCS3 in the skeletal muscle of mice protects against obesity-related insulin resistance.
SOCS3 contributes to both leptin resistance and insulin resistance as a result of increased ceramide synthesis. For that reason, studies have shown that removal of the SOCS gene prevents against insulin resistance in obesity
Studies of the mouse counterpart of this gene suggested the roles of this gene in the negative regulation of fetal liver hematopoiesis, and placental development.
The SOCS3 protein can bind to JAK2 kinase, and inhibits the activity of JAK2 kinase.
# Interactions
SOCS3 has been shown to interact with:
- Erythropoietin receptor,
- Glycoprotein 130,
- Insulin-like growth factor 1 receptor,
- Janus kinase 2,
- PTPN11, and
- RAS p21 protein activator 1.
# Regulation
There is some evidence that the expression of SOCS3 is regulated by the microRNA miR-203. | SOCS3
Suppressor of cytokine signaling 3 (SOCS3 or SOCS-3) is a protein that in humans is encoded by the SOCS3 gene.[1][2]
This gene encodes a member of the STAT-induced STAT inhibitor (SSI), also known as suppressor of cytokine signaling (SOCS), family. SSI family members are cytokine-inducible negative regulators of cytokine signaling.
# Function
The expression of SOCS3 gene is induced by various cytokines, including IL6, IL10, and interferon (IFN)-gamma.
For signaling of IL-6, Epo, GCSF and Leptin, binding of SOCS3 to the respective cytokine receptor has been found to be crucial for the inhibitory function of SOCS3.
Overexpression of SOCS3 inhibits insulin signaling in adipose tissue and the liver, but not in muscle.[3] But deletion of SOCS3 in the skeletal muscle of mice protects against obesity-related insulin resistance.[3]
SOCS3 contributes to both leptin resistance and insulin resistance as a result of increased ceramide synthesis.[4] For that reason, studies have shown that removal of the SOCS gene prevents against insulin resistance in obesity[3]
Studies of the mouse counterpart of this gene suggested the roles of this gene in the negative regulation of fetal liver hematopoiesis, and placental development.[5]
The SOCS3 protein can bind to JAK2 kinase, and inhibits the activity of JAK2 kinase.
# Interactions
SOCS3 has been shown to interact with:
- Erythropoietin receptor,[6][7]
- Glycoprotein 130,[8]
- Insulin-like growth factor 1 receptor,[9]
- Janus kinase 2,[2][6][10]
- PTPN11,[8] and
- RAS p21 protein activator 1.[11]
# Regulation
There is some evidence that the expression of SOCS3 is regulated by the microRNA miR-203.[12][13] | https://www.wikidoc.org/index.php/SOCS3 | |
56c39aa97c915185c788fd74554fa6cbae1820b3 | wikidoc | SOCS7 | SOCS7
Suppressor of cytokine signaling 7 is a protein that in humans is encoded by the SOCS7 gene.
# Model organisms
Model organisms have been used in the study of SOCS7 function. A conditional knockout mouse line, called Socs7tm1a(EUCOMM)Wtsi was generated as part of the International Knockout Mouse Consortium program—a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty five tests were carried out on mutant mice and one significant abnormality was observed: homozygous mutant males showed a decreased response to stress-induced hyperthermia.
# Interactions
SOCS7 has been shown to interact with NCK1. | SOCS7
Suppressor of cytokine signaling 7 is a protein that in humans is encoded by the SOCS7 gene.[1][2][3]
# Model organisms
Model organisms have been used in the study of SOCS7 function. A conditional knockout mouse line, called Socs7tm1a(EUCOMM)Wtsi[9][10] was generated as part of the International Knockout Mouse Consortium program—a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[11][12][13]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[7][14] Twenty five tests were carried out on mutant mice and one significant abnormality was observed: homozygous mutant males showed a decreased response to stress-induced hyperthermia.[7]
# Interactions
SOCS7 has been shown to interact with NCK1.[1] | https://www.wikidoc.org/index.php/SOCS7 | |
bf8d62277a88266b11d13a7622eadb8aa7855fc0 | wikidoc | SOGA2 | SOGA2
SOGA2, also known as Suppressor of glucose autophagy associated 2 or CCDC165, is a protein that in humans is encoded by the SOGA2 gene.
SOGA2 has two human paralogs, SOGA1 and SOGA3.
In humans, the gene coding sequence is 151,349 base pairs long, with an mRNA of 6092 base pairs, and a protein sequence of 1586 amino acids. The SOGA2 gene is conserved in gorilla, baboon, galago, rat, mouse, cat, and more. There is distant conservation seen in organisms such as zebra finches and anoles.
SOGA2 is ubiquitously expressed in humans, with especially high expression in brain (especially the cerebellum and hippocampus), colon, pituitary gland, small intestine, spinal cord, testis and fetal brain.
# Gene
## Locus
The SOGA2 gene is located from 8717369 - 8832775 on the short arm of chromosome 18 (18p11.22).
# Homology and Evolution
## Paralogs
There are two main paralogs to SOGA2: human protein SOGA1 and human protein SOGA3. SOGA1 has been shown to be involved in suppression of glucose by autophagy. The rate at which orthologs diverge from SOGA2 human(measured by % identity) places the approximate duplication event of SOGA1 from SOGA2 at ~254.1 MYA and the duplication event of SOGA3 from SOGA2 ~329.1 MYA.
## Orthologs
Many orthologs have been identified in Eukaryotes.
## Distant Homologs
## Homologous Domains
SOGA2 is conserved farthest back in its N-terminal region, where it contains its three domains of unknown function.
# Protein
## Protein internal composition
SOGA2 is rich in glycine (ratio r of SOGA2 composition to average human protein is 1.723), glutamate (r = 1.647), and arganine
(r = 1.357). It also has a lower than usual composition of tyrosine (r = 0.3406), isoleucine (r = 0.4430),
phenylalanine (r = 0.5808), and valine (r = 0.6161).
## Primary structure and isoforms
SOGA2 has 4 isoforms: Q9Y4B5-1, Q9Y4B5-2, Q9Y4B5-3, Q9Y4B5-4.
## Domains and motifs
SOGA2 contains Domain of Unknown Function 4201 (DUF4201) from aa 16-235. This domain is specific to the Coiled Coil Domain Containing family of proteins in eukaryotes. It also contains two copies of Domain of Unknown Function 3166 (DUF3166): one from aa 140-235 and one from aa 269-364.
## Post-translational modifications
SOGA2 is expected to undergo a number of post-translational modifications. Modifications of human SOGA2 that are shared by orthologs include:
- Sumoylation at amino acids 87, 152, 235, 392, and 1379.
- Sulfination at tyrosines 14 and 1249.
- Phosphorylation at a number of sites, highlighted in the following graphic:
## Secondary structure
The consensus of the prediction software PELE, GOR4, and SOSUICoil is that the secondary structure of SOGA2 is dominated by alpha helices with interspersed regions of random coil. GOR4 indicated that SOGA2 is dominated by alpha-helices; it predicted a mere 5.61% of
residues in an extended strand (parallel or antiparallel Beta-sheet) conformation, as opposed to
47.79% alpha helix and 46.6% random coils.
## Tertiary structure
SOGA2 shares sequence features in its highly conserved N-terminal region. This homology allows prediction of its tertiary structure on the basis of homology to published 3d structures via Phyre2 and NCBI structure.
# Gene expression
## Promoter
The promoter for human SOGA2 is below.
## Gene expression data
The EST profile shows that, in humans, SOGA2 is highly expressed in many sites throughout the body, including bone, brain, ear, eye, and many others. There are a large number of transcripts in liver cancer samples. Human microarray data show that SOGA2 is moderately expressed, with especially high expression in brain (especially the cerebellum and hippocampus), colon, pituitary gland, small intestine, spinal cord, testis and fetal brain. Brain-tissue-specific microarray data show that SOGA2 has high expression throughout the posterior lobe of the cerebellar hemispheres and posterial lobe of the vermis in the mouse brain. There is low expression in most other areas of the brain.
## Transcript variants
In humans, the SOGA2 gene produces 17 different transcripts, 8 of which form a protein product (one undergoes nonsense mediated decay). The main transcript in humans is transcript ID ENST00000359865, or SOGA2-001.
# Function
## Possible transcription factors
Possible transcription factors for human SOGA2 include:
- Modulator recognition factor 2
- cAMP-responsive element binding protein 1
- alternative splicing variant of FOXP1
- MDS1/EVI1-like gene 1
- Ikaros 2, possible regulator of lymphocyte differentiation
## Interactions
Protein complex co-immunoprecipitation (Co-IP) experiments revealed interacting proteins such as cell death regulators, ATP-binding cassette (ABC) transporters and protein kinase A binding proteins.
The 540 interacting proteins include ABCF1, ACTB, ACTL6A, BCLAF1, BCLAF1, CHEK1, and MAGEE2.
K-nearest neighbor analysis by wolf pSort indicates that in humans, SOGA2 is focused mainly in the nucleus, cytoplasm, and the cytonuclear
space. There is a small chance that it is localizes to the golgi.
A number of protein interactants were also identified via the STRING database, including MARK2, MARK4, and PPP2R2B.
# Clinical significance
SOGA2 has no currently known disease associations or mutations. | SOGA2
SOGA2, also known as Suppressor of glucose autophagy associated 2 or CCDC165, is a protein that in humans is encoded by the SOGA2 gene.[1][2]
SOGA2 has two human paralogs, SOGA1 and SOGA3.[3][4]
In humans, the gene coding sequence is 151,349 base pairs long, with an mRNA of 6092 base pairs, and a protein sequence of 1586 amino acids. The SOGA2 gene is conserved in gorilla, baboon, galago, rat, mouse, cat, and more. There is distant conservation seen in organisms such as zebra finches and anoles.[5]
SOGA2 is ubiquitously expressed in humans, with especially high expression in brain (especially the cerebellum and hippocampus), colon, pituitary gland, small intestine, spinal cord, testis and fetal brain.[6]
# Gene
## Locus
The SOGA2 gene is located from 8717369 - 8832775 on the short arm of chromosome 18 (18p11.22).[7]
# Homology and Evolution
## Paralogs
There are two main paralogs to SOGA2: human protein SOGA1 and human protein SOGA3.[5] SOGA1 has been shown to be involved in suppression of glucose by autophagy.[8] The rate at which orthologs diverge from SOGA2 human(measured by % identity) places the approximate duplication event of SOGA1 from SOGA2 at ~254.1 MYA and the duplication event of SOGA3 from SOGA2 ~329.1 MYA.
## Orthologs
Many orthologs have been identified in Eukaryotes.[5]
## Distant Homologs
## Homologous Domains
SOGA2 is conserved farthest back in its N-terminal region, where it contains its three domains of unknown function.[9]
# Protein
## Protein internal composition
SOGA2 is rich in glycine (ratio r of SOGA2 composition to average human protein is 1.723), glutamate (r = 1.647), and arganine
(r = 1.357). It also has a lower than usual composition of tyrosine (r = 0.3406), isoleucine (r = 0.4430),
phenylalanine (r = 0.5808), and valine (r = 0.6161).[10][11]
## Primary structure and isoforms
SOGA2 has 4 isoforms: Q9Y4B5-1, Q9Y4B5-2, Q9Y4B5-3, Q9Y4B5-4.[12]
## Domains and motifs
SOGA2 contains Domain of Unknown Function 4201 (DUF4201) from aa 16-235. This domain is specific to the Coiled Coil Domain Containing family of proteins in eukaryotes.[13] It also contains two copies of Domain of Unknown Function 3166 (DUF3166): one from aa 140-235 and one from aa 269-364.[7]
## Post-translational modifications
SOGA2 is expected to undergo a number of post-translational modifications. Modifications of human SOGA2 that are shared by orthologs include:
- Sumoylation at amino acids 87, 152, 235, 392, and 1379.[14]
- Sulfination at tyrosines 14 and 1249.[15]
- Phosphorylation at a number of sites, highlighted in the following graphic:
## Secondary structure
The consensus of the prediction software PELE,[17] GOR4,[18] and SOSUICoil is that the secondary structure of SOGA2 is dominated by alpha helices with interspersed regions of random coil. GOR4 indicated that SOGA2 is dominated by alpha-helices; it predicted a mere 5.61% of
residues in an extended strand (parallel or antiparallel Beta-sheet) conformation, as opposed to
47.79% alpha helix and 46.6% random coils.
[19]
## Tertiary structure
SOGA2 shares sequence features in its highly conserved N-terminal region. This homology allows prediction of its tertiary structure on the basis of homology to published 3d structures via Phyre2[20] and NCBI structure.[21]
# Gene expression
## Promoter
The promoter for human SOGA2 is below.
## Gene expression data
The EST profile shows that, in humans, SOGA2 is highly expressed in many sites throughout the body, including bone, brain, ear, eye, and many others.[22] There are a large number of transcripts in liver cancer samples. Human microarray data show that SOGA2 is moderately expressed, with especially high expression in brain (especially the cerebellum and hippocampus), colon, pituitary gland, small intestine, spinal cord, testis and fetal brain.[6] Brain-tissue-specific microarray data show that SOGA2 has high expression throughout the posterior lobe of the cerebellar hemispheres and posterial lobe of the vermis in the mouse brain. There is low expression in most other areas of the brain.[23]
## Transcript variants
In humans, the SOGA2 gene produces 17 different transcripts, 8 of which form a protein product (one undergoes nonsense mediated decay). The main transcript in humans is transcript ID ENST00000359865, or SOGA2-001.[24]
# Function
## Possible transcription factors
Possible transcription factors for human SOGA2 include:[25]
- Modulator recognition factor 2
- cAMP-responsive element binding protein 1
- alternative splicing variant of FOXP1
- MDS1/EVI1-like gene 1
- Ikaros 2, possible regulator of lymphocyte differentiation
## Interactions
Protein complex co-immunoprecipitation (Co-IP) experiments revealed interacting proteins such as cell death regulators, ATP-binding cassette (ABC) transporters and protein kinase A binding proteins.[26]
The 540 interacting proteins include ABCF1, ACTB, ACTL6A, BCLAF1, BCLAF1, CHEK1, and MAGEE2.[26]
K-nearest neighbor analysis by wolf pSort indicates that in humans, SOGA2 is focused mainly in the nucleus, cytoplasm, and the cytonuclear
space. There is a small chance that it is localizes to the golgi.[27]
A number of protein interactants were also identified via the STRING database, including MARK2, MARK4, and PPP2R2B.
# Clinical significance
SOGA2 has no currently known disease associations or mutations. | https://www.wikidoc.org/index.php/SOGA2 | |
bdbefb55d2230344dd3991ad43cd7e7f03429ad8 | wikidoc | SORL1 | SORL1
Sortilin-related receptor, L(DLR class) A repeats containing is a protein that in humans is encoded by the SORL1 gene.
SORL1 (also known as SORLA, SORLA1, or LR11) is a neuronal apolipoprotein E receptor, the gene for which is predominantly expressed in the central nervous system.
# Clinical significance
Mutation of the gene for apolipoprotein E (APOE) is predictive of Alzheimer's disease. Lack of the APOE receptor is suspected to be a contributory factor to Alzheimer's: a significant reduction in SORL1 (LR11) expression has been found in brain tissue of Alzheimer's disease patients. The APOE receptor has also been linked with regulation of amyloid precursor protein, faulty processing of which is implicated in Alzheimer's. A more recent study by a group of international researchers supports the proposition that SORL1 plays a part in seniors developing Alzheimer's disease, the findings being significant across racial and ethnic strata. | SORL1
Sortilin-related receptor, L(DLR class) A repeats containing is a protein that in humans is encoded by the SORL1 gene.[1]
SORL1 (also known as SORLA, SORLA1, or LR11) is a neuronal apolipoprotein E receptor, the gene for which is predominantly expressed in the central nervous system.[2]
# Clinical significance
Mutation of the gene for apolipoprotein E (APOE) is predictive of Alzheimer's disease.[3] Lack of the APOE receptor is suspected to be a contributory factor to Alzheimer's: a significant reduction in SORL1 (LR11) expression has been found in brain tissue of Alzheimer's disease patients.[4] The APOE receptor has also been linked with regulation of amyloid precursor protein, faulty processing of which is implicated in Alzheimer's.[5] A more recent study by a group of international researchers [6] supports the proposition that SORL1 plays a part in seniors developing Alzheimer's disease, the findings being significant across racial and ethnic strata.[7] | https://www.wikidoc.org/index.php/SORL1 | |
6cb80e22ea06f2b6de74539280bd235dd8ac61d4 | wikidoc | SOX10 | SOX10
Transcription factor SOX-10 is a protein that in humans is encoded by the SOX10 gene.
# Function
This gene encodes a member of the SOX (SRY-related HMG-box) family of transcription factors involved in the regulation of embryonic development and determination of cell fate. The encoded protein act as a transcriptional activator after forming a protein complex with other proteins. This protein acts as a nucleocytoplasmic shuttle protein and is important for neural crest and peripheral nervous system development.
In melanocytic cells there is evidence that SOX10 gene expression may be regulated by MITF.
# Clinical significance
Mutations in this gene are associated with Waardenburg-Shah, Waardenburg-Hirschsprung disease, and with uveal melanoma .
# Interactions
The interaction between SOX10 and PAX3 is studied best in human patients with Waardenburg syndrome, an autosomal dominant disorder which is divided into four different types based upon mutations in additional genes. SOX10 and PAX3 interactions are thought to be regulators of other genes involved in the symptoms of Waardenburg syndrome, particularly MITF which influences the development of melanocytes as well as neural crest formation. MITF expression can be transactivated by both SOX10 and PAX3 to have an additive effect. The two genes have binding sites near one another on the upstream enhancer of the c-RET gene.
SOX10 is also thought to target dopachrome tautomerase through a synergistic interaction with MITF which then results in other melanocyte alteration.
SOX10 can influence the generation of myelin protein transcription through its interactions proteins such as OLIG1 and EGR2, which is important for the functionality of neurons. Other cofactors have been identified, such as SP1, OCT6, NMI, FOXD3 and SOX2
The interaction between SOX10 and NMI seems to be coexpressed in glial cells, gliomas, and the spinal cord and has been shown to modulate the transcriptional activity of SOX10. | SOX10
Transcription factor SOX-10 is a protein that in humans is encoded by the SOX10 gene.[1][2][3][4]
# Function
This gene encodes a member of the SOX (SRY-related HMG-box) family of transcription factors involved in the regulation of embryonic development and determination of cell fate. The encoded protein act as a transcriptional activator after forming a protein complex with other proteins. This protein acts as a nucleocytoplasmic shuttle protein and is important for neural crest and peripheral nervous system development.[4]
In melanocytic cells there is evidence that SOX10 gene expression may be regulated by MITF.[5]
# Clinical significance
Mutations in this gene are associated with Waardenburg-Shah, Waardenburg-Hirschsprung disease,[4] and with uveal melanoma .[6]
# Interactions
The interaction between SOX10 and PAX3 is studied best in human patients with Waardenburg syndrome, an autosomal dominant disorder which is divided into four different types based upon mutations in additional genes. SOX10 and PAX3 interactions are thought to be regulators of other genes involved in the symptoms of Waardenburg syndrome, particularly MITF which influences the development of melanocytes as well as neural crest formation. MITF expression can be transactivated by both SOX10 and PAX3 to have an additive effect.[7][8] The two genes have binding sites near one another on the upstream enhancer of the c-RET gene.[9]
SOX10 is also thought to target dopachrome tautomerase through a synergistic interaction with MITF which then results in other melanocyte alteration.[10]
SOX10 can influence the generation of myelin protein transcription through its interactions proteins such as OLIG1 and EGR2,[11][12] which is important for the functionality of neurons. Other cofactors have been identified, such as SP1, OCT6, NMI, FOXD3 and SOX2[13]
The interaction between SOX10 and NMI seems to be coexpressed in glial cells, gliomas, and the spinal cord and has been shown to modulate the transcriptional activity of SOX10.[14] | https://www.wikidoc.org/index.php/SOX10 | |
0c022f5ba02ceaaa3d6e57469f702c76ad3a374a | wikidoc | SOX11 | SOX11
Transcription factor SOX-11 is a protein that in humans is encoded by the SOX11 gene.
# Function
This intronless gene encodes a member of the group C SOX (SRY-related HMG-box) transcription factor family involved in the regulation of embryonic development and in the determination of the cell fate. The encoded protein may act as a transcriptional regulator after forming a protein complex with other proteins. The protein may function in the developing nervous system and play a role in tumorigenesis and adult neurogenesis. Tuj1 and Tead2 are suggested as direct target of Sox11.
# Clinical aspect
Mutations in SOX11 are associated to Coffin-Siris syndrome . | SOX11
Transcription factor SOX-11 is a protein that in humans is encoded by the SOX11 gene.[1][2][3]
# Function
This intronless gene encodes a member of the group C SOX (SRY-related HMG-box) transcription factor family involved in the regulation of embryonic development and in the determination of the cell fate. The encoded protein may act as a transcriptional regulator after forming a protein complex with other proteins. The protein may function in the developing nervous system and play a role in tumorigenesis and adult neurogenesis.[3][4] Tuj1 and Tead2 are suggested as direct target of Sox11.[5][6][7]
# Clinical aspect
Mutations in SOX11 are associated to Coffin-Siris syndrome .[8] | https://www.wikidoc.org/index.php/SOX11 | |
4e8b27227de61ba3afbbef05ba272e6df21bed25 | wikidoc | SOX13 | SOX13
Transcription factor SOX-13 is a protein that in humans is encoded by the SOX13 gene.
# Function
This gene encodes a member of the SOX (SRY-related HMG-box) family of transcription factors involved in the regulation of embryonic development and in the determination of cell fate. The encoded protein may act as a transcriptional regulator after forming a protein complex with other proteins. It has also been determined to be a type-1 diabetes autoantigen, also known as islet cell antibody 12.
In melanocytic cells SOX13 gene expression may be regulated by MITF. | SOX13
Transcription factor SOX-13 is a protein that in humans is encoded by the SOX13 gene.[1][2]
# Function
This gene encodes a member of the SOX (SRY-related HMG-box) family of transcription factors involved in the regulation of embryonic development and in the determination of cell fate. The encoded protein may act as a transcriptional regulator after forming a protein complex with other proteins. It has also been determined to be a type-1 diabetes autoantigen, also known as islet cell antibody 12.[2]
In melanocytic cells SOX13 gene expression may be regulated by MITF.[3] | https://www.wikidoc.org/index.php/SOX13 | |
8ad404271e1896f9ad4bd822278ef20639e5068f | wikidoc | SOX21 | SOX21
Transcription factor SOX-21 is a protein that in humans is encoded by the SOX21 gene. It is a member of the Sox gene family of transcription factors.
# Function
In the chick embryo, Sox21 promotes neuronal cellular differentiation by counteracting the activity of Sox1, Sox2, and Sox3, which maintain neural cells in an undifferentiated state.
SOX21 knockout mice display hair loss beginning from postnatal day 11. New hair regrowth was initiated a few days later but was followed by renewed hair loss. Sox21 is also expressed in the hair shaft cuticle in humans and consequently variants of the Sox21 gene could be responsible for some hair loss conditions in humans. | SOX21
Transcription factor SOX-21 is a protein that in humans is encoded by the SOX21 gene.[1][2] It is a member of the Sox gene family of transcription factors.
# Function
In the chick embryo, Sox21 promotes neuronal cellular differentiation by counteracting the activity of Sox1, Sox2, and Sox3, which maintain neural cells in an undifferentiated state.[3]
SOX21 knockout mice display hair loss beginning from postnatal day 11. New hair regrowth was initiated a few days later but was followed by renewed hair loss. Sox21 is also expressed in the hair shaft cuticle in humans and consequently variants of the Sox21 gene could be responsible for some hair loss conditions in humans.[4] | https://www.wikidoc.org/index.php/SOX21 | |
0951adfb5f59d203783d102f612d568681b8eb8e | wikidoc | SPDEF | SPDEF
SAM pointed domain-containing Ets transcription factor is a protein that in humans is encoded by the SPDEF gene.
PDEF is an ETS transcription factor expressed in prostate epithelial cells. It acts as an androgen-independent transactivator of PSA (MIM 176820) expression.
# Interactions
SPDEF has been shown to interact with NKX3-1.
The Protein Kinase CK2 has been shown to control the stability of PDEF.
Needed for the differentiation of both pulmonary and intestinal goblet cells | SPDEF
SAM pointed domain-containing Ets transcription factor is a protein that in humans is encoded by the SPDEF gene.[1][2][3]
PDEF is an ETS transcription factor expressed in prostate epithelial cells. It acts as an androgen-independent transactivator of PSA (MIM 176820) expression.[supplied by OMIM][3]
# Interactions
SPDEF has been shown to interact with NKX3-1.[4]
The Protein Kinase CK2 has been shown to control the stability of PDEF.[5]
Needed for the differentiation of both pulmonary and intestinal goblet cells | https://www.wikidoc.org/index.php/SPDEF | |
dfc75a7e581d35184637f0da221e8fd700904693 | wikidoc | SPG20 | SPG20
Spartin is a protein that in humans is encoded by the SPG20 gene.
This gene encodes a protein that contains a MIT (Microtubule Interacting and Trafficking molecule) domain. This protein may be involved in endosomal trafficking, microtubule dynamics, or both functions. Frameshift mutations associated with this gene cause autosomal recessive spastic paraplegia 20 (Troyer syndrome).
Troyer syndrome (SPG20) is a complicated type of hereditary spastic paraplegias (HSPs). HSP is a category of neurological disorder characterized by spasticity and muscle weakness in the lower limbs.
# Background
The original description of this gene mutation and associated symptoms were described in 1967. This mutation is commonly found in high frequency with the Amish population. Newer studies have found that the mutation is not isolated to the Amish population, but also resides in the Omani population.
# Presentation
This syndrome is not only characterized by spasticity and weakness in the lower limbs, but also with dysarthria, mental retardation or mild developmental delay, and muscle wasting or muscle atrophy.
## Physical
Individuals appear to have difficulty walking, and report a clumsy, spastic gait which worsens over time. Some additional common physical features include overgrowth of the jaw bone, hammer toes, hand and feet abnormalities, and pes cavus.
## Cognitive
Cognitive challenges, including developmental delay and difficulty with performance in school, may affect individuals with this syndrome.
## Neurologic
Neurologic examination of individuals with this mutation may show dysmetria in the upper extremities, hyperreflexia, distal amyotrophy and ankle clonus, in addition to spasticity, weakness and dysarthria.
## Diagnostic Imaging
The cerebellar vermis may present with mild atrophy and a loss of white matter volume.
## Through Lifespan
Facial dysmorphism and subtle skeletal features are common in younger children. The condition progressively worsens, as spasticity and distal amyotrophy symptoms are revealed more in teenage years. SPG20 expression in the adult is relatively modest, however it is widespread in the nervous system. Longitudinal comparison of magnetic resonance imaging concluded that there was a progression of the syndrome; thus, the condition appears to worsen over time. | SPG20
Spartin is a protein that in humans is encoded by the SPG20 gene.[1][2][3]
This gene encodes a protein that contains a MIT (Microtubule Interacting and Trafficking molecule) domain. This protein may be involved in endosomal trafficking, microtubule dynamics, or both functions. Frameshift mutations associated with this gene cause autosomal recessive spastic paraplegia 20 (Troyer syndrome).[3]
Troyer syndrome (SPG20) is a complicated type of hereditary spastic paraplegias (HSPs).[4] HSP is a category of neurological disorder characterized by spasticity and muscle weakness in the lower limbs.[4]
# Background
The original description of this gene mutation and associated symptoms were described in 1967.[5] This mutation is commonly found in high frequency with the Amish population.[2] Newer studies have found that the mutation is not isolated to the Amish population, but also resides in the Omani population.[5]
# Presentation
This syndrome is not only characterized by spasticity and weakness in the lower limbs, but also with dysarthria, mental retardation or mild developmental delay, and muscle wasting or muscle atrophy.[4]
## Physical
Individuals appear to have difficulty walking, and report a clumsy, spastic gait which worsens over time.[5] Some additional common physical features include overgrowth of the jaw bone, hammer toes, hand and feet abnormalities, and pes cavus.[5]
## Cognitive
Cognitive challenges, including developmental delay and difficulty with performance in school, may affect individuals with this syndrome.[5]
## Neurologic
Neurologic examination of individuals with this mutation may show dysmetria in the upper extremities, hyperreflexia, distal amyotrophy and ankle clonus, in addition to spasticity, weakness and dysarthria.[5]
## Diagnostic Imaging
The cerebellar vermis may present with mild atrophy and a loss of white matter volume.[5]
## Through Lifespan
Facial dysmorphism and subtle skeletal features are common in younger children.[5] The condition progressively worsens, as spasticity and distal amyotrophy symptoms are revealed more in teenage years.[5] SPG20 expression in the adult is relatively modest, however it is widespread in the nervous system.[5] Longitudinal comparison of magnetic resonance imaging concluded that there was a progression of the syndrome; thus, the condition appears to worsen over time.[5] | https://www.wikidoc.org/index.php/SPG20 | |
c2d0e51e5aaf7463b0b2e872fc1dff8b9f07d30a | wikidoc | SPNS2 | SPNS2
Spinster homolog 2 (Drosophila) is a protein that in humans is encoded by the SPNS2 gene.
# Model organisms
Model organisms have been used in the study of SPNS2 function. A conditional knockout mouse line, called Spns2tm1a(KOMP)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.
Animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty eight tests were carried out on homozygous mutant mice of both sex and nine significant abnormalities were observed, including an absence of pinna reflex, abnormal eye pigmentation and morphology including cataracts, decreased leukocyte cell number, abnormal brainstem auditory evoked potential, increased bone mineral content and a range of atypical peripheral blood lymphocyte parameters. Males additionally displayed decreased circulating glucose and increased circulating bilirubin levels.
The orthologous protein in zebrafish has been shown to transport sphingosine-1-phosphate (S1P) out of cells during vascular development, and human SPNS2 can transport S1P analogues, including the immunomodulating drug FTY720-P. | SPNS2
Spinster homolog 2 (Drosophila) is a protein that in humans is encoded by the SPNS2 gene.[1]
# Model organisms
Model organisms have been used in the study of SPNS2 function. A conditional knockout mouse line, called Spns2tm1a(KOMP)Wtsi[12][13] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[14][15][16]
Animals underwent a standardized phenotypic screen to determine the effects of deletion.[10][17] Twenty eight tests were carried out on homozygous mutant mice of both sex and nine significant abnormalities were observed, including an absence of pinna reflex, abnormal eye pigmentation and morphology including cataracts, decreased leukocyte cell number, abnormal brainstem auditory evoked potential, increased bone mineral content and a range of atypical peripheral blood lymphocyte parameters.[10] Males additionally displayed decreased circulating glucose and increased circulating bilirubin levels.[10]
The orthologous protein in zebrafish has been shown to transport sphingosine-1-phosphate (S1P) out of cells during vascular development, and human SPNS2 can transport S1P analogues, including the immunomodulating drug FTY720-P.[18][19] | https://www.wikidoc.org/index.php/SPNS2 | |
25147d74351ddfe1de4e6fe54d5f6c34b3dc4ecb | wikidoc | SPRY2 | SPRY2
Sprouty homolog 2 (Drosophila), also known as SPRY2, is a protein which in humans is encoded by the SPRY2 gene.
# Function
This gene encodes a protein belonging to the sprouty family. The encoded protein contains a carboxyl-terminal cysteine-rich domain essential for the inhibitory activity on receptor tyrosine kinase signaling proteins and is required for growth factor stimulated translocation of the protein to membrane ruffles. In primary dermal endothelial cells this gene is transiently upregulated in response to fibroblast growth factor two. This protein is indirectly involved in the non-cell autonomous inhibitory effect on fibroblast growth factor two signaling. The protein interacts with Cas-Br-M (murine) ectropic retroviral transforming sequence, and can function as a bimodal regulator of epidermal growth factor receptor/mitogen-activated protein kinase signaling. This protein may play a role in alveoli branching during lung development as shown by a similar mouse protein.
SPRY2 is a negative feedback regulator of multiple receptor tyrosine kinases (RTK's) including receptors for fibroblast growth factor (FGF), epidermal growth factor (EGF), and hepatocyte growth factor (HGF). Antagonization of growth factor mediated pathways, cell migration, and cellular differentiation occurs through the ERK pathway. Spry2 can also enhance EGFR signaling by sequestering CBL. Spry gene expression has been reported silenced or repressed in cancer of the breast, liver, lung, prostate, and in lymphoma. Human spry2 expression is localized to the microtubules in unstimulated cells. All sprouty isoforms inhibit the ERK pathway by themselves, but can also form heterodimers and homodimers which have enhanced inhibition.
# Interactions
SPRY2 has been shown to interact with Cbl gene. | SPRY2
Sprouty homolog 2 (Drosophila), also known as SPRY2, is a protein which in humans is encoded by the SPRY2 gene.[1]
# Function
This gene encodes a protein belonging to the sprouty family. The encoded protein contains a carboxyl-terminal cysteine-rich domain essential for the inhibitory activity on receptor tyrosine kinase signaling proteins and is required for growth factor stimulated translocation of the protein to membrane ruffles. In primary dermal endothelial cells this gene is transiently upregulated in response to fibroblast growth factor two. This protein is indirectly involved in the non-cell autonomous inhibitory effect on fibroblast growth factor two signaling. The protein interacts with Cas-Br-M (murine) ectropic retroviral transforming sequence, and can function as a bimodal regulator of epidermal growth factor receptor/mitogen-activated protein kinase signaling. This protein may play a role in alveoli branching during lung development as shown by a similar mouse protein.[2]
SPRY2 is a negative feedback regulator of multiple receptor tyrosine kinases (RTK's) including receptors for fibroblast growth factor (FGF),[1] epidermal growth factor (EGF),[3] and hepatocyte growth factor (HGF).[4] Antagonization of growth factor mediated pathways, cell migration, and cellular differentiation occurs through the ERK pathway.[3] Spry2 can also enhance EGFR signaling by sequestering CBL. Spry gene expression has been reported silenced or repressed in cancer of the breast, liver, lung, prostate,[3] and in lymphoma.[5] Human spry2 expression is localized to the microtubules in unstimulated cells.[6] All sprouty isoforms inhibit the ERK pathway by themselves, but can also form heterodimers and homodimers which have enhanced inhibition.[6]
# Interactions
SPRY2 has been shown to interact with Cbl gene.[7][8][9] | https://www.wikidoc.org/index.php/SPRY2 | |
b789265cdb12c9c0c2a1689bd34c283a77a46718 | wikidoc | SRPK1 | SRPK1
Serine/threonine-protein kinase SRPK1 is an enzyme that in humans is encoded by the SRPK1 gene.
# Function
This gene encodes a serine/arginine protein kinase specific for the SR (serine/arginine-rich domain) family of splicing factors. The protein localizes to the nucleus and the cytoplasm. It is thought to play a role in regulation of both constitutive and alternative splicing by regulating intracellular localization of splicing factors. A second alternatively spliced transcript variant for this gene has been described, but its full length nature has not been determined.
SRPK1 enables angiogenesis, which is regulated by VEGF, which either initiates or inhibits vessel formation depending on alternative splicing.
# Medical applications
Some cancers are vascular endothelial growth factor (VEGF) dependant (for angiogenesis). SRPK1 activates (phosphorylates) VEGF splicing factor. SRPK1 inhibitors (e.g. 'SPHINX compounds' ) are under investigation as treatments for prostate cancer, acute myeloid leukemia and neovascular eye disease.
# Interactions
SRPK1 has been shown to interact with:
- ASF/SF2 and
- SNRP70.
- C6orf201 | SRPK1
Serine/threonine-protein kinase SRPK1 is an enzyme that in humans is encoded by the SRPK1 gene.[1][2][3]
# Function
This gene encodes a serine/arginine protein kinase specific for the SR (serine/arginine-rich domain) family of splicing factors. The protein localizes to the nucleus and the cytoplasm. It is thought to play a role in regulation of both constitutive and alternative splicing by regulating intracellular localization of splicing factors. A second alternatively spliced transcript variant for this gene has been described, but its full length nature has not been determined.[3]
SRPK1 enables angiogenesis, which is regulated by VEGF, which either initiates or inhibits vessel formation depending on alternative splicing.
# Medical applications
Some cancers are vascular endothelial growth factor (VEGF) dependant (for angiogenesis). SRPK1 activates (phosphorylates) VEGF splicing factor. SRPK1 inhibitors (e.g. 'SPHINX compounds' [4]) are under investigation as treatments for prostate cancer, acute myeloid leukemia and neovascular eye disease.[5][6][7][8]
# Interactions
SRPK1 has been shown to interact with:
- ASF/SF2[9][10][11][12] and
- SNRP70.[9][13]
- C6orf201 [14] | https://www.wikidoc.org/index.php/SRPK1 | |
75a11b95eed634ec290a5f7f2e3ab9cc3ca4a960 | wikidoc | STAG2 | STAG2
Cohesin subunit SA-2 is a protein that in humans is encoded by the STAG2 gene.
# Function
STAG2 is part of the cohesin complex, which is a structure that holds the sister chromatids together after DNA replication. STAG2 has been shown to interact with STAG1.
# Role in Disease
Of the cohesin complex, STAG2 is the subunit where the most variants have been reported in cancer. This is thought to be because this gene is located in the X chromosome, therefore only one mutation is needed to inactivate it. | STAG2
Cohesin subunit SA-2 is a protein that in humans is encoded by the STAG2 gene.[1][2]
# Function
STAG2 is part of the cohesin complex, which is a structure that holds the sister chromatids together after DNA replication.[3] STAG2 has been shown to interact with STAG1.[4]
# Role in Disease
Of the cohesin complex, STAG2 is the subunit where the most variants have been reported in cancer. [5] This is thought to be because this gene is located in the X chromosome, therefore only one mutation is needed to inactivate it.[6] | https://www.wikidoc.org/index.php/STAG2 | |
0efa7bd4613810f17be9d64b0f7ec1f06cb016c7 | wikidoc | STAM2 | STAM2
Signal transducing adapter molecule 2 is a protein that in humans is encoded by the STAM2 gene.
# Function
The protein encoded by this gene is closely related to STAM, an adaptor protein involved in the downstream signaling of cytokine receptors, both of which contain a SH3 domain and the immunoreceptor tyrosine-based activation motif (ITAM). Similar to STAM, this protein acts downstream of JAK kinases, and is phosphorylated in response to cytokine stimulation. This protein and STAM thus are thought to exhibit compensatory effects on the signaling pathway downstream of JAK kinases upon cytokine stimulation.
# Interactions
STAM2 has been shown to interact with HGS, Janus kinase 1 and USP8. | STAM2
Signal transducing adapter molecule 2 is a protein that in humans is encoded by the STAM2 gene.[1][2][3]
# Function
The protein encoded by this gene is closely related to STAM, an adaptor protein involved in the downstream signaling of cytokine receptors, both of which contain a SH3 domain and the immunoreceptor tyrosine-based activation motif (ITAM). Similar to STAM, this protein acts downstream of JAK kinases, and is phosphorylated in response to cytokine stimulation. This protein and STAM thus are thought to exhibit compensatory effects on the signaling pathway downstream of JAK kinases upon cytokine stimulation.[3]
# Interactions
STAM2 has been shown to interact with HGS,[4][5] Janus kinase 1[1][2] and USP8.[6][7] | https://www.wikidoc.org/index.php/STAM2 | |
15ddd42e8aadffd3e01d79940a16cc524d996bbf | wikidoc | STAT1 | STAT1
Signal transducer and activator of transcription 1 (STAT1) is a transcription factor which in humans is encoded by the STAT1 gene. It is a member of the STAT protein family.
# Function
All STAT molecules are phosphorylated by receptor associated kinases, that causes activation, dimerization by forming homo- or heterodimers and finally translocate to nucleus to work as transcription factors. Specifically STAT1 can be activated by several ligands such as Interferon alpha (IFNa), Interferon gamma (IFNg), Epidermal Growth Factor (EGF), Platelet Derived Growth Factor (PDGF) or Interleukin 6 (IL-6)
Type I interferons (IFN-a, IFN-b) bind to receptors, cause signaling via kinases, phosphorylate and activate the Jak kinases TYK2 and JAK1 and also STAT1 and STAT2. STAT molecules form dimers and bind to ISGF3G/IRF-9, which is Interferon stimulated gene factor 3 complex with Interferon regulatory Factor 9. This allows STAT1 to enter the nucleus. STAT1 has a key role in many gene expressions that cause survival of the cell, viability or pathogen response. There are two possible transcripts (due to alternative splicing) that encode 2 isoforms of STAT1
STAT1 is involved in upregulating genes due to a signal by either type I, type II, or type III interferons. In response to IFN-γ stimulation, STAT1 forms homodimers or heterodimers with STAT3 that bind to the GAS (Interferon-Gamma-Activated Sequence) promoter element; in response to either IFN-α or IFN-β stimulation, STAT1 forms a heterodimer with STAT2 that can bind the ISRE (Interferon-Stimulated Response Element) promoter element. In either case, binding of the promoter element leads to an increased expression of ISG (Interferon-Stimulated Genes).
Expression of STAT1 can be induced with diallyl disulfide, a compound in garlic.
## Mutations of STAT1
Mutations in the STAT1 molecule can be gain of function (GOF) or loss of function (LOF). Both of them can cause different phenotypes and symptoms. Repeting common infections are frequent by both GOF and LOF mutations.
### Loss of function
STAT1 loss of function, therefore STAT1 deficiency can have many variants. There are two main genetic impairments that can cause response to interferons type I and III. First there can be autosomal recessive partial or even complete deficiency of STAT1. That causes intracellular bacterial diseases or viral infections and impaired IFN a, b, g and IL27 responses are diagnosed. In partial form there can also be found high levels of IFNg in blood serum. When tested from whole blood, monocytes do not respond to BCG and IFNg doses with IL-12 production. In complete recessive form there is a very low response to anti-viral and antimycotical medication Second, partial STAT1 deficiency can also be autosomal dominant mutation; phenotypically causes impaired IFNg responses and patients suffer with selective intracellular bacterial diseases (MSMD)
In knock-out mice prepared in the 90s, there was discovered low amount of CD4+ and CD25+ regulatory T-cells and almost no IFNa, b and g response, which lead to parasital, viral and bacterial infections. The very first reported case of STAT1 deficiency in human was autosomal dominant mutation and patients were showing propensity to mycobacterial infections. Another case reported was about autosomal recessive form. 2 related patients had a homozygous missense STAT1 mutation which caused impaired splicing, therefore a defect in mature protein. Patients had partially damaged response to both IFNa and IFNg. Scientists now claim that recessive STAT1 deficiency is a new form of primary immunodeficiency and whenever a patient suffers sudden, severe and not expected bacterial and viral infections, should be considered as potentially STAT1 deficient
### Gain of function
Gain of function mutation was first discovered in patients with chronic mucocutaneous candidiasis (CMC). This disease is characteristic with its symptoms as persistent infections of the skin, mucosae - oral or genital and nails infections caused by Candida, mostly Candida albicans. CMC may very often result from primary immunodeficiency. Patients with CMC often suffer also with bacterial infections (mostly Staphylococcus aureus), also with infections of the respiratory system and skin. In these patients we can also find viral infections caused mostly by Herpesviridae, that also affect the skin. The mycobacterial infections are often caused by Mycobacterium tuberculosis or environmental bacteria. Very common are also autoimmune symptoms like type 1 diabetes, cytopenia, regression of the thymus or systemic lupus erythematosus. When T-cell deficient, these autoimmune díseases are very common. CMC was also reported as a common symptom in patients with hyper immunoglobulin E syndrome (hyper-IgE) and with autoimmune polyendocrine syndrome type I. There was reported an interleukin 17A role, because of low levels of IL-17A producing T-cells in CMC patients.
With various genomic and genetic methods was discovered, that a heterozygous gain of function mutation of STAT1 is a cause of more than a half CMC cases. This mutation is caused by defect in the coiled-coil domain, domain that binds DNA, N-terminal domain or SH2 domain. Because of this there is increased phosphorylation because of impossible dephosphorylation in nucleus. These processes are dependent on cytokines like interferon alpha or beta, interferon gamma or interleukin 27. As mentioned above, low levels of interleukin 17A were observed, therefore impaired the Th17 polarization of the immune response.
Patients with STAT1 gain of function mutation and CMC poorly or not at all respond to treatment with azole drugs such as Fluconazole, Itraconazole or Posaconazole. Besides common viral and bacterial infections, these patients develop autoimmunities or even carcinomas. It is very complicated to find a treatment because of various symptoms and resistancies, inhibitors of JAK/STAT pathway such as Ruxolitinib are being tested and are a possible choice of treatment for these patients
# Interactions
STAT1 has been shown to interact with:
- BRCA1,
- C-jun,
- CD117,
- CREB-binding protein,
- Calcitriol receptor,
- Epidermal growth factor receptor,
- Fanconi anemia, complementation group C,
- GNB2L1,
- IFNAR2,
- IRF1,
- ISGF3G
- Interleukin 27 receptor, alpha subunit,
- MCM5,
- Mammalian target of rapamycin,
- PIAS1,
- PRKCD,
- PTK2,
- Protein kinase R,
- STAT2,
- STAT3,
- Src, and
- TRADD. | STAT1
Signal transducer and activator of transcription 1 (STAT1) is a transcription factor which in humans is encoded by the STAT1 gene. It is a member of the STAT protein family.
# Function
All STAT molecules are phosphorylated by receptor associated kinases, that causes activation, dimerization by forming homo- or heterodimers and finally translocate to nucleus to work as transcription factors. Specifically STAT1 can be activated by several ligands such as Interferon alpha (IFNa), Interferon gamma (IFNg), Epidermal Growth Factor (EGF), Platelet Derived Growth Factor (PDGF) or Interleukin 6 (IL-6)[1]
Type I interferons (IFN-a, IFN-b) bind to receptors, cause signaling via kinases, phosphorylate and activate the Jak kinases TYK2 and JAK1 and also STAT1 and STAT2. STAT molecules form dimers and bind to ISGF3G/IRF-9, which is Interferon stimulated gene factor 3 complex with Interferon regulatory Factor 9. This allows STAT1 to enter the nucleus.[2] STAT1 has a key role in many gene expressions that cause survival of the cell, viability or pathogen response. There are two possible transcripts (due to alternative splicing) that encode 2 isoforms of STAT1[3][4]
STAT1 is involved in upregulating genes due to a signal by either type I, type II, or type III interferons. In response to IFN-γ stimulation, STAT1 forms homodimers or heterodimers with STAT3 that bind to the GAS (Interferon-Gamma-Activated Sequence) promoter element; in response to either IFN-α or IFN-β stimulation, STAT1 forms a heterodimer with STAT2 that can bind the ISRE (Interferon-Stimulated Response Element) promoter element.[5] In either case, binding of the promoter element leads to an increased expression of ISG (Interferon-Stimulated Genes).
Expression of STAT1 can be induced with diallyl disulfide, a compound in garlic.[6]
## Mutations of STAT1
Mutations in the STAT1 molecule can be gain of function (GOF) or loss of function (LOF). Both of them can cause different phenotypes and symptoms. Repeting common infections are frequent by both GOF and LOF mutations.
### Loss of function
STAT1 loss of function, therefore STAT1 deficiency can have many variants. There are two main genetic impairments that can cause response to interferons type I and III. First there can be autosomal recessive partial or even complete deficiency of STAT1. That causes intracellular bacterial diseases or viral infections and impaired IFN a, b, g and IL27 responses are diagnosed. In partial form there can also be found high levels of IFNg in blood serum. When tested from whole blood, monocytes do not respond to BCG and IFNg doses with IL-12 production. In complete recessive form there is a very low response to anti-viral and antimycotical medication Second, partial STAT1 deficiency can also be autosomal dominant mutation; phenotypically causes impaired IFNg responses and patients suffer with selective intracellular bacterial diseases (MSMD)[7]
In knock-out mice prepared in the 90s, there was discovered low amount of CD4+ and CD25+ regulatory T-cells and almost no IFNa, b and g response, which lead to parasital, viral and bacterial infections. The very first reported case of STAT1 deficiency in human was autosomal dominant mutation and patients were showing propensity to mycobacterial infections.[3] Another case reported was about autosomal recessive form. 2 related patients had a homozygous missense STAT1 mutation which caused impaired splicing, therefore a defect in mature protein. Patients had partially damaged response to both IFNa and IFNg. Scientists now claim that recessive STAT1 deficiency is a new form of primary immunodeficiency and whenever a patient suffers sudden, severe and not expected bacterial and viral infections, should be considered as potentially STAT1 deficient[8][9]
### Gain of function
Gain of function mutation was first discovered in patients with chronic mucocutaneous candidiasis (CMC). This disease is characteristic with its symptoms as persistent infections of the skin, mucosae - oral or genital and nails infections caused by Candida, mostly Candida albicans. CMC may very often result from primary immunodeficiency. Patients with CMC often suffer also with bacterial infections (mostly Staphylococcus aureus), also with infections of the respiratory system and skin. In these patients we can also find viral infections caused mostly by Herpesviridae, that also affect the skin. The mycobacterial infections are often caused by Mycobacterium tuberculosis or environmental bacteria. Very common are also autoimmune symptoms like type 1 diabetes, cytopenia, regression of the thymus or systemic lupus erythematosus. When T-cell deficient, these autoimmune díseases are very common. CMC was also reported as a common symptom in patients with hyper immunoglobulin E syndrome (hyper-IgE) and with autoimmune polyendocrine syndrome type I. There was reported an interleukin 17A role, because of low levels of IL-17A producing T-cells in CMC patients.
With various genomic and genetic methods was discovered, that a heterozygous gain of function mutation of STAT1 is a cause of more than a half CMC cases. This mutation is caused by defect in the coiled-coil domain, domain that binds DNA, N-terminal domain or SH2 domain. Because of this there is increased phosphorylation because of impossible dephosphorylation in nucleus. These processes are dependent on cytokines like interferon alpha or beta, interferon gamma or interleukin 27. As mentioned above, low levels of interleukin 17A were observed, therefore impaired the Th17 polarization of the immune response.
Patients with STAT1 gain of function mutation and CMC poorly or not at all respond to treatment with azole drugs such as Fluconazole, Itraconazole or Posaconazole. Besides common viral and bacterial infections, these patients develop autoimmunities or even carcinomas. It is very complicated to find a treatment because of various symptoms and resistancies, inhibitors of JAK/STAT pathway such as Ruxolitinib are being tested and are a possible choice of treatment for these patients[10][1][11]
# Interactions
STAT1 has been shown to interact with:
- BRCA1,[12]
- C-jun,[13]
- CD117,[14]
- CREB-binding protein,[15]
- Calcitriol receptor,[16]
- Epidermal growth factor receptor,[17][18]
- Fanconi anemia, complementation group C,[19][20][21]
- GNB2L1,[22][23]
- IFNAR2,[22][24]
- IRF1,[25]
- ISGF3G[26]
- Interleukin 27 receptor, alpha subunit,[27]
- MCM5,[28][29]
- Mammalian target of rapamycin,[30]
- PIAS1,[31]
- PRKCD,[30]
- PTK2,[32]
- Protein kinase R,[33][34]
- STAT2,[35][36][37]
- STAT3,[18][38][39]
- Src,[17][40] and
- TRADD.[41] | https://www.wikidoc.org/index.php/STAT1 | |
c8b7087959860c81d9b0c6c6286efb2947325dc5 | wikidoc | STAT3 | STAT3
Signal transducer and activator of transcription 3 (STAT3) is a transcription factor which in humans is encoded by the STAT3 gene. It is a member of the STAT protein family.
# Function
STAT3 is a member of the STAT protein family. In response to cytokines and growth factors, STAT3 is phosphorylated by receptor-associated Janus kinases (JAK), form homo- or heterodimers, and translocate to the cell nucleus where they act as transcription activators. Specifically, STAT3 becomes activated after phosphorylation of tyrosine 705 in response to such ligands as interferons, epidermal growth factor (EGF), Interleukin (IL-)5 and IL-6. Additionally, activation of STAT3 may occur via phosphorylation of serine 727 by Mitogen-activated protein kinases (MAPK) and through c-src non-receptor tyrosine kinase. STAT3 mediates the expression of a variety of genes in response to cell stimuli, and thus plays a key role in many cellular processes such as cell growth and apoptosis.
STAT3-deficient mouse embryos cannot develop beyond embryonic day 7, when gastrulation begins. It appears that at these early stages of development, STAT3 activation is required for self-renewal of embryonic stem cells (ESCs). Indeed, LIF, which is supplied to murine ESC cultures to maintain their undifferentiated state, can be omitted if STAT3 is activated through some other means.
STAT3 is essential for the differentiation of the TH17 helper T cells, which have been implicated in a variety of autoimmune diseases. During viral infection, mice lacking STAT3 in T-cells display impairment in the ability to generate T-follicular helper (Tfh) cells and fail to maintain antibody based immunity.
# Clinical significance
Loss-of-function mutations in the STAT3 gene result in Hyperimmunoglobulin E syndrome, associated with recurrent infections as well as disordered bone and tooth development.
Gain-of-function mutations in the STAT3 gene have been reported to cause multi-organ early onset auto-immune diseases; such as thyroid disease, diabetes, intestinal inflammation, and low blood counts, while constitutive STAT3 activation is associated with various human cancers and commonly suggests poor prognosis. It has anti-apoptotic as well as proliferative effects.
STAT3 can promote oncogenesis by being constitutively active through various pathways as mentioned elsewhere. A tumor suppressor role of STAT3 has also been reported. In the report on human glioblastoma tumor, or brain cancer, STAT3 was shown to have an oncogenic or a tumor suppressor role depending upon the mutational background of the tumor. A direct connection between the PTEN-Akt-FOXO axis (suppressive) and the leukemia inhibitory factor receptor beta (LIFRbeta)-STAT3 signaling pathway (oncogenic) was shown.
Increased activity of STAT3 in cancer cells, leads to changes in the function of protein complexes that control expression of inflammatory genes, with result profound change in the secretome and the cell phenotypes, their activity in the tumor, and their capacity for metastasis.
# Interactions
STAT3 has been shown to interact with:
- AR,
- ELP2,
- EP300,
- EGFR,
- HIF1A,
- JAK1,
- JUN
- KHDRBS1,
- mTOR,
- MYOD1,
- NDUFA13,
- NFKB1,
- NR3C1,
- NCOA1,
- PML,
- RAC1,
- RELA,
- RET,
- RPA2,
- STAT1,
- Stathmin,
- Src, and
- TRIP10.
- KPNA4.
Niclosamide seems to inhibit the STAT3 signalling pathway. | STAT3
Signal transducer and activator of transcription 3 (STAT3) is a transcription factor which in humans is encoded by the STAT3 gene.[1] It is a member of the STAT protein family.
# Function
STAT3 is a member of the STAT protein family. In response to cytokines and growth factors, STAT3 is phosphorylated by receptor-associated Janus kinases (JAK), form homo- or heterodimers, and translocate to the cell nucleus where they act as transcription activators. Specifically, STAT3 becomes activated after phosphorylation of tyrosine 705 in response to such ligands as interferons, epidermal growth factor (EGF), Interleukin (IL-)5 and IL-6. Additionally, activation of STAT3 may occur via phosphorylation of serine 727 by Mitogen-activated protein kinases (MAPK)[2] and through c-src non-receptor tyrosine kinase.[3][4] STAT3 mediates the expression of a variety of genes in response to cell stimuli, and thus plays a key role in many cellular processes such as cell growth and apoptosis.[5]
STAT3-deficient mouse embryos cannot develop beyond embryonic day 7, when gastrulation begins.[6] It appears that at these early stages of development, STAT3 activation is required for self-renewal of embryonic stem cells (ESCs). Indeed, LIF, which is supplied to murine ESC cultures to maintain their undifferentiated state, can be omitted if STAT3 is activated through some other means.[7]
STAT3 is essential for the differentiation of the TH17 helper T cells, which have been implicated in a variety of autoimmune diseases.[8] During viral infection, mice lacking STAT3 in T-cells display impairment in the ability to generate T-follicular helper (Tfh) cells and fail to maintain antibody based immunity.[9]
# Clinical significance
Loss-of-function mutations in the STAT3 gene result in Hyperimmunoglobulin E syndrome, associated with recurrent infections as well as disordered bone and tooth development.[10]
Gain-of-function mutations in the STAT3 gene have been reported to cause multi-organ early onset auto-immune diseases; such as thyroid disease, diabetes, intestinal inflammation, and low blood counts,[11] while constitutive STAT3 activation is associated with various human cancers and commonly suggests poor prognosis.[12][13][14][15] It has anti-apoptotic as well as proliferative effects.[12]
STAT3 can promote oncogenesis by being constitutively active through various pathways as mentioned elsewhere. A tumor suppressor role of STAT3 has also been reported.[16][17][18] In the report on human glioblastoma tumor, or brain cancer, STAT3 was shown to have an oncogenic or a tumor suppressor role depending upon the mutational background of the tumor. A direct connection between the PTEN-Akt-FOXO axis (suppressive) and the leukemia inhibitory factor receptor beta (LIFRbeta)-STAT3 signaling pathway (oncogenic) was shown.
Increased activity of STAT3 in cancer cells, leads to changes in the function of protein complexes that control expression of inflammatory genes, with result profound change in the secretome and the cell phenotypes, their activity in the tumor, and their capacity for metastasis.[19]
# Interactions
STAT3 has been shown to interact with:
- AR,[20][21]
- ELP2,[22]
- EP300,[23]
- EGFR,[24][25]
- HIF1A,[26]
- JAK1,[20][27]
- JUN[28]
- KHDRBS1,[29]
- mTOR,[30][31]
- MYOD1,[32]
- NDUFA13,[33]
- NFKB1,[34]
- NR3C1,[35][36]
- NCOA1,[37]
- PML,[38]
- RAC1,[39]
- RELA,[34]
- RET,[24][40][41]
- RPA2,[42]
- STAT1,[27][43][44]
- Stathmin,[45]
- Src,[46] and
- TRIP10.[47]
- KPNA4.[48]
Niclosamide seems to inhibit the STAT3 signalling pathway.[49] | https://www.wikidoc.org/index.php/STAT3 | |
cab180f99c6f6e86de0c4fe27e7dfb58de595fe1 | wikidoc | STAT4 | STAT4
Signal transducer and activator of transcription 4 (STAT4) is a transcription factor belonging to the STAT protein family. It is required for the development of Th1 cells from naive CD4+ T cells and IFN-γ production in response to IL-12.
# Structure
Human as well murine STAT4 genes lie next to STAT1 gene locus suggesting that the genes arose by gene duplication. STAT proteins have several functional domains, including an N-terminal interaction domain, a central DNA-binding domain, an SH2 domain, and the C-terminal transactivation domain.
# Expression
Distribution of STAT4 is restricted to myeloid cells, thymus and testis. In resting human T cells it is expressed at very low levels, but its production is amplified by PHA stimulation.
# Activation
Two chains of IL-12 receptor form heterodimer after IL-12 binding and activate the receptor associated JAK kinases, termed JAK2 and TYK2. Stat4 is phosphorylated by these tyrosine kinases, homodimerizes via its SH2 domain and translocates into nucleus to activate gene transcription.
# Target genes
STAT4 binds to hundreds of sites in the genome, among others to the promoters of genes for cytokines (IFN-γ, TNF), receptors (IL18R1, IL12rβ2, IL18RAP), and signaling factors (MYD88). | STAT4
Signal transducer and activator of transcription 4 (STAT4) is a transcription factor belonging to the STAT protein family.[1] It is required for the development of Th1 cells from naive CD4+ T cells[2] and IFN-γ production in response to IL-12.[3]
# Structure
Human as well murine STAT4 genes lie next to STAT1 gene locus suggesting that the genes arose by gene duplication.[1] STAT proteins have several functional domains, including an N-terminal interaction domain, a central DNA-binding domain, an SH2 domain, and the C-terminal transactivation domain.[4]
# Expression
Distribution of STAT4 is restricted to myeloid cells, thymus and testis.[1] In resting human T cells it is expressed at very low levels, but its production is amplified by PHA stimulation.[3]
# Activation
Two chains of IL-12 receptor form heterodimer after IL-12 binding and activate the receptor associated JAK kinases, termed JAK2 and TYK2. Stat4 is phosphorylated by these tyrosine kinases, homodimerizes via its SH2 domain and translocates into nucleus to activate gene transcription.[5]
# Target genes
STAT4 binds to hundreds of sites in the genome,[6] among others to the promoters of genes for cytokines (IFN-γ, TNF), receptors (IL18R1, IL12rβ2, IL18RAP), and signaling factors (MYD88).[6] | https://www.wikidoc.org/index.php/STAT4 | |
c21dcb07b638193c5f16bc17210c09ade56a479a | wikidoc | STAT5 | STAT5
Signal transducer and activator of transcription 5 (STAT5) refers to two highly related proteins, STAT5A and STAT5B, which are part of the seven-membered STAT family of proteins. Though STAT5A and STAT5B are encoded by separate genes, the proteins are 90% identical at the amino acid level. STAT5 proteins are involved in cytosolic signalling and in mediating the expression of specific genes. Aberrant STAT5 activity has been shown to be closely connected to a wide range of human cancers, and silencing this aberrant activity is an area of active research in medicinal chemistry.
# Activation and function
In order to be functional, STAT5 proteins must first be activated. This activation is carried out by kinases associated with transmembrane receptors:
- first, ligands binding to these transmembrane receptors on the outside of the cell activate the kinases;
- second, the stimulated kinases add a phosphate group to a specific tyrosine residue on the receptor;
- STAT5 then binds to these phosphorylated-tyrosines using their SH2 domain (STAT domains illustrated below);
- the bound STAT5 is then phosphorylated by the kinase, the phosphorylation occurring at particular tyrosine residues on the C-terminus of the protein;
- phosphorylation causes STAT5 to dissociate from the receptor;
- the phosphorylated STAT5 finally goes on to form either homodimers, STAT5-STAT5, or heterodimers, STAT5-STATX, with other STAT proteins. The SH2 domains of the STAT5 proteins are once again used for this dimerization. STAT5 can also form homo-tetramers, usually in concert with the histone methyltransferase EZH2, and act as a transcriptional repressor.
In the activation pathway illustrated to the left, the ligand involved is a cytokine and the specific kinase taking part in activation is JAK. The dimerized STAT5 represents the active form of the protein, which is ready for translocation into the nucleus.
Once in the nucleus, the dimers bind to STAT5 response elements, inducing transcription of specific sets of genes. Upregulation of gene expression by STAT5 dimers has been observed for genes dealing with:
- controlled cell growth and division, or cell proliferation
- programmed cell death, or apoptosis
- cell specialization, or differentiation and
- inflammation.
Activated STAT5 dimers are, however, short-lived and the dimers are made to undergo rapid deactivation. Deactivation may be carried out by a direct pathway, removing the phosphate groups using phosphatases like PIAS or SHP-2 for example, or by an indirect pathway, which involves reducing cytokine signalling.
# STAT5 and cancer
STAT5 has been found to be constitutively phosphorylated in cancer cells, implying that the protein is always present in its active form. This constant activation is brought about either by mutations or by aberrant expressions of cell signalling, resulting in poor regulation, or complete lack of control, of the activation of transcription for genes influenced by STAT5. This leads to constant and increased expression of these genes. For example, mutations may lead to increased expression of anti-apoptotic genes, the products of which actively prevent cell death. The constant presence of these products preserve the cell in spite of it having become cancerous, causing the cell to eventually become malignant.
## Treatment approaches
Attempts at treatment for cancer cells with constitutively phosphorylated STAT5 have included both indirect and direct inhibition of STAT5 activity. While more medicinal work has been done in indirect inhibition, this approach can lead to increased toxicity in cells and can also result in non-specific effects, both of which are better handled by direct inhibition.
Indirect inhibition targets kinases associated with STAT5, or targets proteases that carry out terminal truncation of proteins. Different inhibitors have been designed to target different kinases:
- inhibition of BCR/ABl constitutes the basis of the functioning of drugs like imatinib
- inhibition of FLT3 is carried out by drugs like lestaurtinib
- inhibition of JAK2 is carried out by the drug CYT387, which was successful in preclinical trials and is currently undergoing clinical trials.
Direct inhibition of STAT5 activity makes use of small molecule inhibitors that prevent STAT5 from properly binding to DNA, or prevent proper dimerization. The inhibiting of DNA binding utilizes RNA interference, antisense oligodeoxynucleotide, and short hairpin RNA. The inhibition of proper dimerization, on the other hand, is brought about by the use of small molecules that target the SH2 domain. Recent work on drug development in the latter field have proved particularly effective. | STAT5
Signal transducer and activator of transcription 5 (STAT5) refers to two highly related proteins, STAT5A and STAT5B, which are part of the seven-membered STAT family of proteins. Though STAT5A and STAT5B are encoded by separate genes, the proteins are 90% identical at the amino acid level.[1] STAT5 proteins are involved in cytosolic signalling and in mediating the expression of specific genes.[2] Aberrant STAT5 activity has been shown to be closely connected to a wide range of human cancers,[3] and silencing this aberrant activity is an area of active research in medicinal chemistry.[4]
# Activation and function
In order to be functional, STAT5 proteins must first be activated. This activation is carried out by kinases associated with transmembrane receptors:[3]
- first, ligands binding to these transmembrane receptors on the outside of the cell activate the kinases;
- second, the stimulated kinases add a phosphate group to a specific tyrosine residue on the receptor;
- STAT5 then binds to these phosphorylated-tyrosines using their SH2 domain (STAT domains illustrated below);
- the bound STAT5 is then phosphorylated by the kinase, the phosphorylation occurring at particular tyrosine residues on the C-terminus of the protein;
- phosphorylation causes STAT5 to dissociate from the receptor;
- the phosphorylated STAT5 finally goes on to form either homodimers, STAT5-STAT5, or heterodimers, STAT5-STATX, with other STAT proteins. The SH2 domains of the STAT5 proteins are once again used for this dimerization. STAT5 can also form homo-tetramers, usually in concert with the histone methyltransferase EZH2, and act as a transcriptional repressor.[5]
In the activation pathway illustrated to the left, the ligand involved is a cytokine and the specific kinase taking part in activation is JAK. The dimerized STAT5 represents the active form of the protein, which is ready for translocation into the nucleus.
Once in the nucleus, the dimers bind to STAT5 response elements, inducing transcription of specific sets of genes. Upregulation of gene expression by STAT5 dimers has been observed for genes dealing with:[2]
- controlled cell growth and division, or cell proliferation
- programmed cell death, or apoptosis
- cell specialization, or differentiation and
- inflammation.
Activated STAT5 dimers are, however, short-lived and the dimers are made to undergo rapid deactivation. Deactivation may be carried out by a direct pathway, removing the phosphate groups using phosphatases like PIAS or SHP-2 for example, or by an indirect pathway, which involves reducing cytokine signalling.[6]
# STAT5 and cancer
STAT5 has been found to be constitutively phosphorylated in cancer cells,[4] implying that the protein is always present in its active form. This constant activation is brought about either by mutations or by aberrant expressions of cell signalling, resulting in poor regulation, or complete lack of control, of the activation of transcription for genes influenced by STAT5. This leads to constant and increased expression of these genes. For example, mutations may lead to increased expression of anti-apoptotic genes, the products of which actively prevent cell death. The constant presence of these products preserve the cell in spite of it having become cancerous, causing the cell to eventually become malignant.
## Treatment approaches
Attempts at treatment for cancer cells with constitutively phosphorylated STAT5 have included both indirect and direct inhibition of STAT5 activity. While more medicinal work has been done in indirect inhibition, this approach can lead to increased toxicity in cells and can also result in non-specific effects, both of which are better handled by direct inhibition.[4]
Indirect inhibition targets kinases associated with STAT5, or targets proteases that carry out terminal truncation of proteins. Different inhibitors have been designed to target different kinases:
- inhibition of BCR/ABl constitutes the basis of the functioning of drugs like imatinib[7]
- inhibition of FLT3 is carried out by drugs like lestaurtinib[8]
- inhibition of JAK2 is carried out by the drug CYT387, which was successful in preclinical trials and is currently undergoing clinical trials.[9]
Direct inhibition of STAT5 activity makes use of small molecule inhibitors that prevent STAT5 from properly binding to DNA, or prevent proper dimerization. The inhibiting of DNA binding utilizes RNA interference,[10] antisense oligodeoxynucleotide,[10] and short hairpin RNA.[11] The inhibition of proper dimerization, on the other hand, is brought about by the use of small molecules that target the SH2 domain. Recent work on drug development in the latter field have proved particularly effective.[12] | https://www.wikidoc.org/index.php/STAT5 | |
2ca036c62ed2500e83d8b006d5b1b791582d3021 | wikidoc | STAT6 | STAT6
Signal transducer and activator of transcription 6 (STAT6) is a human gene. The protein encoded by this gene is a member of the STAT family of transcription factors.
In response to cytokines and growth factors, STAT family members are phosphorylated by the receptor associated kinases, and then form homo- or heterodimers that translocate to the cell nucleus where they act as transcription activators. This protein plays a central role in exerting IL4 mediated biological responses. It is found to induce the expression of BCL2L1/BCL-X(L), which is responsible for the anti-apoptotic activity of IL4. Knockout studies in mice suggested the roles of this gene in differentiation of T helper 2 (Th2), expression of cell surface markers, and class switch of immunoglobulins.
# Interactions
STAT6 has been shown to interact with:
- CREB-binding protein,
- EP300,
- IRF4,
- NFKB1,
- Nuclear receptor coactivator 1, and
- SND1.
# Pathology
- Gene fusion
Recurrent somatic fusions of the two genes, NGFI-A–binding protein 2 (NAB2) and STAT6, located at chromosomal region 12q13, have been identified in solitary fibrous tumors.
- Recurrent somatic fusions of the two genes, NGFI-A–binding protein 2 (NAB2) and STAT6, located at chromosomal region 12q13, have been identified in solitary fibrous tumors.
- Amplification
STAT6 is amplified in a subset of dedifferentiated liposarcoma.
- STAT6 is amplified in a subset of dedifferentiated liposarcoma. | STAT6
Signal transducer and activator of transcription 6 (STAT6) is a human gene. The protein encoded by this gene is a member of the STAT family of transcription factors.[1][2]
In response to cytokines and growth factors, STAT family members are phosphorylated by the receptor associated kinases, and then form homo- or heterodimers that translocate to the cell nucleus where they act as transcription activators. This protein plays a central role in exerting IL4 mediated biological responses. It is found to induce the expression of BCL2L1/BCL-X(L), which is responsible for the anti-apoptotic activity of IL4. Knockout studies in mice suggested the roles of this gene in differentiation of T helper 2 (Th2), expression of cell surface markers, and class switch of immunoglobulins.[3]
# Interactions
STAT6 has been shown to interact with:
- CREB-binding protein,[4][5]
- EP300,[4]
- IRF4,[6]
- NFKB1,[7]
- Nuclear receptor coactivator 1,[5][8] and
- SND1.[9]
# Pathology
- Gene fusion
Recurrent somatic fusions of the two genes, NGFI-A–binding protein 2 (NAB2) and STAT6, located at chromosomal region 12q13, have been identified in solitary fibrous tumors.[10]
- Recurrent somatic fusions of the two genes, NGFI-A–binding protein 2 (NAB2) and STAT6, located at chromosomal region 12q13, have been identified in solitary fibrous tumors.[10]
- Amplification
STAT6 is amplified in a subset of dedifferentiated liposarcoma.[11]
- STAT6 is amplified in a subset of dedifferentiated liposarcoma.[11] | https://www.wikidoc.org/index.php/STAT6 | |
421644f8cc49952b9a7a33f2dad39a903d8a86de | wikidoc | STIM1 | STIM1
Stromal interaction molecule 1 is a protein that in humans is encoded by the STIM1 gene. STIM1 has a single transmembrane domain, and is localized to the endoplasmic reticulum, and to a lesser extent to the plasma membrane.
Even though the protein has been identified earlier, its function was unknown until recently. In 2005, it was discovered that STIM1 functions as a calcium sensor in the endoplasmic reticulum. Upon activation of the IP3 receptor, the calcium concentration in the endoplasmic reticulum decreases, which is sensed by STIM1, via its EF hand domain. STIM1 activates the "store-operated" ORAI1 calcium ion channels in the plasma membrane, via intracellular STIM1 movement, clustering under plasma membrane and protein protein interaction with ORAI isoforms. STIM1-mediated calcium entry is required for thrombin-induced disassembly of VE-cadherin adherens junctions. 2-Aminoethoxydiphenyl borate (2-APB) and 4-chloro-3-ethylphenol (4-CEP) cause STIM1 clustering in a cell and prevent STIM1 moving toward plasma membrane.
# Interactions
STIM1 has been shown to interact with ORAI1, TMEM110 (STIMATE), SERCA, TMEM66 (SARAF), and STIM2. | STIM1
Stromal interaction molecule 1 is a protein that in humans is encoded by the STIM1 gene.[1][2][3] STIM1 has a single transmembrane domain, and is localized to the endoplasmic reticulum, and to a lesser extent to the plasma membrane.[4]
Even though the protein has been identified earlier, its function was unknown until recently. In 2005, it was discovered that STIM1 functions as a calcium sensor in the endoplasmic reticulum.[5][6] Upon activation of the IP3 receptor, the calcium concentration in the endoplasmic reticulum decreases, which is sensed by STIM1, via its EF hand domain. STIM1 activates the "store-operated" ORAI1 calcium ion channels in the plasma membrane, via intracellular STIM1 movement, clustering under plasma membrane and protein protein interaction with ORAI isoforms.[7][8][9] STIM1-mediated calcium entry is required for thrombin-induced disassembly of VE-cadherin adherens junctions.[10] 2-Aminoethoxydiphenyl borate (2-APB) and 4-chloro-3-ethylphenol (4-CEP) cause STIM1 clustering in a cell and prevent STIM1 moving toward plasma membrane.[11]
# Interactions
STIM1 has been shown to interact with ORAI1, TMEM110 (STIMATE[12]), SERCA, TMEM66 (SARAF), and STIM2.[2] | https://www.wikidoc.org/index.php/STIM1 | |
a78eb55004407c3bff6c957efecb62cb528cbde8 | wikidoc | STIM2 | STIM2
Stromal interaction molecule 2 (STIM2) is a protein that in humans is encoded by the STIM2 gene.
This gene is a member of the stromal interaction molecule (STIM) family which comprises only two members together with its homologue STIM1, and likely arose from a common ancestral gene. They encode type 1 transmembrane proteins that are located in the sarco/endoplasmic reticulum (SR / ER) into the cell. Alternative translation initiation from an AUG and a non-AUG (UUG) start site results in the production of two different STIM2 isoforms.
Both members of the STIM family were identified in 2005 as free-calcium (Ca2+) sensors which participate in a mechanism of Ca2+ entry into the cell referred to as store-operated Ca2+ entry (SOCE). Many cellular processes and signaling pathways are started by previous release of Ca2+ stored in subcellular organelles, which needs of a continuous refilling. SOCE is considered the mechanism of store refilling and an essential mechanism of Ca2+ signaling in non-electrically excitable cells. While STIM1 triggers SOCE, research on STIM2 function suggests a major role as feedback regulator that stabilizes basal cytosolic and S/ER Ca2+ concentration . STIM2 detects small decreases in Ca2+ content stored in the S/ER, switches to the activated state and interacts with so called store-operated Ca2+ (SOC) channels located in the plasma membrane, such as Orai or TRPC channels, allowing SOCE. Although the functional role of STIM2 has been elusive for many years, studies performed in 2009-2010 on murine models suggested that STIM2 participates in processes of the development and functioning of many cell types, including smooth muscle myoblasts, cells of the immune system and neurons, and is involved in tumorigenesis, the development of autoimmune diseases and mechanisms of neuronal damage after transient ischemic conditions.
# Gene
In 2001, STIM2 was identified as a new human homologue of the STIM1 gene, representing the second member of a two-gene family in vertebrates. The STIM2 gene contains 12 exons and 11 introns located on the human chromosome 4p15.1, and on the large arm of the mouse chromosome 5, close to the centromere. The members of STIM family most probably have evolved from a single gene in lower multicellular eukaryotes into two related genes in vertebrates, since human STIM1 and STIM2 as well as Drosophila melanogaster Stim (D-Stim) have a conserved genomic organization. The D-STIM protein of 570 aas exhibits equal similarity to both STIM1 (33% identical; 50% of amino acid sequence conserved) and STIM2 (31% identical; 46% of amino acid sequence conserved). Unicellular eukaryotes such as Monosiga brevicollis, a unicellular choanoflagellate has been reported to have a STIM-like gene, however no STIM-like genes have been identified in prokaryotes. No additional STIM-like proteins have been identified until now in vertebrates.
# Protein structure
STIM2 protein is a type I transmembrane protein located in the S/ER. Human STIM2 consists of 833 amino acid residues (aas) (105-115 kDa) (Fig. 1), 148 additional aas compared to human STIM1. Their N-terminal regions share 66% similarity over 577 aas (85% of the amino acid sequence of STIM1). Only the extreme of the C-terminal region shows a significant sequence divergence. The domain architecture of both isoforms is highly conserved in vertebrates (Fig. 1).
Mouse STIM2 shares a 92% identity with human STIM2 in the aminoacid sequence according to the pairwise alignment generated by BLAST. Their domain structure is also highly conserved (Fig. 1).
Human STIM2 is post-translationally modified in vivo, such as maturation by cleavage of N-terminal S/ER signaling peptide (14 aas), glycosylation and variable degrees of phosphorylation, but the phosphorylated sites are still unknown (Fig. 1).
## Domain architecture
The N-terminal region of STIM2 is located in the S/ER lumen and contains a canonical EF-hand Ca2+-binding motif, a “hidden” EF-hand Ca2+-binding motif discovered recently and a sterile a-motif (SAM) domain, a well-known protein–protein interaction motif (Fig. 1).
The N-terminal portion is separated from the C-terminal region by a single-pass transmembrane motif that is highly conserved in all STIM proteins. The C-terminal region contains a high degree of α-helical structures. A large proportion close to the transmembrane domain comprises a region similar to an ezrin/radixin/moesin (ERM) domain that contains two coiled-coil domains. The coiled-coil domains mediate interactions between STIM proteins, allowing them to bind each other and form homo and heterodimers (Fig. 1). Finally, further towards the C-terminus, STIM2 contains a proline/histidine-rich motif and a lysine-rich tail of 17 aas (Fig. 1).
## EF-hand-SAM region
Since the EF-hand and SAM (EF-SAM) domains are vital to STIM function and SOCE regulation, they are now discussed in detail. The EF-hand domain is a Ca2+ sensor used by STIM protein to detect changes in Ca2+ concentration inside the S/ER. STIM isoforms become activated when Ca2+ bound to the EF-hand motif is released as a result of a decrease in Ca2+ levels inside the S/ER store after IP3 receptor–mediated depletion. It has been reported that STIM EF-hand mutants that are not able to bind Ca2+ are constitutively active and continually activate SOCE independently of S/ER , in vitro and in vivo.
The SAM domain is important for STIM oligomerization, since mutants in this domain lack the ability to form inducible punctae.
Ca2+-binding experiments in vitro using human STIM1 EF–SAM (residue 58–201) or STIM2 EF–SAM (residue 149–292) fragments show that both isoforms bind Ca2+ with similar affinity (STIM2 Kd~0.5 mM; STIM1 Kd~0.2–0.6 mM), which is within the range of values reported for S/ER . However, STIM2 differs from STIM1 in that it is already partially active at basal S/ER and becomes fully activated earlier during S/ER store depletion. Despite the same Ca2+ affinity shown by STIM EF-SAM fragments, the full STIM2 protein showed a lower sensitivity than STIM1 in transfected cells in vitro. This discrepancy indicates that other protein regions in addition contribute to the different sensitivity or activation threshold shown by both isoforms.
The “hidden” EF-hand domain does not bind Ca2+, but it is critical for intramolecular association, folding and stability of the EF-hand and SAM domains. Very recently it has been reported that structurally critical mutations in the canonical EF-hand, ‘‘hidden’’ EF-hand, or SAM domain disrupt Ca2+ sensitivity due to the destabilization of the entire EF-SAM region.
## C-terminal region
Besides the N-terminus, the C-terminal region is also an essential part of STIM proteins. It shows a significant sequence divergence between both isoforms and in STIM1, the C-terminal region is essential for the interaction with SOC channels. Human STIM2 contains a proline- and histidine-rich motif (PHAPHPSHPRHPHHPQHTPHSLPSPDP) at a similar position to a serine- and proline-rich region (SPSAPPGGSPHLDSSRSHSPSSPDPDTPSP) in STIM1. The significant divergence in these regions could indicate a divergence in function of STIM isoforms. Unlike STIM1, STIM2 has a dilysine ER retention signal (K(X)KXX) at its extreme C-terminus which retains the protein in the ER, whereas STIM1 can travel to cell surface. Finally, similar lysine-rich tails of 14 and 17 residues in STIM1 and STIM2 respectively are located at the very end of the C-terminal region.
Linear peptides from C-terminal polybasic region of human STIM1 (residues 667-685) and STIM2 (residues 730-746) bind to calmodulin with high or low affinity in presence or absence of Ca2+, respectively. Most of studies on interactions of the C-terminal region have been performed with the STIM1 isoform. The addition of thapsigargin (the SERCA pump inhibitor that stimulates SOCE by passive depletion of intracellular Ca2+ stores) to human salivary gland cells as well as dispersed mouse submandibular gland cells increase coimmunoprecipitation of TRPC1 and Orai1 with STIM1.
By in vitro co-expression of different human STIM1 mutants that lack the different C-terminal regions in HEK293 cells, three recent works reported that the ERM domain in the C-terminus (aas 251-535, Fig. 1), containing the coiled-coil domains, mediates the binding of STIM1 to TRPC(1, 2,4 and 5) and the STIM1 migration to the plasma membrane.
Furthermore, the cationic lysine-rich region is essential for gating of TRPC1. Li et al. further delineated these regions (aas 425-672) as possible STIM1-Orai1 interaction sites. In vitro coimmunoprecipitation experiments after transient coexpression of STIM2 and Orai1 proteins in HEK293 cells revealed that also STIM2 can physically interact with Orai1, probably though the STIM2 C-terminal region.
# Expression and tissue distribution
STIM2 mRNA is expressed by most human tissues. The STIM2 protein is expressed by many human cell lines together with STIM1, indicating that STIM isoforms are co-expressed in the same cell, at least in the established cell lines. STIM2 protein is widely expressed in tissues, usually present at lower levels than STIM1 except in brain or liver, were STIM2 seems to be the dominant isoform. Stim2 transcription is also dynamically regulated, for instance being upregulated upon differentiation of naive T cells into Th1 or Th2 lymphocytes.
# Function
The STIM2 function has been controversial. Initial studies found that siRNA knockdown of STIM1, but not STIM2, strongly reduced SOCE in mammalian cells. Liou et al. reported a slight reduction in SOCE also by knockdown of STIM2 in HeLa cells. Soboloff et al. suggested that STIM2 inhibits SOCE when expressed alone, but coexpressed with Orai1 causes substantial constitutive SOCE. In contrast, Brandman et al. suggested that STIM2 could act as a regulator that stabilizes basal cytosolic and ER Ca2+ levels. Parvez et al., using in vitro transient coexpression of human STIM2 and different SOC channels in HEK293 cells, reported that STIM2 mediates SOCE via two store-dependent and store independent modes. Taking together, these results indicate a complex interaction finely regulated by the STIM1: STIM2: Orai cellular ratio and their endogenous levels.
Studies performed in 2009-2010 using human in vitro or murine in vivo models confirmed Brandman et al. results and suggested that STIM2 participates in processes of the development and functioning of many cell types, including smooth muscle myoblasts, cells of the immune system and neurons. Moreover, it is involved in tumorigenesis, the development of autoimmune diseases and mechanisms of neuronal damage after transient ischemic conditions. In resting conditions, cultured HEK293 cells overexpressing or cortical neurons lacking STIM2 have increased or decreased resting intracellular Ca2+ levels respectively, supporting the idea that STIM2 is essential for regulation of intracellular basal Ca2+ levels. However, cells are very active in vivo and intracellular Ca2+ levels are continuously fluctuating. The development of new methods to study the in vivo role of STIM2 in intracellular Ca2+ levels would be necessary. In cultured human myoblast, STIM2 participate in cell differentiation into myotubes. In the immune system, STIM2 participates in T cell activation-induced production of interleukin2 (IL-2) and interferon gamma (IFNγ), probably by stabilization of NFAT residence in the nucleus, as well as in differentiation of naive T cells into Th17 lymphocytes, which presumably are important in early phases of autoimmune diseases. In fact, STIM2-deficient mice showed mild symptomatology in the early phase of autoimmune diseases. In neuronal tissue, STIM2 plays a crucial role in ischemia-induced neuronal damage, and the absence of STIM2 in knockout mice reduced the neuronal damage produced by ischemia after transient interruption of blood flow in brain. This neuroprotective effect of STIM2-deficiency after an ischemic episode indicates that inhibitors of STIM2 function may thus have a potential therapeutic value as neuroprotective agents to treat ischemic injury and other neurodegenerative disorders involving altered Ca2+ homeostasis. Moreover, the same scientific study suggested an important role of STIM2 in hippocampus-dependent spatial memory, synaptic transmission and plasticity.
Finally, an oncogenic function has been demonstrated for STIM2, together with STIM1, in glioblastoma multiforme, where both proteins have increased expression and/or increased copy number. Additionally, STIM2 is located in chromosome 4p15.1, a region implicated in invasive carcinomas of the lung, breast, neck and head.
# Interactions
As mentioned before, STIM2 has been shown to interact with STIM1, SOC channels such as Orai (ICRACM) or TRPC, calmodulin (CaM) and also plasma membrane phosphoinositides. The expression of STIM2 has been shown to be influenced or regulated by presenilins in mouse embryonic fibroblasts and human B lymphocytes. | STIM2
Stromal interaction molecule 2 (STIM2) is a protein that in humans is encoded by the STIM2 gene.[1][2]
This gene is a member of the stromal interaction molecule (STIM) family which comprises only two members together with its homologue STIM1, and likely arose from a common ancestral gene. They encode type 1 transmembrane proteins that are located in the sarco/endoplasmic reticulum (SR / ER) into the cell. Alternative translation initiation from an AUG and a non-AUG (UUG) start site results in the production of two different STIM2 isoforms.
Both members of the STIM family were identified in 2005 as free-calcium (Ca2+) sensors which participate in a mechanism of Ca2+ entry into the cell referred to as store-operated Ca2+ entry (SOCE). Many cellular processes and signaling pathways are started by previous release of Ca2+ stored in subcellular organelles, which needs of a continuous refilling. SOCE is considered the mechanism of store refilling and an essential mechanism of Ca2+ signaling in non-electrically excitable cells. While STIM1 triggers SOCE, research on STIM2 function suggests a major role as feedback regulator that stabilizes basal cytosolic and S/ER Ca2+ concentration [Ca2+]. STIM2 detects small decreases in Ca2+ content stored in the S/ER, switches to the activated state and interacts with so called store-operated Ca2+ (SOC) channels located in the plasma membrane, such as Orai or TRPC channels, allowing SOCE. Although the functional role of STIM2 has been elusive for many years, studies performed in 2009-2010 on murine models suggested that STIM2 participates in processes of the development and functioning of many cell types, including smooth muscle myoblasts, cells of the immune system and neurons, and is involved in tumorigenesis, the development of autoimmune diseases and mechanisms of neuronal damage after transient ischemic conditions.
# Gene
In 2001, STIM2 was identified as a new human homologue of the STIM1 gene, representing the second member of a two-gene family in vertebrates.[1] The STIM2 gene contains 12 exons and 11 introns located on the human chromosome 4p15.1, and on the large arm of the mouse chromosome 5, close to the centromere. The members of STIM family most probably have evolved from a single gene in lower multicellular eukaryotes into two related genes in vertebrates, since human STIM1 and STIM2 as well as Drosophila melanogaster Stim (D-Stim) have a conserved genomic organization. The D-STIM protein of 570 aas exhibits equal similarity to both STIM1 (33% identical; 50% of amino acid sequence conserved) and STIM2 (31% identical; 46% of amino acid sequence conserved). Unicellular eukaryotes such as Monosiga brevicollis, a unicellular choanoflagellate has been reported to have a STIM-like gene,[3] however no STIM-like genes have been identified in prokaryotes. No additional STIM-like proteins have been identified until now in vertebrates.[1]
# Protein structure
STIM2 protein is a type I transmembrane protein located in the S/ER. Human STIM2 consists of 833 amino acid residues (aas) (105-115 kDa) (Fig. 1), 148 additional aas compared to human STIM1. Their N-terminal regions share 66% similarity over 577 aas (85% of the amino acid sequence of STIM1). Only the extreme of the C-terminal region shows a significant sequence divergence. The domain architecture of both isoforms is highly conserved in vertebrates (Fig. 1).
Mouse STIM2 shares a 92% identity with human STIM2 in the aminoacid sequence according to the pairwise alignment generated by BLAST. Their domain structure is also highly conserved (Fig. 1).
Human STIM2 is post-translationally modified in vivo, such as maturation by cleavage of N-terminal S/ER signaling peptide (14 aas), glycosylation and variable degrees of phosphorylation, but the phosphorylated sites are still unknown (Fig. 1).[1]
## Domain architecture
The N-terminal region of STIM2 is located in the S/ER lumen and contains a canonical EF-hand Ca2+-binding motif, a “hidden” EF-hand Ca2+-binding motif discovered recently and a sterile a-motif (SAM) domain, a well-known protein–protein interaction motif (Fig. 1).[4][5][6]
The N-terminal portion is separated from the C-terminal region by a single-pass transmembrane motif that is highly conserved in all STIM proteins. The C-terminal region contains a high degree of α-helical structures. A large proportion close to the transmembrane domain comprises a region similar to an ezrin/radixin/moesin (ERM) domain that contains two coiled-coil domains.[7] The coiled-coil domains mediate interactions between STIM proteins, allowing them to bind each other and form homo and heterodimers (Fig. 1).[8][9][10] Finally, further towards the C-terminus, STIM2 contains a proline/histidine-rich motif and a lysine-rich tail of 17 aas (Fig. 1).[1]
## EF-hand-SAM region
Since the EF-hand and SAM (EF-SAM) domains are vital to STIM function and SOCE regulation, they are now discussed in detail. The EF-hand domain is a Ca2+ sensor used by STIM protein to detect changes in Ca2+ concentration inside the S/ER. STIM isoforms become activated when Ca2+ bound to the EF-hand motif is released as a result of a decrease in Ca2+ levels inside the S/ER store after IP3 receptor–mediated depletion. It has been reported that STIM EF-hand mutants that are not able to bind Ca2+ are constitutively active and continually activate SOCE independently of S/ER [Ca2+], in vitro[11] and in vivo.[12][13][14]
The SAM domain is important for STIM oligomerization, since mutants in this domain lack the ability to form inducible punctae.[15]
Ca2+-binding experiments in vitro using human STIM1 EF–SAM (residue 58–201) or STIM2 EF–SAM (residue 149–292) fragments show that both isoforms bind Ca2+ with similar affinity (STIM2 Kd~0.5 mM; STIM1 Kd~0.2–0.6 mM),[16][17] which is within the range of values reported for S/ER [Ca2+].[18][19] However, STIM2 differs from STIM1 in that it is already partially active at basal S/ER [Ca2+] and becomes fully activated earlier during S/ER store depletion. Despite the same Ca2+ affinity shown by STIM EF-SAM fragments, the full STIM2 protein showed a lower [Ca2+] sensitivity than STIM1 in transfected cells in vitro.[20] This discrepancy indicates that other protein regions in addition contribute to the different [Ca2+] sensitivity or activation threshold shown by both isoforms.
The “hidden” EF-hand domain does not bind Ca2+, but it is critical for intramolecular association, folding and stability of the EF-hand and SAM domains. Very recently it has been reported that structurally critical mutations in the canonical EF-hand, ‘‘hidden’’ EF-hand, or SAM domain disrupt Ca2+ sensitivity due to the destabilization of the entire EF-SAM region.[21]
## C-terminal region
Besides the N-terminus, the C-terminal region is also an essential part of STIM proteins. It shows a significant sequence divergence between both isoforms and in STIM1, the C-terminal region is essential for the interaction with SOC channels.[22] Human STIM2 contains a proline- and histidine-rich motif (PHAPHPSHPRHPHHPQHTPHSLPSPDP) at a similar position to a serine- and proline-rich region (SPSAPPGGSPHLDSSRSHSPSSPDPDTPSP) in STIM1. The significant divergence in these regions could indicate a divergence in function of STIM isoforms. Unlike STIM1, STIM2 has a dilysine ER retention signal (K(X)KXX) at its extreme C-terminus which retains the protein in the ER, whereas STIM1 can travel to cell surface.[23] Finally, similar lysine-rich tails of 14 and 17 residues in STIM1 and STIM2 respectively are located at the very end of the C-terminal region.
Linear peptides from C-terminal polybasic region of human STIM1 (residues 667-685) and STIM2 (residues 730-746) bind to calmodulin with high or low affinity in presence or absence of Ca2+, respectively.[24] Most of studies on interactions of the C-terminal region have been performed with the STIM1 isoform. The addition of thapsigargin (the SERCA pump inhibitor that stimulates SOCE by passive depletion of intracellular Ca2+ stores) to human salivary gland cells as well as dispersed mouse submandibular gland cells increase coimmunoprecipitation of TRPC1 and Orai1 with STIM1.[25]
By in vitro co-expression of different human STIM1 mutants that lack the different C-terminal regions in HEK293 cells, three recent works reported that the ERM domain in the C-terminus (aas 251-535, Fig. 1), containing the coiled-coil domains, mediates the binding of STIM1 to TRPC(1, 2,4 and 5) and the STIM1 migration to the plasma membrane.
Furthermore, the cationic lysine-rich region is essential for gating of TRPC1.[10][22][26] Li et al. further delineated these regions (aas 425-672) as possible STIM1-Orai1 interaction sites.[10] In vitro coimmunoprecipitation experiments after transient coexpression of STIM2 and Orai1 proteins in HEK293 cells revealed that also STIM2 can physically interact with Orai1, probably though the STIM2 C-terminal region.[27]
# Expression and tissue distribution
STIM2 mRNA is expressed by most human tissues. The STIM2 protein is expressed by many human cell lines together with STIM1, indicating that STIM isoforms are co-expressed in the same cell, at least in the established cell lines.[1] STIM2 protein is widely expressed in tissues, usually present at lower levels than STIM1 except in brain or liver, were STIM2 seems to be the dominant isoform.[1][28] Stim2 transcription is also dynamically regulated, for instance being upregulated upon differentiation of naive T cells into Th1 or Th2 lymphocytes.[29]
# Function
The STIM2 function has been controversial. Initial studies found that siRNA knockdown of STIM1, but not STIM2, strongly reduced SOCE in mammalian cells.[11][20][30][31][32] Liou et al. reported a slight reduction in SOCE also by knockdown of STIM2 in HeLa cells.[11] Soboloff et al. suggested that STIM2 inhibits SOCE when expressed alone,[9] but coexpressed with Orai1 causes substantial constitutive SOCE.[33] In contrast, Brandman et al. suggested that STIM2 could act as a regulator that stabilizes basal cytosolic and ER Ca2+ levels.[20] Parvez et al., using in vitro transient coexpression of human STIM2 and different SOC channels in HEK293 cells, reported that STIM2 mediates SOCE via two store-dependent and store independent modes.[27] Taking together, these results indicate a complex interaction finely regulated by the STIM1: STIM2: Orai cellular ratio and their endogenous levels.
Studies performed in 2009-2010 using human in vitro or murine in vivo models confirmed Brandman et al. results and suggested that STIM2 participates in processes of the development and functioning of many cell types, including smooth muscle myoblasts, cells of the immune system and neurons. Moreover, it is involved in tumorigenesis, the development of autoimmune diseases and mechanisms of neuronal damage after transient ischemic conditions. In resting conditions, cultured HEK293 cells overexpressing or cortical neurons lacking STIM2 have increased or decreased resting intracellular Ca2+ levels respectively,[27][28] supporting the idea that STIM2 is essential for regulation of intracellular basal Ca2+ levels. However, cells are very active in vivo and intracellular Ca2+ levels are continuously fluctuating. The development of new methods to study the in vivo role of STIM2 in intracellular Ca2+ levels would be necessary. In cultured human myoblast, STIM2 participate in cell differentiation into myotubes.[34] In the immune system, STIM2 participates in T cell activation-induced production of interleukin2 (IL-2) and interferon gamma (IFNγ), probably by stabilization of NFAT residence in the nucleus, as well as in differentiation of naive T cells into Th17 lymphocytes, which presumably are important in early phases of autoimmune diseases.[29][35] In fact, STIM2-deficient mice showed mild symptomatology in the early phase of autoimmune diseases.[35] In neuronal tissue, STIM2 plays a crucial role in ischemia-induced neuronal damage, and the absence of STIM2 in knockout mice reduced the neuronal damage produced by ischemia after transient interruption of blood flow in brain.[28] This neuroprotective effect of STIM2-deficiency after an ischemic episode indicates that inhibitors of STIM2 function may thus have a potential therapeutic value as neuroprotective agents to treat ischemic injury and other neurodegenerative disorders involving altered Ca2+ homeostasis. Moreover, the same scientific study suggested an important role of STIM2 in hippocampus-dependent spatial memory, synaptic transmission and plasticity.[28]
Finally, an oncogenic function has been demonstrated for STIM2, together with STIM1, in glioblastoma multiforme, where both proteins have increased expression and/or increased copy number.[36][37] Additionally, STIM2 is located in chromosome 4p15.1, a region implicated in invasive carcinomas of the lung, breast, neck and head.[38][39][40]
# Interactions
As mentioned before, STIM2 has been shown to interact with STIM1,[8][9][10] SOC channels such as Orai (ICRACM) or TRPC,[27] calmodulin (CaM)[24][27] and also plasma membrane phosphoinositides.[41] The expression of STIM2 has been shown to be influenced or regulated by presenilins in mouse embryonic fibroblasts and human B lymphocytes.[42] | https://www.wikidoc.org/index.php/STIM2 | |
502aa14fab7503017ab20fba158703f8cc13df6c | wikidoc | STK11 | STK11
Serine/threonine kinase 11 (STK11) also known as liver kinase B1 (LKB1) or renal carcinoma antigen NY-REN-19 is a protein kinase that in humans is encoded by the STK11 gene.
# Expression
Testosterone and DHT treatment of murine 3T3-L1 or human SGBS adipocytes for 24 h significantly decreased the mRNA expression of LKB1 via the androgen receptor and consequently reduced the activation of AMPK by phosphorylation. In contrast, 17β-estradiol treatment increased LKB1 mRNA, an effect mediated by oestrogen receptor alpha.
However, in ER-positive breast cancer cell line MCF-7, estradiol caused a dose-dependent decrease in LKB1 transcript and protein expression leading to a significant decrease in the phosphorylation of the LKB1 target AMPK. ERα binds to the STK11 promoter in a ligand-independent manner and this interaction is decreased in the presence of estradiol. Moreover, STK11 promoter activity is significantly decreased in the presence of estradiol.
# Function
The STK11/LKB1 gene, which encodes a member of the serine/threonine kinase family, regulates cell polarity and functions as a tumour suppressor.
LKB1 is a primary upstream kinase of adenosine monophosphate-activated protein kinase (AMPK), a necessary element in cell metabolism that is required for maintaining energy homeostasis. It is now clear that LKB1 exerts its growth suppressing effects by activating a group of ~14 other kinases, comprising AMPK and AMPK-related kinases. Activation of AMPK by LKB1 suppresses growth and proliferation when energy and nutrient levels are scarce. Activation of AMPK-related kinases by LKB1 plays vital roles maintaining cell polarity thereby inhibiting inappropriate expansion of tumour cells. A picture from current research is emerging that loss of LKB1 leads to disorganization of cell polarity and facilitates tumour growth under energetically unfavorable conditions.
# Clinical significance
Germline mutations in this gene have been associated with Peutz-Jeghers syndrome, an autosomal dominant disorder characterized by the growth of polyps in the gastrointestinal tract, pigmented macules on the skin and mouth, and other neoplasms. However, the LKB1 gene was also found to be mutated in lung cancer of sporadic origin, predominantly adenocarcinomas. Further, more recent studies have uncovered a large number of somatic mutations of the LKB1 gene that are present in cervical, breast, intestinal, testicular, pancreatic and skin cancer.
# Activation
LKB1 is activated allosterically by binding to the pseudokinase STRAD and the adaptor protein MO25. The LKB1-STRAD-MO25 heterotrimeric complex represents the biologically active unit, that is capable of phosphorylating and activating AMPK and at least 12 other kinases that belong to the AMPK-related kinase family.
# Structure
The crystal structure of the LKB1-STRAD-MO25 complex was elucidated using X-ray crystallography, and revealed the mechanism by which LKB1 is allosterically activated. LKB1 has a structure typical of other protein kinases, with two (small and large) lobes on either side of the ligand ATP-binding pocket. STRAD and MO25 together cooperate to promote LKB1 active conformation. The LKB1 activation loop, a critical element in the process of kinase activation, is held in place by MO25, thus explaining the huge increase in LKB1 activity in the presence of STRAD and MO25 .
# Splice variants
Alternate transcriptional splice variants of this gene have been observed and characterized. There are two main splice isoforms denoted LKB1 long (LKB1L) and LKB1 short (LKB1S). The short LKB1 variant is predominantly found in testes.
# Interactions
STK11 has been shown to interact with:
- CDC37,
- - Fyn
- HSP90AA1
- LYK5, and
- SMARCA4.
- ERalpha | STK11
Serine/threonine kinase 11 (STK11) also known as liver kinase B1 (LKB1) or renal carcinoma antigen NY-REN-19 is a protein kinase that in humans is encoded by the STK11 gene.[1]
# Expression
Testosterone and DHT treatment of murine 3T3-L1 or human SGBS adipocytes for 24 h significantly decreased the mRNA expression of LKB1 via the androgen receptor and consequently reduced the activation of AMPK by phosphorylation. In contrast, 17β-estradiol treatment increased LKB1 mRNA, an effect mediated by oestrogen receptor alpha.[2]
However, in ER-positive breast cancer cell line MCF-7, estradiol caused a dose-dependent decrease in LKB1 transcript and protein expression leading to a significant decrease in the phosphorylation of the LKB1 target AMPK. ERα binds to the STK11 promoter in a ligand-independent manner and this interaction is decreased in the presence of estradiol. Moreover, STK11 promoter activity is significantly decreased in the presence of estradiol.[3]
# Function
The STK11/LKB1 gene, which encodes a member of the serine/threonine kinase family, regulates cell polarity and functions as a tumour suppressor.
LKB1 is a primary upstream kinase of adenosine monophosphate-activated protein kinase (AMPK), a necessary element in cell metabolism that is required for maintaining energy homeostasis. It is now clear that LKB1 exerts its growth suppressing effects by activating a group of ~14 other kinases, comprising AMPK and AMPK-related kinases. Activation of AMPK by LKB1 suppresses growth and proliferation when energy and nutrient levels are scarce. Activation of AMPK-related kinases by LKB1 plays vital roles maintaining cell polarity thereby inhibiting inappropriate expansion of tumour cells. A picture from current research is emerging that loss of LKB1 leads to disorganization of cell polarity and facilitates tumour growth under energetically unfavorable conditions.
# Clinical significance
Germline mutations in this gene have been associated with Peutz-Jeghers syndrome, an autosomal dominant disorder characterized by the growth of polyps in the gastrointestinal tract, pigmented macules on the skin and mouth, and other neoplasms.[4][5][6] However, the LKB1 gene was also found to be mutated in lung cancer of sporadic origin, predominantly adenocarcinomas.[7] Further, more recent studies have uncovered a large number of somatic mutations of the LKB1 gene that are present in cervical, breast, intestinal, testicular, pancreatic and skin cancer.[8][9]
# Activation
LKB1 is activated allosterically by binding to the pseudokinase STRAD and the adaptor protein MO25. The LKB1-STRAD-MO25 heterotrimeric complex represents the biologically active unit, that is capable of phosphorylating and activating AMPK and at least 12 other kinases that belong to the AMPK-related kinase family.
# Structure
The crystal structure of the LKB1-STRAD-MO25 complex was elucidated using X-ray crystallography,[10] and revealed the mechanism by which LKB1 is allosterically activated. LKB1 has a structure typical of other protein kinases, with two (small and large) lobes on either side of the ligand ATP-binding pocket. STRAD and MO25 together cooperate to promote LKB1 active conformation. The LKB1 activation loop, a critical element in the process of kinase activation, is held in place by MO25, thus explaining the huge increase in LKB1 activity in the presence of STRAD and MO25 .
# Splice variants
Alternate transcriptional splice variants of this gene have been observed and characterized. There are two main splice isoforms denoted LKB1 long (LKB1L) and LKB1 short (LKB1S). The short LKB1 variant is predominantly found in testes.
# Interactions
STK11 has been shown to interact with:
- CDC37,[11]
- * Fyn[12]
- HSP90AA1[11]
- LYK5,[13][14] and
- SMARCA4.[15]
- ERalpha | https://www.wikidoc.org/index.php/STK11 | |
10583f6c328f243cb156b2774a597155f846d7eb | wikidoc | STK24 | STK24
Serine/threonine-protein kinase 24 is an enzyme that in humans is encoded by the STK24 gene located in the chromosome 13, band q32.2. It is also known as Mammalian STE20-like protein kinase 3 (MST-3). The protein is 443 amino acids long and its mass is 49 kDa.
# Classification and discovery
The yeast 'Sterile 20' gene (STE20) functions upstream of the mitogen-activated protein kinase (MAPK) cascade. In mammals, protein kinases related to STE20 can be divided into 2 subfamilies based on their structure and regulation. Members of the PAK subfamily (see PAK3) contain a C-terminal catalytic domain and an N-terminal regulatory domain that has a CDC42-binding domain. In contrast, members of the GCK subfamily (MAP4K2), also called the Sps1 subfamily, have an N-terminal catalytic domain and a C-terminal regulatory domain without a CDC42-binding domain. STK24 belongs to the GCK subfamily of STE20-like kinases.
The sterile 20 protein was first found in yeast. The MST-20 related kinases family is growing, having 28 members divided into two groups - p21-activated kinase and germinal center kinase (GCK) families. STK24 belongs to the germinal center kinase (GCK) III subfamily of sterile 20 kinases.
# Function
Kinases of GCKIII subfamily are involved in regulation of multiple functions of the cells and interaction with programmed cell death 10 (CCM3). CCM is a pathological vascular situation that, influencing the blood vessels in central nervous system (CNS), may cause stroke, seizure and even cerebral hemorrhage. It has been shown that STK24 and STK25 operate in the same cardiovascular development pathway with CCM3. According to the results of the experiment by Zhang et al, lack of STK24 has no effect on the amount of neutrophils or leucocytes, as well as it does not affect the chemotaxis of neutrophils. Zhang et al also the interaction between STK24 an CCM. Using tandem affinity purification with mass spectrometry, they found that CCM3 is the main protein that binds to STK24 in HEK293 cells.
STK24 operates on serine and threonine residues and, as a response to oxidative stress and caspase activity, develops cell death.
STK24 is activated by autophosphorylation at Thr-190 and phosphorylation at this site is essential for its function. Phosphorylation by protein kinase A activates the isoform B of STK24.
The mutagenesis of four residues in STK24 have been carried out. In position 18, the replacement of threonine (T) with alanine (A) causes the reduction of phosphorylation by PKA. the modification in positions 65, where lysine (K) is replaced with A, and the position 190, where T is replaced with A, affects the activity and autophosphorylation. In residue 321, the change of aspartic acid (D) to Asparagine (N) reveals as loss of proteolytic cleavage by caspases. Those residues may play an important role apoptotic signal transduction.
# Structure and tissue distribution
STK24 has two subunits, 36kDa N-terminal subunit and 12 kDa C-terminal subunit. In the cells, STK24 is located in nucleus and less in cytoplasm and membrane. There are two isoforms of the protein, isoform A is ubiquitous and is expressed in 237 organs, isoform B is expressed in brain hippocampus and cerebral cortex.
# Interactions
STK24 has been shown to interact with PDCD10, TRAF3IP3, STRN3, MOBKL3, STRN, SLMAP, PPP2R1A, CTTNBP2NL, FAM40A and STRN4. | STK24
Serine/threonine-protein kinase 24 is an enzyme that in humans is encoded by the STK24 gene [1][2][3] located in the chromosome 13, band q32.2. It is also known as Mammalian STE20-like protein kinase 3 (MST-3).[4] The protein is 443 amino acids long and its mass is 49 kDa.[4]
# Classification and discovery
The yeast 'Sterile 20' gene (STE20) functions upstream of the mitogen-activated protein kinase (MAPK) cascade. In mammals, protein kinases related to STE20 can be divided into 2 subfamilies based on their structure and regulation. Members of the PAK subfamily (see PAK3) contain a C-terminal catalytic domain and an N-terminal regulatory domain that has a CDC42-binding domain. In contrast, members of the GCK subfamily (MAP4K2), also called the Sps1 subfamily, have an N-terminal catalytic domain and a C-terminal regulatory domain without a CDC42-binding domain. STK24 belongs to the GCK subfamily of STE20-like kinases.[2][3]
The sterile 20 protein was first found in yeast.[5] The MST-20 related kinases family is growing, having 28 members divided into two groups - p21-activated kinase and germinal center kinase (GCK) families.[6] STK24 belongs to the germinal center kinase (GCK) III subfamily of sterile 20 kinases.
# Function
Kinases of GCKIII subfamily are involved in regulation of multiple functions of the cells[6] and interaction with programmed cell death 10 (CCM3).[7] CCM is a pathological vascular situation that, influencing the blood vessels in central nervous system (CNS), may cause stroke, seizure and even cerebral hemorrhage.[8] It has been shown that STK24 and STK25 operate in the same cardiovascular development pathway with CCM3. According to the results of the experiment by Zhang et al,[8] lack of STK24 has no effect on the amount of neutrophils or leucocytes, as well as it does not affect the chemotaxis of neutrophils.[8] Zhang et al also the interaction between STK24 an CCM. Using tandem affinity purification with mass spectrometry, they found that CCM3 is the main protein that binds to STK24 in HEK293 cells.[8]
STK24 operates on serine and threonine residues and, as a response to oxidative stress and caspase activity, develops cell death.[4]
STK24 is activated by autophosphorylation at Thr-190 and phosphorylation at this site is essential for its function. Phosphorylation by protein kinase A activates the isoform B of STK24.[4]
The mutagenesis of four residues in STK24 have been carried out. In position 18, the replacement of threonine (T) with alanine (A) causes the reduction of phosphorylation by PKA.[2] the modification in positions 65, where lysine (K) is replaced with A, and the position 190, where T is replaced with A, affects the activity and autophosphorylation.[6] In residue 321, the change of aspartic acid (D) to Asparagine (N) reveals as loss of proteolytic cleavage by caspases.[6] Those residues may play an important role apoptotic signal transduction.[6]
# Structure and tissue distribution
STK24 has two subunits, 36kDa N-terminal subunit and 12 kDa C-terminal subunit.[4] In the cells, STK24 is located in nucleus and less in cytoplasm and membrane. There are two isoforms of the protein, isoform A is ubiquitous and is expressed in 237 organs, isoform B is expressed in brain hippocampus and cerebral cortex.[4]
# Interactions
STK24 has been shown to interact with PDCD10,[9][10][11] TRAF3IP3,[11] STRN3,[10][11] MOBKL3,[10][11] STRN,[10][11] SLMAP,[10][11] PPP2R1A,[10][11] CTTNBP2NL,[11] FAM40A[10][11] and STRN4.[10][11] | https://www.wikidoc.org/index.php/STK24 | |
f21b8420e120bb722cc1fa406799bb355576b1a8 | wikidoc | STK39 | STK39
STE20/SPS1-related proline-alanine-rich protein kinase is an enzyme that in humans is encoded by the STK39 gene.
This gene encodes a serine/threonine kinase that is thought to function in the cellular stress response pathway. The kinase is activated in response to hypotonic stress, leading to phosphorylation of several cation-chloride-coupled cotransporters. The catalytically active kinase specifically activates the p38 MAP kinase pathway, and its interaction with p38 decreases upon cellular stress, suggesting that this kinase may serve as an intermediate in the response to cellular stress.
Some studies suggest that this gene might be linked to high blood pressure. | STK39
STE20/SPS1-related proline-alanine-rich protein kinase is an enzyme that in humans is encoded by the STK39 gene.[1][2]
This gene encodes a serine/threonine kinase that is thought to function in the cellular stress response pathway. The kinase is activated in response to hypotonic stress, leading to phosphorylation of several cation-chloride-coupled cotransporters. The catalytically active kinase specifically activates the p38 MAP kinase pathway, and its interaction with p38 decreases upon cellular stress, suggesting that this kinase may serve as an intermediate in the response to cellular stress.[2]
Some studies suggest that this gene might be linked to high blood pressure.[3] | https://www.wikidoc.org/index.php/STK39 | |
9dd61b5e9ffe7ec993f086afebc240c56d744a81 | wikidoc | STUB1 | STUB1
STUB1 (STIP1 homology and U-Box containing protein 1) is a human gene that codes for the protein CHIP (C terminus of HSC70-Interacting Protein).
# Function
The CHIP protein encoded by this gene binds to and inhibits the ATPase activity of the chaperone proteins HSC70 and HSP70 and blocks the forward reaction of the HSC70-HSP70 substrate-binding cycle. In addition, CHIP possesses E3 ubiquitin ligase activity and promotes ubiquitylation, mainly of chaperone-bound misfolded proteins.
CHIP enhances HSP70 induction during acute stress and also mediates its turnover during the stress recovery process. Hence CHIP appears to maintain protein homeostasis by controlling chaperone levels during stress and recovery.
Mutations in STUB1 cause spinocerebellar ataxia type 16.
# Interactions
STUB1 has been shown to interact with:
- C-Raf,
- DNAJB1,
- HSPA1A,
- HSPA4,
- HSPA8,
- Parkin (ligase), and
- RUNX2. | STUB1
STUB1 (STIP1 homology and U-Box containing protein 1) is a human gene that codes for the protein CHIP (C terminus of HSC70-Interacting Protein). [1][2]
# Function
The CHIP protein encoded by this gene binds to and inhibits the ATPase activity of the chaperone proteins HSC70 and HSP70 and blocks the forward reaction of the HSC70-HSP70 substrate-binding cycle.[2] In addition, CHIP possesses E3 ubiquitin ligase activity and promotes ubiquitylation[3], mainly of chaperone-bound misfolded proteins.
CHIP enhances HSP70 induction during acute stress and also mediates its turnover during the stress recovery process. Hence CHIP appears to maintain protein homeostasis by controlling chaperone levels during stress and recovery.[4]
Mutations in STUB1 cause spinocerebellar ataxia type 16.[5]
# Interactions
STUB1 has been shown to interact with:
- C-Raf,[6]
- DNAJB1,[2]
- HSPA1A,[2][7]
- HSPA4,[2]
- HSPA8,[2]
- Parkin (ligase),[7] and
- RUNX2.[8] | https://www.wikidoc.org/index.php/STUB1 | |
e1d46079471c3ae506a2671d94bf08bd7883b8af | wikidoc | STX10 | STX10
Syntaxin-10 (STX10) is a SNARE protein that is encoded by the STX10 gene. This protein is found in most vertebrates (including humans) but is noticeably absent from mice. As with other SNARE proteins, STX10 facilitates vesicle fusion and thus is important for intracellular trafficking of proteins and other cellular components. More specifically, STX10 has been implicated in endosome to Golgi trafficking of the mannose 6-phosphate receptor and glucose transporter type 4.
STX10 has been detected in the trans-Golgi network (TGN) by immunofluorescence.
# Structure and function
Human STX10 is a 249 amino acid protein that has three N-terminal α-helices and a single SNARE domain followed by a single-pass transmembrane domain. Human STX10 is 60% identical to human STX6.
STX10 is structurally classified as a Qc-SNARE (contributes a glutamine (Q) residue in the formation of the assembled core SNARE complex) and is functionally classified as a t-SNARE (or target-SNARE which is often located in the membranes of target compartments).
# Interactions
STX10 is known to interact with the t-SNAREs VTI1A and STX16 and with the v-SNAREs VAMP3 and VAMP4. The SNARE complex of STX10, STX16, VTI1A, and VAMP3 are required for late endosome to Golgi trafficking of the mannose 6-phosphate receptor. Early endosome to Golgi trafficking of Shiga toxin requires the SNARE complex of STX6, STX16, VTI1A, and VAMP3 or VAMP4.
Thus, STX10 distinguishes early endosome to Golgi trafficking from late endosome to Golgi trafficking. | STX10
Syntaxin-10 (STX10) is a SNARE protein that is encoded by the STX10 gene.[1] This protein is found in most vertebrates (including humans) but is noticeably absent from mice.[2][3] As with other SNARE proteins, STX10 facilitates vesicle fusion and thus is important for intracellular trafficking of proteins and other cellular components. More specifically, STX10 has been implicated in endosome to Golgi trafficking of the mannose 6-phosphate receptor[2] and glucose transporter type 4.[3]
STX10 has been detected in the trans-Golgi network (TGN) by immunofluorescence.[1]
# Structure and function
Human STX10 is a 249 amino acid protein that has three N-terminal α-helices and a single SNARE domain followed by a single-pass transmembrane domain. Human STX10 is 60% identical to human STX6.[1]
STX10 is structurally classified as a Qc-SNARE (contributes a glutamine (Q) residue in the formation of the assembled core SNARE complex) and is functionally classified as a t-SNARE (or target-SNARE which is often located in the membranes of target compartments).[4]
# Interactions
STX10 is known to interact with the t-SNAREs VTI1A and STX16[5] and with the v-SNAREs VAMP3[2] and VAMP4.[5] The SNARE complex of STX10, STX16, VTI1A, and VAMP3 are required for late endosome to Golgi trafficking of the mannose 6-phosphate receptor.[2] Early endosome to Golgi trafficking of Shiga toxin requires the SNARE complex of STX6, STX16, VTI1A, and VAMP3 or VAMP4.[6]
Thus, STX10 distinguishes early endosome to Golgi trafficking from late endosome to Golgi trafficking.[2] | https://www.wikidoc.org/index.php/STX10 | |
e837180292c1aae06377489513f9b38e4afa20e2 | wikidoc | STX1A | STX1A
Syntaxin-1A is a protein that in humans is encoded by the STX1A gene.
# Function
Synaptic vesicles store neurotransmitters that are released during calcium-regulated exocytosis. The specificity of neurotransmitter release requires the localization of both synaptic vesicles and calcium channels to the presynaptic active zone. Syntaxins function in this vesicle fusion process.
Syntaxin-1A is a member of the syntaxin superfamily. Syntaxins are nervous system-specific proteins implicated in the docking of synaptic vesicles with the presynaptic plasma membrane. Syntaxins possess a single C-terminal transmembrane domain, a SNARE domain (known as H3), and an N-terminal regulatory domain (Habc). Syntaxins bind synaptotagmin in a calcium-dependent fashion and interact with voltage dependent calcium and potassium channels via the C-terminal H3 domain. Syntaxin-1A is a key protein in ion channel regulation and synaptic exocytosis.
# Clinical significance
Syntaxins serve as a substrate for botulinum neurotoxin type C, a metalloprotease that blocks exocytosis and has high affinity for a molecular complex that includes the alpha-latrotoxin receptor which produces explosive exocytosis.
The expression level of STX1A is directly correlated with intelligence in Williams syndrome.
# Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.
- ↑ The interactive pathway map can be edited at WikiPathways: "NicotineDopaminergic_WP1602"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
# Interactions
STX1A has been shown to interact with:
- CPLX1,
- CFTR,
- NAPA,
- RNF40,
- SCNN1G,
- SLC6A1,
- SNAP-25,
- SNAP23,
- STXBP1,
- STXBP5,
- SYT1
- UNC13B,
- VAMP2, and
- VAMP8. | STX1A
Syntaxin-1A is a protein that in humans is encoded by the STX1A gene.[1]
# Function
Synaptic vesicles store neurotransmitters that are released during calcium-regulated exocytosis. The specificity of neurotransmitter release requires the localization of both synaptic vesicles and calcium channels to the presynaptic active zone. Syntaxins function in this vesicle fusion process.
Syntaxin-1A is a member of the syntaxin superfamily. Syntaxins are nervous system-specific proteins implicated in the docking of synaptic vesicles with the presynaptic plasma membrane. Syntaxins possess a single C-terminal transmembrane domain, a SNARE [Soluble NSF (N-ethylmaleimide-sensitive fusion protein)-Attachment protein REceptor] domain (known as H3), and an N-terminal regulatory domain (Habc). Syntaxins bind synaptotagmin in a calcium-dependent fashion and interact with voltage dependent calcium and potassium channels via the C-terminal H3 domain. Syntaxin-1A is a key protein in ion channel regulation and synaptic exocytosis.[2]
# Clinical significance
Syntaxins serve as a substrate for botulinum neurotoxin type C, a metalloprotease that blocks exocytosis and has high affinity for a molecular complex that includes the alpha-latrotoxin receptor which produces explosive exocytosis.[3]
The expression level of STX1A is directly correlated with intelligence in Williams syndrome.[4]
# Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.[§ 1]
- ↑ The interactive pathway map can be edited at WikiPathways: "NicotineDopaminergic_WP1602"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
# Interactions
STX1A has been shown to interact with:
- CPLX1,[5][6][7]
- CFTR,[8][9]
- NAPA,[10][11]
- RNF40,[12]
- SCNN1G,[13]
- SLC6A1,[14][15][16]
- SNAP-25,[5][6][10][17][18][19][20][21][22][23][24]
- SNAP23,[22][24][25][26][27]
- STXBP1,[5][10][18][28][29]
- STXBP5,[30][31]
- SYT1[32][33]
- UNC13B,[34]
- VAMP2,[5][6][10][29][35][36] and
- VAMP8.[37] | https://www.wikidoc.org/index.php/STX1A | |
eef0840b1dfce56333a9c954b0c3bd6289b86b8f | wikidoc | SUDS3 | SUDS3
Sin3 histone deacetylase corepressor complex component SDS3 is an enzyme that in humans is encoded by the SUDS3 gene.
# Function
SDS3 is a subunit of the histone deacetylase (see HDAC1; MIM 601241)-dependent SIN3A (MIM 607776) corepressor complex (Fleischer et al., 2003).
# Interactions
SUDS3 has been shown to interact with HDAC1, Host cell factor C1, SIN3B and SIN3A. | SUDS3
Sin3 histone deacetylase corepressor complex component SDS3 is an enzyme that in humans is encoded by the SUDS3 gene.[1][2]
# Function
SDS3 is a subunit of the histone deacetylase (see HDAC1; MIM 601241)-dependent SIN3A (MIM 607776) corepressor complex (Fleischer et al., 2003).[supplied by OMIM][2]
# Interactions
SUDS3 has been shown to interact with HDAC1,[1][3] Host cell factor C1,[4] SIN3B[1] and SIN3A.[1][3] | https://www.wikidoc.org/index.php/SUDS3 | |
c3b3900507f828b16e53e641dd66b105dd2a839b | wikidoc | SUHW4 | SUHW4
Zinc finger protein 280D, also known as Suppressor Of Hairy Wing Homolog 4, SUWH4, Zinc Finger Protein 634, ZNF634, or KIAA1584, is a protein that in humans is encoded by the ZNF280D gene located on chromosome 15q21.3.
# Gene
There are a total of 24 possible exons in any variant of the ZNF280D gene. ZNF280D is oriented on the minus strand of Chromosome 15 and spans 288.396 kb.
Surrounding genes at the same locus include TEX9, HMGB1P33, MNS1, LOC645877, and LOC145783.
# mRNA
At least 24 spliced variants have been identified. There are 7 probable alternative promoters. The mRNAs appear to differ by truncation of the 5' end, truncation of the 3' end, presence or absence of 12 cassette exons, overlapping exons with different boundaries, splicing versus retention of 5 introns. The longest splice form contains 4428 bp.
# Protein
## Composition and Domains
The ZNF280D protein is 979 amino acids in length.
The protein contains a domain of unknown function (DUF4195) spanning from amino acid 45 to amino acid 230.
DUF4195 (pfam13826) is a family that is found at the N-terminus of metazoan proteins that carry PHD-like zinc-finger domains; the function is unknown.
ZNF280D protein also contains five highly conserved Cys2His2-type zinc finger domains.
Zinc fingers have the ability to bind DNA, which supports the speculative role of ZNF280D as a transcription factor.
The protein has a weight of approximately 109.3 kdal.
Charge cluster analysis reveals a negative charge cluster near the N-terminus from amino acids 16-43.
Charge clusters are associated with functional domains of cellular transcription factors, providing further support for ZNF280D as a possible transcription factor.
## Interactions
ZNF280D has been experimentally determined to interact with CBX5 and CBX3 proteins.
These proteins both play a role in the formation of heterochromatin, which presents a possible functional role of ZNF280D as a transcriptional repressor.
## SNPs
There are a number of SNPs that have been observed in the human population. The image below lists some of the most frequently occurring.
# Regulation
## mRNA Level
A number of transcription factors are predicted to bind to the predicted promoter region.
## Protein Level
ZNF280D protein contains 66 serine, 17 threonine, and 6 tyrosine residues all of which are potential phosphorylation sites.
The glycine residue at position 2 is a probable candidate for N-terminal acetylation.
There are seven probable sumoylation sites.
# Expression
ZNF280D is ubiquitously expressed at relatively low levels throughout almost all tissues in the human body.
In one study, the expression of ZNF280D was compared between endothelial progenitor cells in cord blood and peripheral blood. The results show that expression was significantly higher in cord blood. This supports a possible involvement of ZNF280D in embryonic development or cell differentiation.
# Evolution
A number of orthologs and distant homologs have been identified for the human ZNF280D protein. There are also four paralogs to ZNF280D in the human genome. | SUHW4
Zinc finger protein 280D, also known as Suppressor Of Hairy Wing Homolog 4, SUWH4, Zinc Finger Protein 634, ZNF634, or KIAA1584, is a protein that in humans is encoded by the ZNF280D gene located on chromosome 15q21.3.[1][2]
# Gene
There are a total of 24 possible exons in any variant of the ZNF280D gene.[3] ZNF280D is oriented on the minus strand of Chromosome 15 and spans 288.396 kb.[4]
Surrounding genes at the same locus include TEX9, HMGB1P33, MNS1, LOC645877, and LOC145783.[5]
# mRNA
At least 24 spliced variants have been identified.[6] There are 7 probable alternative promoters. The mRNAs appear to differ by truncation of the 5' end, truncation of the 3' end, presence or absence of 12 cassette exons, overlapping exons with different boundaries, splicing versus retention of 5 introns.[6] The longest splice form contains 4428 bp.[7]
# Protein
## Composition and Domains
The ZNF280D protein is 979 amino acids in length.[8]
The protein contains a domain of unknown function (DUF4195) spanning from amino acid 45 to amino acid 230.[8]
DUF4195 (pfam13826) is a family that is found at the N-terminus of metazoan proteins that carry PHD-like zinc-finger domains; the function is unknown.[9]
ZNF280D protein also contains five highly conserved Cys2His2-type zinc finger domains.[10]
Zinc fingers have the ability to bind DNA, which supports the speculative role of ZNF280D as a transcription factor.[11]
The protein has a weight of approximately 109.3 kdal.[12]
Charge cluster analysis reveals a negative charge cluster near the N-terminus from amino acids 16-43.[12]
Charge clusters are associated with functional domains of cellular transcription factors, providing further support for ZNF280D as a possible transcription factor.[13]
## Interactions
ZNF280D has been experimentally determined to interact with CBX5 and CBX3 proteins.[14]
These proteins both play a role in the formation of heterochromatin, which presents a possible functional role of ZNF280D as a transcriptional repressor.[15][16]
## SNPs
There are a number of SNPs that have been observed in the human population.[17] The image below lists some of the most frequently occurring.
# Regulation
## mRNA Level
A number of transcription factors are predicted to bind to the predicted promoter region.[18]
## Protein Level
ZNF280D protein contains 66 serine, 17 threonine, and 6 tyrosine residues all of which are potential phosphorylation sites.[19]
The glycine residue at position 2 is a probable candidate for N-terminal acetylation.[20]
There are seven probable sumoylation sites.[21]
# Expression
ZNF280D is ubiquitously expressed at relatively low levels throughout almost all tissues in the human body.[22]
In one study, the expression of ZNF280D was compared between endothelial progenitor cells in cord blood and peripheral blood. The results show that expression was significantly higher in cord blood. This supports a possible involvement of ZNF280D in embryonic development or cell differentiation.[23]
# Evolution
A number of orthologs and distant homologs have been identified for the human ZNF280D protein. There are also four paralogs to ZNF280D in the human genome.[24] | https://www.wikidoc.org/index.php/SUHW4 | |
faa772e93ae077b6b48b85579b565b38776f10f0 | wikidoc | SULF1 | SULF1
Sulfatase 1, also known as SULF1, is an enzyme which in humans is encoded by the SULF1 gene.
Heparan sulfate proteoglycans (HSPGs) act as co-receptors for numerous heparin-binding growth factors and cytokines and are involved in cell signaling. Heparan sulfate 6-O-endo-sulfatases, such as SULF1, selectively remove 6-O-sulfate groups from heparan sulfate. This activity modulates the effects of heparan sulfate by altering binding sites for signaling molecules.
# Function
Heparan sulfate proteoglycans (HSPGs) are widely expressed throughout most tissues of nearly all multicellular species. The function of HSPGs extends beyond providing an extracellular matrix (ECM) structure and scaffold for cells. They are integral regulators of essential cell signaling pathways affecting cell growth, proliferation, differentiation, and migration. Although the core protein is important, the large heparan sulfate (HS) chains extending from the core are responsible for most receptor signaling. HS chains are heterogeneous structures that differ in specific and conditional cell contexts. Of particular importance is the HS sulfation pattern, which was once thought to be static after HS biosynthesis in the Golgi. However, this paradigm changed after the discovery of two extracellular 6-O-S glucosamine arylsulfatases, Sulf1 and Sulf2. These two enzymes allow rapid extracellular modification of sulfate content in HSPGs, impacting signaling involving Shh, Wnt, BMP, FGF, VEGF, HB-EGF, GDNF, and HGF. In addition, Sulfs may exercise another level of regulation over HS composition by down or upregulating HS biosynthetic enzymes present in the Golgi through the very same signaling pathways they modify.
# Discovery
Before the cloning and characterization of Sulf1 and Sulf2, HS composition was thought to be unchanging after localization to the cell surface. However, this changed when the quail orthologue of Sulf1, QSulf1, was identified in a screen for Sonic hedgehog (Shh) response genes activated during somite formation in quail embryos. Sequence alignment analysis indicates QSsulf1 is homologous with lysosomal N-acetyl glucosamine sulfatases (G6-sulfatases) that catalyze the hydrolysis of 6-O sulfates from N-acetyl glucosamines of heparan sulfate during the degradation of HSPGs. In contrast to lysosomal active sulfatases, QSulf1 localizes exclusively to the cell surface by interacting hydrophilically with a non-heparan sulfate outer membrane component, and is enzymatically active at a neutral pH. By mutating the catalytically active cysteines to alanine, thereby blocking N-formylglycine formation, they found QSulf1 was responsible for Wingless (Wnt) release from HS chains to activate the Frizzled receptor; this was the first evidence that an extracellular sulf was capable of modifying HS and therefore cell signaling. The overall structure of QSulf is followed closely by its orthologues and paralogues, including human and mouse. The human and murine orthologues of QSulf1, HSulf1 and MSulf1, respectively, were cloned and characterized after the discovery of QSulf1. In addition, a paralogue, Sulf2, sharing 63-65% identity (both mouse and human) with Sulf1 also was discovered through BLAST sequence analysis. The HSulf1 gene (GenBank accession number AY101175) has an open reading frame of 2616 bp, encoding a protein of 871 amino acid (aa), and HSulf2 (GenBank accession number AY101176) has an open reading frame of 2613 bp, encoding a protein of 870 aa. The HSulf1 and 2 genes localize to 8q13.2-13.3 and 20q13.12, respectively. They contain putative Asn-linked glycosylation sites, and furin cleavage sites responsible for proteolytic processing in the Golgi. The function or substrate specificity these cleavage sites impart has yet to be determined.
Validation of the predicted N-linked glycosylation sites on QSulf1 were performed using tunicamycin and QSulf1 variants missing the N-terminal (catalytic) domain or HD, which contain predicted N-linked glycosylation sites. The N- and C-terminal showed unbranched N-linked glycosylation, but was absent in the hydrophilic domain even though it contains two putative sites. In addition, O-linked or sialylated glycosylation were not present in QSulf1. Importantly, proper glycosylation is necessary to localize to the cell surface, possibly to bind HS moieties, and was required for enzymatic activity.
# Structure and mechanism
Sulf1 and Sulf2 are new members of a superfamily of arylsulfatases, being closely related to arylsulfatase A, B (ARSA; ARSB) and glucosamine 6-sulfatase (G6S). The x-ray crystal structure of neither Sulf1 or Sulf2 has been attempted, but ARSA active site crystal structure was deciphered. In ARSA, the conserved cysteine, which is posttranslationally modified to a C alpha formylglycine (FG) is critical for catalytic activity. In the first step, one of the two oxygens of the aldehyde hydrate attacks the sulfur of the sulfate ester. This leads to a transesterification of the sulfate group onto the aldehyde hydrate. Simultaneously the substrate alcohol is released. In the second step, sulfate is eliminated from the enzyme-sulfate intermediate by an intramolecular rearrangement. The “intramolecular hydrolysis” allows the aldehyde group to be regenerated. The active site of ARSA contains nine conserved residues that were found to be critical for catalytic activity. Some residues, such as Lys123 and Lys302, bind the substrate while others either participate in catalysis directly, such as His125 and Asp281, or indirectly. In addition a magnesium ion is needed to coordinate the oxygen that attacks the sulfur in the first step of sulfate cleavage. The crystal structure and residue mutations need to be performed in Sulf1 and Sulf2 to determine if any differences exist from lysosomal sulfatases.
# Enzymatic specificity
HS enzymatic specificity of QSulf1 was first analyzed. QSulf1 enzymatic specificity on 6-O sulfates was linked to the trisulfated disaccharides (HexA,2SGlcNS,6S) in S domains of HS (HS regions where most of the GlcNS residues are in contiguous sequences) and not NA/NS domains (regions of alternating N-acetylated and N-sulfated units; transition zones). Sulf1 and 2 null murine embryonic fibroblasts were generated to test the HS specificity of mammalian Sulf as opposed to avian Sulf (QSulf). Investigators found mSulf1−/−;mSulf2−/− HS showed overall large increases in all 6S disaccharides. Cooperativity between mSulf1/2 was found because a 2-fold increase in S-domain-associated disaccharides (UA–GlcNS(6S) and UA(2S)–GlcNS(6S)) was observed in double knock-out HS as compared with either single knock-out HS alone. However, one difference from mSulf1 is that mSulf2−/− HS shows an increase in 6S almost exclusively within the non-sulfated and transition zones. This sulfation effect on non-sulfated and transition zones is also different from QSulfs, which catalyze desulfation exclusively in S-domains. Although 6S changes were dominant, other small changes in NS and 2S sulfation do occur in the Sulf knock out MEFs, which may be a compensatory mechanism. Further biochemical studies elucidated specificity and localization of human Sulfs 1 and 2. Sulf1 and 2 hydrophilic domains associate with the cell membrane components through electrostatic interactions and not by integration with into the lipid bilayer. In addition to cell membrane association, Sulfs also secreted freely into the media, which contrasts the findings with QSulf1 and 2. Biochemical analysis of HSPGs in Sulf 1 and 2 knockout MEFS reveal enzyme specificities to disulfated and, primarily, trisulfated 6S disaccharide units UA-GlcNS(6S) and UA(2S)-GlcNS(6S) within the HS chain, with specific exclusion of monosulfated disaccharide units. In vivo studies, however, demonstrate that loss of Sulf1 and Sulf2 result in sulfation changes of nonsubstrates (UA-GlcNAc(6S), N and 2-O Sulfate), indicating Sulf modulates HS biosynthetic machinery. This was further demonstrated by PCR analysis, showing dynamic changes in HS biosynthesis enzymes after Sulf1 and 2 loss. Also, the authors showed in an MEF model system, that Sulf1 and Sulf2 definitively and differentially modify HS proteoglycan fractions including cell surface, GPI-anchored (glypican), shed, and ECM-associated proteoglycans.
# Role in cancer
The next section gives a detailed description of Sulf1 and Sulf2’s involvement in cancer. Much of what is known about signaling pathways mediated by Sulfs has been determined through investigating extracellular Sulf role and function in cancer. Therefore, they will be described in tandem. Additionally, this emphasizes how small changes in HS sulfation patterns have major impacts in health and disease.
## Ovarian Cancer
The first signs of Sulf1 dysregulation were found in ovarian cancer. The expression of Sulf1 mRNA was found to be downregulated or absent in a majority of ovarian cancer specimens. The same investigators also found lowered mRNA expression in breast, pancreatic, and hepatic malignant cell lines. This absent or hypomorhic Sulf1 expression results in highly sulfated HSPGs. The lack of Sulf1 expression also augments heparin binding-epidermal growth factor (HB-EGF) response by way of greater EGF Receptor (EGFR) and extracellular signal-regulated kinase (ERK) signaling, which are common signatures of ovarian cancer. Even further, Sulf1 N-terminal sulfatase actitivity was specifically required for cisplatin-induced apoptosis of the ovarian cancer cell line, OV207. The mechanism by which Sulf1 is downregulated in ovarian cancer was investigated. Epigenetic silencing of CpG sites within Sulf1 exon 1A by methylation is associated with ovarian cancer cells and primary ovarian cancer tissues lacking Sulf1 expression. Furthermore, CpG sites showed increased levels of histone H3 K9 methylation in Sulf1 negative ovarian cancer cell lines.
## Breast Cancer
Breast cancer expression of Sulf1 at the mRNA level was shown to be downregulated. Investigations into this relationship revealed that angiogenesis in breast cancer was shown to be regulated in part by Sulf1. Breast cancer xenografts overexpressing Sulf1 in athymic mice showed marked decreases in angiogenesis. Specifically, Sulf1 inhibited the ability of vascular endothelial cell heparan sulfate to participate in complex formation with FGF-2, thereby abolishing growth signaling. FGF-2 is a HB-GF, requiring the formation of a ternary complex with HS and the FGF Receptor (FGFR) to cause receptor dimerization, activation, and autophosphorylation, which then leads to induction of the mitogen-activated protein kinase (MAPK) pathway (in addition to other pathways). This results in several responses including cell proliferation and angiogenesis. Importantly, this response is dependent upon the degree and signature of HS-GAG sulfation. To further validate the response in breast cancer, human umbilical vein endothelial cells (HUVECs), overexpressing Sulf1 inhibited vascular endothelial growth factor 165 (VEGF165) signaling which is dependent upon HS, but not HS-independent VEGF121. Sulf2 also was implicated in breast cancer. In contrast to Sulf1, Sulf2 was upregulated at both the mRNA and protein levels in tumor tissue in two mammary carcinoma mouse models.
Sulf1 displays regulation of amphiregulin and HB-EGF-mediated autocrine and paracrine signaling in breast cancer. Loss of Sulf1 in a breast cancer cell line, MDA-MB-468, shows increased ERK1/2 and EGFR activation, which was shown to be mediated by HB-EGF and amphiregulin, which require complexes with specifically sulfated HS. Breast cancer samples show loss of Sulf1 expression in invasive lobular carcinomas. These carcinomas are predominantly, estrogen receptor (ER) and progesterone receptor (PR)-positive, and HER-2, p53, and EGFR-negative (markers indicating increased aggressiveness of breast cancer), but do not confer an increased survival. The authors suggest that enhanced amphiregulin and HB-EGF signaling due to a lack of Sulf1, and therefore oversulfation of HS, may make lobular carcinomas more aggressive than expected. The mechanism by which Sulf1 is downregulated in breast cancer (and gastric cancer) was further investigated. The authors found aberrant hypermethylation of the Sulf1 promoter in both breast cancer and gastric cancer cell lines and patient samples, leading to a reduction of Sulf1 expression, which is similar to ovarian cancer.
Despite this evidence, disagreements are found in the literature regarding the role of Sulf in breast cancer. In contrast to previous reports, Sulf1 transcript expression was highly upregulated in invasive ductal carcinoma with respect to confined ductal carcinoma in situ. The authors, therefore, propose that Sulf1 is involved in the acquisition of the capacity to invade adjacent tissues in ductal carcinoma in situ.
## Hepatocellular Carcinoma
Cancer cell lines with downregulation of Sulf1 were investigated in the same fashion as ovarian cancer. Nine of 11 hepatocellular carcinoma (HCC) cell lines displayed either absent or severely reduced levels of Sulf1 mRNA. Less than half of HCC tumor samples showed loss of heterozygosity (LOH), and DNA methylation inhibition treatment of Sulf1 absent HCC cell lines reactivated the expression of Sulf1, indicating hypermethylation may be partly responsible for its downregulation. As in ovarian cancer, loss of Sulf1 largely contributed to decreased HPSG sulfation in HCC. In addition, Sulf1 expression is required to suppress sustained activation of ERK1/2 and c-met by the heparin binding growth factors (HB-GF), fibroblast growth factor (FGF) and hepatocyte growth factor (HGF), thereby decreasing cell proliferation. In extension, Sulf1 mediated HCC cell apoptotic sensitivity to cisplatin and staurosporine. As a review, HGF, or scatter factor, activates its receptor c-Met which activates mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) and PI3K signaling that are ultimately responsible for expression of proangiogenic factors, interleukin-8 (IL-8) and vascular endothelial growth factor (VEGF). The HGF/c-Met axis mediates the invasive growth phenotype necessary for metastasis through coordination of cell motility and degradation of extracellular matrix (ECM).
In vivo studies on HCC found Sulf1 overexpressing HCC xenografts displayed delayed tumor growth in mice, and the mechanism involves inhibition of histone deacetylase (HDAC). Sulf1 enhances acetylation of Histone H4 by inhibiting HDAC, which subsequently inhibits the activation of the MAPK and Akt pathways ultimately decreasing HCC tumorogenesis.
Sulf2’s role in HCC contrasted with Sulf1. Sulf2 was upregulated in a majority of HCCs and HCC cell lines, and Sulf2 knockdown eliminated migration and proliferation. Sulf2 also upregulated glypican-3, which is commonly overexpressed in HCC, by increasing ERK, AKT activation through enhanced FGF2 signaling. GPC3 is important in Sulf2-enhanced FGF signaling in vitro, so glypican-3 may mediate its own upregulation through Sulf2. Given that Sulf1 and Sulf2 have redundant functions, Sulf2 contrasting function in HCC was unexpected.
## Pancreatic Cancer
Sulf1 mRNA expression in pancreatic cancer differed from ovarian and liver cancer. Only 50% of pancreatic cancer cell lines tested exhibited a significant decrease in Sulf1. Further, in situ hybridization demonstrated that Sulf1 mRNA expression was not uniformly absent in pancreatic cancer tissue. In fact, Sulf1 was present weakly in normal acinar cells, but present at high levels in the endothelium and malignant cells in pancreatic cancer tissue (Li, Kleeff et al. 2005). This indicates that downregulation of Sulf1 is not a ubiquitous process in carcinogenesis. Nevertheless, endogenous expression of Sulf1 in a Sulf1-negative pancreatic cancer cell line, PANC-1, inhibited FGF-2 signaling, but did not affect HB-EGF, EGF, or insulin-like growth factor-1 (IGF-1) signaling, indicating cell specific effects. In further contrast to ovarian cancer and HCC, Hsulf-1 expressing Panc-1 cells were more resistant to gemcitabine, suggesting Hsulf-1 over-expression might confer increased chemoresistance, and therefore a growth advantage, to pancreatic cancer cells. In further reports Sulf1 displays a complicated expression pattern in pancreatic cancer that is more than merely up or downregulation. For instance, primary pancreatic cancer show higher sulfated HSPGs indicating a lack of Sulf1, but upon metastasis sulfation of HSPGs is reduced. Corroborating patient data were mouse tumor in vivo studies of Sulf1 overexpressing Panc-1 cells showing decreased growth, but increased local invasiveness.
## Other Cancers
In vivo studies were used to investigate HSulf1 and 2 in myeloma. Myeloma cells overexpressing Sulf1 and 2 were subcutaneously injected in severe combined immunodeficient (SCID) mice. Enhanced Sulf expression markedly inhibited growth of these tumors with respect to the control. Again, FGF-2 signaling and subsequent phosphorylation of ERK was attenuated in vitro by both Sulf1 and Sulf2 expression. Sulf1/2 expression resulted in more ECM (collagen fibril deposition) than control tumors, which may be another mechanism by which Sulfs slow down tumor growth. The authors also find Sulf1/2 specifically acts on HS-GAGs on the surface of tumor cells and not in the surrounding stroma, which consequently acts to block FGF-2/FGFR/HS ternary complex formation and inhibition of a downstream signal.
Squamous cell head and neck carcinoma (SCCHN) has three cell lines lacking Sulf1 expression. Transfected-in Sulf1 expression reduces FGF-2 and HGF-mediated phosphorylation and activation of ERK and phosphatidylinositol 3'-kinase (PI3K)/Akt pathways. Without these active pathways, a marked decreased in proliferation and mitogenecity is observed. Sulf1 expression even attenuates cell motility and invasion mediated by HGF, implicating Sulf1 loss in metastasis.
# Animal models
In addition to cancer, Sulf1 and Sulf2 were studied with respect to normal development including neural, muscle, vasculogenesis and skeletal development. Recently, much of what is known was from studies on Sulf1/2 knockout mice.
## Skeletal Development
Through common genetrapping mechanisms, homozygous MSulf2 mice were created to assess the in vivo phenotypic traits. Strain specific nonpenetrant lethality resulted (48% fewer than expected), pups were smaller, and some lung defects were observed, but MSulf2-/- were largely as healthy and viable as wild type litter mates. MSulf2 nulls indicate MSulf1 and MSulf2 may have overlapping functions in regulating sulfation patterns in HSPGs. Given that MSulf2 null mice did not present major abnormal phenotypes double MSulf1/2 knockouts were generated. Again, MSulf1 and MSulf2 nulls individually did not display damaging phenotypes; however MSulf-/-;MSulf2-/- mice showed highly penetrant perinatal lethality. However, some double null mice survived into adulthood, and displayed smaller stature, skeletal lesions, and unusually small but functioning kidneys. The skeletal lesions (axial and appendicular skeleton showing decreases in ossified bone volume; sternal fusion and defective basisphenoid patterning) display similar phenotype to heparan sulfate 2-O-transferase (Hs2st)-deficient mice, BMP deficient mice and hypermorphic Fgfr1 and 3 mice. This provides evidence that Sulf1 and 2 is linked to HS modulation effecting BMP and FGF. In addition, this confirms that Sulf1 and 2 perform overlapping functions, but are needed for survival. Further studies on MSulf1-/-;MSulf2-/- mice extended the role of Sulfs in skeletal development. Double nulls displayed reduced bone length, premature ossification, and sternum and tail vertebrae fusion (Ratzka, Kalus et al. 2008). Also, the zone of proliferating chondrocytes was reduced by 90%, indicating defects in chondrogenesis.
The important role Sulf1 and Sulf2 in skeletal development is not surprising given its regulation of bone-related growth factors. For example, QSulf1 reduces specific HS 6-O sulfation which releases Noggin, an inhibitor of bone morphogenetic protein (BMP), allowing cells to become BMP-4 responsive. Therefore, this directly links Sulf1 to the complex developmental patterning mediated by BMPs. Wnt signaling also is regulated by QSulf1. Investigators found lowered Wnt activation through the Frizzled receptor in the absence of QSulf1 expression in non-expressing embryonic cells. 6-O sulfate HS binds with highly affinity to Wnt, abrogating receptor activation. QSulf1 is required to desulfate 6-O chains, not entirely releasing Wnt but lowering the affinity with HS. This low affinity complex then binds and activates the Frizzled receptor.
Additional studies emphasized the role of Sulfs in chondrogenesis. The role of QSulf1 was determined in quail cartilage development and joint formation because of its association with chondrogenic growth factor signaling (Wnt and BMP). Sulf1 was expressed highly in condensing mesenchyme and, in cell culture, caused prechondrocytes to differentiate into chondrocytes, indicating QSulf1 is needed for early chondrogenesis. QSulf1 displayed perichondrial staining during early development but was downregulated during later stages of development. In addition, QSulf1 shows transient expression in the early joint line followed by its rapid loss of expression in later stages of joint development, suggesting it would have an inhibitory effect in later joint development. Because Sulfs were important in normal chondrogenesis, they were investigated in cartilage diseases. Expression patterns of Sulf1 and Sulf2 were determined in normal and osteoarthritic (AO) cartilage. Both Sulf1 and Sulf2 showed enhanced expression in OA and aging cartilage. Given several HSPGs (perlecan, syndecan 1/3, glypican) are upregulated and growth factor signaling through FGF-2, Wnt, BMP, and Noggin are modulated in OA, Sulfs and the modifications of HS may mediate an entirely new level of control over OA development.
## Nervous System Development
Sulf null mice and other model systems implicated Sulfs in other developmental and disease systems. For example, studies detected esophageal defects in surviving MSulf-/-;MSulf2-/- adult mice. Specifically, esophagi had impaired smooth muscle contractility with reduced neuronal innervation and enteric glial cell numbers. It was postulated to be mediated by decreased glial-derived neurotrophic factor (GDNF), which is responsible for neurite sprouting in the embryonic esophagus. Sulf expression is not obligatory for GDNF signaling, but it does enhance the signal greatly. MSulf1 and 2 are believed to decrease 6-O sulfation, releasing GDNF from HS to bind and activate its receptor, thereby mediating its effects on esophageal innervation. Sulf1 even functions in basic neural development. Sulf1 modulation of HS chains sulfation is critical in nervous system development. Specifically, Sufl1 expression leads to the switch of ventral neural progenitor cells toward an oligodendroglial fate by modulating Shh distribution and increasing signaling on apical neuroepithelial cells.
## Muscle Development and Other Regulation
Sulf1 and 2 also display regulation over muscle development, angiogenesis, leukocyte rolling and wound healing. In adult mice, Sulf1 and Sulf2 have overlapping functions in regulating muscle regeneration. Functionally, Sulfs cooperatively desulfate HS 6-O present on activated satellite cells to suppress FGF2 signaling and therefore promote myogenic differentiation to regenerate muscle. Because of this role, Sulfs may have a direct role in diseases such as muscular dystrophy. QSulf1 was used as a tool to either decrease sulfation of HS or increase sulfation by employing a dominant negative QSulf1 (DNQSulf1). Vascular smooth muscle cells (VSMC) are highly influenced by degrees of HS sulfation. Overexpression of QSulf1 decreased adhesion, and increased proliferation and apoptosis of VSMC, while DNQSulf1 also decreased adhesion and increased proliferation, apoptosis, migration and chemotaxis of VSMC. Displaying cell specific effects, both overexpression of Sulf1 and DNQSulf1 increased ERK1/2 phosphorylation in VSMCs, a different response from cancer cell lines. Essentially, these experiments display that a fine-tuned 6-O sulfation pattern is needed for proper function of VSMCs.
Sulf2 was investigated with respect to angiogenesis in a chick model. In contrast to Sulf1, Sulf2 actually induced angiogenesis in a chick chorioallantoic membrane assay. Sulf2 was measured for its ability to modulate binding of growth factors to trisulfated disaccharide motif heparin and HS. Sulf2 inhibited both pre- and post-binding of VEGF165, FGF-1, and SDF-1, a HS-binding chemokine, to both heparin and HS. Investigators hypothesize that Sulf-2 may mobilize ECM-sequestered angiogenic factors, increasing their bioavailability to endothelial cells that express the appropriate receptors.
Investigators found that HSPGs such as perlecan and collagen type XVIII are modified during human renal ischemia/reperfusion, which is associated with severe endothelial damage. Vascular basement membrane (BM) HSPGs are modified to bind L-selectin and monocyte chemoattractant protein-1 (MCP-1) during leukocyte infiltration. Specifically, they require 6-0 sulfation to bind HS chains. The authors show evidence and propose that Sulf1 is usually present on microvascular BM but is downregulated to allow resulfation of 6-O HS for binding of L-selectin and MCP-1. This in turn implicates Sulf1 in human renal allograft rejection which is highly dependent upon HSPG function in peritubular capillaries.
Finally, in a transcriptome wide assay in chronic wound, fortyfold higher expression Sulf1 was noted in wound-site vessels. This increase was attributed to its ability to inhibit angiogenesis as it had in breast cancer models. | SULF1
Sulfatase 1, also known as SULF1, is an enzyme which in humans is encoded by the SULF1 gene.[1]
Heparan sulfate proteoglycans (HSPGs) act as co-receptors for numerous heparin-binding growth factors and cytokines and are involved in cell signaling. Heparan sulfate 6-O-endo-sulfatases, such as SULF1, selectively remove 6-O-sulfate groups from heparan sulfate. This activity modulates the effects of heparan sulfate by altering binding sites for signaling molecules.[1]
# Function
Heparan sulfate proteoglycans (HSPGs) are widely expressed throughout most tissues of nearly all multicellular species.[2] The function of HSPGs extends beyond providing an extracellular matrix (ECM) structure and scaffold for cells. They are integral regulators of essential cell signaling pathways affecting cell growth, proliferation, differentiation, and migration. Although the core protein is important, the large heparan sulfate (HS) chains extending from the core are responsible for most receptor signaling. HS chains are heterogeneous structures that differ in specific and conditional cell contexts. Of particular importance is the HS sulfation pattern, which was once thought to be static after HS biosynthesis in the Golgi. However, this paradigm changed after the discovery of two extracellular 6-O-S glucosamine arylsulfatases, Sulf1 and Sulf2. These two enzymes allow rapid extracellular modification of sulfate content in HSPGs, impacting signaling involving Shh, Wnt, BMP, FGF, VEGF, HB-EGF, GDNF, and HGF. In addition, Sulfs may exercise another level of regulation over HS composition by down or upregulating HS biosynthetic enzymes present in the Golgi through the very same signaling pathways they modify.
# Discovery
Before the cloning and characterization of Sulf1 and Sulf2, HS composition was thought to be unchanging after localization to the cell surface.[3] However, this changed when the quail orthologue of Sulf1, QSulf1, was identified in a screen for Sonic hedgehog (Shh) response genes activated during somite formation in quail embryos.[4] Sequence alignment analysis indicates QSsulf1 is homologous with lysosomal N-acetyl glucosamine sulfatases (G6-sulfatases) that catalyze the hydrolysis of 6-O sulfates from N-acetyl glucosamines of heparan sulfate during the degradation of HSPGs.[4] In contrast to lysosomal active sulfatases, QSulf1 localizes exclusively to the cell surface by interacting hydrophilically with a non-heparan sulfate outer membrane component, and is enzymatically active at a neutral pH.[4] By mutating the catalytically active cysteines to alanine, thereby blocking N-formylglycine formation, they found QSulf1 was responsible for Wingless (Wnt) release from HS chains to activate the Frizzled receptor; this was the first evidence that an extracellular sulf was capable of modifying HS and therefore cell signaling.[4] The overall structure of QSulf is followed closely by its orthologues and paralogues, including human and mouse. The human and murine orthologues of QSulf1, HSulf1 and MSulf1, respectively, were cloned and characterized after the discovery of QSulf1.[5] In addition, a paralogue, Sulf2, sharing 63-65% identity (both mouse and human) with Sulf1 also was discovered through BLAST sequence analysis.[5] The HSulf1 gene (GenBank accession number AY101175) has an open reading frame of 2616 bp, encoding a protein of 871 amino acid (aa), and HSulf2 (GenBank accession number AY101176) has an open reading frame of 2613 bp, encoding a protein of 870 aa.[5] The HSulf1 and 2 genes localize to 8q13.2-13.3 and 20q13.12, respectively.[5] They contain putative Asn-linked glycosylation sites, and furin cleavage sites responsible for proteolytic processing in the Golgi.[5] The function or substrate specificity these cleavage sites impart has yet to be determined.
Validation of the predicted N-linked glycosylation sites on QSulf1 were performed using tunicamycin and QSulf1 variants missing the N-terminal (catalytic) domain or HD, which contain predicted N-linked glycosylation sites.[6] The N- and C-terminal showed unbranched N-linked glycosylation, but was absent in the hydrophilic domain even though it contains two putative sites.[6] In addition, O-linked or sialylated glycosylation were not present in QSulf1.[6] Importantly, proper glycosylation is necessary to localize to the cell surface, possibly to bind HS moieties, and was required for enzymatic activity.[6]
# Structure and mechanism
Sulf1 and Sulf2 are new members of a superfamily of arylsulfatases, being closely related to arylsulfatase A, B (ARSA; ARSB) and glucosamine 6-sulfatase (G6S).[7][8] The x-ray crystal structure of neither Sulf1 or Sulf2 has been attempted, but ARSA active site crystal structure was deciphered.[8] In ARSA, the conserved cysteine, which is posttranslationally modified to a C alpha formylglycine (FG) is critical for catalytic activity. In the first step, one of the two oxygens of the aldehyde hydrate attacks the sulfur of the sulfate ester. This leads to a transesterification of the sulfate group onto the aldehyde hydrate. Simultaneously the substrate alcohol is released. In the second step, sulfate is eliminated from the enzyme-sulfate intermediate by an intramolecular rearrangement. The “intramolecular hydrolysis” allows the aldehyde group to be regenerated.[9] The active site of ARSA contains nine conserved residues that were found to be critical for catalytic activity. Some residues, such as Lys123 and Lys302, bind the substrate while others either participate in catalysis directly, such as His125 and Asp281, or indirectly.[9] In addition a magnesium ion is needed to coordinate the oxygen that attacks the sulfur in the first step of sulfate cleavage.[9] The crystal structure and residue mutations need to be performed in Sulf1 and Sulf2 to determine if any differences exist from lysosomal sulfatases.
# Enzymatic specificity
HS enzymatic specificity of QSulf1 was first analyzed. QSulf1 enzymatic specificity on 6-O sulfates was linked to the trisulfated disaccharides (HexA,2SGlcNS,6S) in S domains of HS (HS regions where most of the GlcNS residues are in contiguous sequences) and not NA/NS domains (regions of alternating N-acetylated and N-sulfated units; transition zones).[10] Sulf1 and 2 null murine embryonic fibroblasts were generated to test the HS specificity of mammalian Sulf as opposed to avian Sulf (QSulf).[11] Investigators found mSulf1−/−;mSulf2−/− HS showed overall large increases in all 6S disaccharides. Cooperativity between mSulf1/2 was found because a 2-fold increase in S-domain-associated disaccharides (UA–GlcNS(6S) and UA(2S)–GlcNS(6S)) was observed in double knock-out HS as compared with either single knock-out HS alone.[11] However, one difference from mSulf1 is that mSulf2−/− HS shows an increase in 6S almost exclusively within the non-sulfated and transition zones.[11] This sulfation effect on non-sulfated and transition zones is also different from QSulfs, which catalyze desulfation exclusively in S-domains.[10] Although 6S changes were dominant, other small changes in NS and 2S sulfation do occur in the Sulf knock out MEFs, which may be a compensatory mechanism.[11][12] Further biochemical studies elucidated specificity and localization of human Sulfs 1 and 2. Sulf1 and 2 hydrophilic domains associate with the cell membrane components through electrostatic interactions and not by integration with into the lipid bilayer.[13] In addition to cell membrane association, Sulfs also secreted freely into the media, which contrasts the findings with QSulf1 and 2. Biochemical analysis of HSPGs in Sulf 1 and 2 knockout MEFS reveal enzyme specificities to disulfated and, primarily, trisulfated 6S disaccharide units UA-GlcNS(6S) and UA(2S)-GlcNS(6S) within the HS chain, with specific exclusion of monosulfated disaccharide units.[13] In vivo studies, however, demonstrate that loss of Sulf1 and Sulf2 result in sulfation changes of nonsubstrates (UA-GlcNAc(6S), N and 2-O Sulfate), indicating Sulf modulates HS biosynthetic machinery. This was further demonstrated by PCR analysis, showing dynamic changes in HS biosynthesis enzymes after Sulf1 and 2 loss.[13] Also, the authors showed in an MEF model system, that Sulf1 and Sulf2 definitively and differentially modify HS proteoglycan fractions including cell surface, GPI-anchored (glypican), shed, and ECM-associated proteoglycans.[13]
# Role in cancer
The next section gives a detailed description of Sulf1 and Sulf2’s involvement in cancer. Much of what is known about signaling pathways mediated by Sulfs has been determined through investigating extracellular Sulf role and function in cancer. Therefore, they will be described in tandem. Additionally, this emphasizes how small changes in HS sulfation patterns have major impacts in health and disease.
## Ovarian Cancer
The first signs of Sulf1 dysregulation were found in ovarian cancer. The expression of Sulf1 mRNA was found to be downregulated or absent in a majority of ovarian cancer specimens.[14] The same investigators also found lowered mRNA expression in breast, pancreatic, and hepatic malignant cell lines.[14] This absent or hypomorhic Sulf1 expression results in highly sulfated HSPGs.[14] The lack of Sulf1 expression also augments heparin binding-epidermal growth factor (HB-EGF) response by way of greater EGF Receptor (EGFR) and extracellular signal-regulated kinase (ERK) signaling, which are common signatures of ovarian cancer.[14] Even further, Sulf1 N-terminal sulfatase actitivity was specifically required for cisplatin-induced apoptosis of the ovarian cancer cell line, OV207.[14] The mechanism by which Sulf1 is downregulated in ovarian cancer was investigated. Epigenetic silencing of CpG sites within Sulf1 exon 1A by methylation is associated with ovarian cancer cells and primary ovarian cancer tissues lacking Sulf1 expression.[15] Furthermore, CpG sites showed increased levels of histone H3 K9 methylation in Sulf1 negative ovarian cancer cell lines.[15]
## Breast Cancer
Breast cancer expression of Sulf1 at the mRNA level was shown to be downregulated. Investigations into this relationship revealed that angiogenesis in breast cancer was shown to be regulated in part by Sulf1. Breast cancer xenografts overexpressing Sulf1 in athymic mice showed marked decreases in angiogenesis.[16] Specifically, Sulf1 inhibited the ability of vascular endothelial cell heparan sulfate to participate in complex formation with FGF-2, thereby abolishing growth signaling.[16] FGF-2 is a HB-GF, requiring the formation of a ternary complex with HS and the FGF Receptor (FGFR) to cause receptor dimerization, activation, and autophosphorylation, which then leads to induction of the mitogen-activated protein kinase (MAPK) pathway (in addition to other pathways).[17][18] This results in several responses including cell proliferation and angiogenesis. Importantly, this response is dependent upon the degree and signature of HS-GAG sulfation.[17] To further validate the response in breast cancer, human umbilical vein endothelial cells (HUVECs), overexpressing Sulf1 inhibited vascular endothelial growth factor 165 (VEGF165) signaling which is dependent upon HS, but not HS-independent VEGF121.[16] Sulf2 also was implicated in breast cancer. In contrast to Sulf1, Sulf2 was upregulated at both the mRNA and protein levels in tumor tissue in two mammary carcinoma mouse models.[19]
Sulf1 displays regulation of amphiregulin and HB-EGF-mediated autocrine and paracrine signaling in breast cancer.[20] Loss of Sulf1 in a breast cancer cell line, MDA-MB-468, shows increased ERK1/2 and EGFR activation, which was shown to be mediated by HB-EGF and amphiregulin, which require complexes with specifically sulfated HS.[20] Breast cancer samples show loss of Sulf1 expression in invasive lobular carcinomas.[20] These carcinomas are predominantly, estrogen receptor (ER) and progesterone receptor (PR)-positive, and HER-2, p53, and EGFR-negative (markers indicating increased aggressiveness of breast cancer), but do not confer an increased survival.[21] The authors suggest that enhanced amphiregulin and HB-EGF signaling due to a lack of Sulf1, and therefore oversulfation of HS, may make lobular carcinomas more aggressive than expected.[20] The mechanism by which Sulf1 is downregulated in breast cancer (and gastric cancer) was further investigated.[22] The authors found aberrant hypermethylation of the Sulf1 promoter in both breast cancer and gastric cancer cell lines and patient samples, leading to a reduction of Sulf1 expression, which is similar to ovarian cancer.[22]
Despite this evidence, disagreements are found in the literature regarding the role of Sulf in breast cancer. In contrast to previous reports, Sulf1 transcript expression was highly upregulated in invasive ductal carcinoma with respect to confined ductal carcinoma in situ.[23] The authors, therefore, propose that Sulf1 is involved in the acquisition of the capacity to invade adjacent tissues in ductal carcinoma in situ.[23]
## Hepatocellular Carcinoma
Cancer cell lines with downregulation of Sulf1 were investigated in the same fashion as ovarian cancer. Nine of 11 hepatocellular carcinoma (HCC) cell lines displayed either absent or severely reduced levels of Sulf1 mRNA.[24] Less than half of HCC tumor samples showed loss of heterozygosity (LOH), and DNA methylation inhibition treatment of Sulf1 absent HCC cell lines reactivated the expression of Sulf1, indicating hypermethylation may be partly responsible for its downregulation.[24] As in ovarian cancer, loss of Sulf1 largely contributed to decreased HPSG sulfation in HCC.[24] In addition, Sulf1 expression is required to suppress sustained activation of ERK1/2 and c-met by the heparin binding growth factors (HB-GF), fibroblast growth factor (FGF) and hepatocyte growth factor (HGF), thereby decreasing cell proliferation.[24] In extension, Sulf1 mediated HCC cell apoptotic sensitivity to cisplatin and staurosporine.[24] As a review, HGF, or scatter factor, activates its receptor c-Met which activates mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) and PI3K signaling that are ultimately responsible for expression of proangiogenic factors, interleukin-8 (IL-8) and vascular endothelial growth factor (VEGF).[25] The HGF/c-Met axis mediates the invasive growth phenotype necessary for metastasis through coordination of cell motility and degradation of extracellular matrix (ECM).[24][26]
In vivo studies on HCC found Sulf1 overexpressing HCC xenografts displayed delayed tumor growth in mice, and the mechanism involves inhibition of histone deacetylase (HDAC).[27] Sulf1 enhances acetylation of Histone H4 by inhibiting HDAC, which subsequently inhibits the activation of the MAPK and Akt pathways ultimately decreasing HCC tumorogenesis.[27]
Sulf2’s role in HCC contrasted with Sulf1. Sulf2 was upregulated in a majority of HCCs and HCC cell lines, and Sulf2 knockdown eliminated migration and proliferation.[28] Sulf2 also upregulated glypican-3, which is commonly overexpressed in HCC, by increasing ERK, AKT activation through enhanced FGF2 signaling.[28] GPC3 is important in Sulf2-enhanced FGF signaling in vitro, so glypican-3 may mediate its own upregulation through Sulf2.[28] Given that Sulf1 and Sulf2 have redundant functions, Sulf2 contrasting function in HCC was unexpected.
## Pancreatic Cancer
Sulf1 mRNA expression in pancreatic cancer differed from ovarian and liver cancer.[29] Only 50% of pancreatic cancer cell lines tested exhibited a significant decrease in Sulf1.[30] Further, in situ hybridization demonstrated that Sulf1 mRNA expression was not uniformly absent in pancreatic cancer tissue. In fact, Sulf1 was present weakly in normal acinar cells, but present at high levels in the endothelium and malignant cells in pancreatic cancer tissue (Li, Kleeff et al. 2005). This indicates that downregulation of Sulf1 is not a ubiquitous process in carcinogenesis.[30] Nevertheless, endogenous expression of Sulf1 in a Sulf1-negative pancreatic cancer cell line, PANC-1, inhibited FGF-2 signaling, but did not affect HB-EGF, EGF, or insulin-like growth factor-1 (IGF-1) signaling, indicating cell specific effects.[30] In further contrast to ovarian cancer and HCC, Hsulf-1 expressing Panc-1 cells were more resistant to gemcitabine, suggesting Hsulf-1 over-expression might confer increased chemoresistance, and therefore a growth advantage, to pancreatic cancer cells.[30] In further reports Sulf1 displays a complicated expression pattern in pancreatic cancer that is more than merely up or downregulation. For instance, primary pancreatic cancer show higher sulfated HSPGs indicating a lack of Sulf1, but upon metastasis sulfation of HSPGs is reduced.[31] Corroborating patient data were mouse tumor in vivo studies of Sulf1 overexpressing Panc-1 cells showing decreased growth, but increased local invasiveness.[31]
## Other Cancers
In vivo studies were used to investigate HSulf1 and 2 in myeloma. Myeloma cells overexpressing Sulf1 and 2 were subcutaneously injected in severe combined immunodeficient (SCID) mice. Enhanced Sulf expression markedly inhibited growth of these tumors with respect to the control.[32] Again, FGF-2 signaling and subsequent phosphorylation of ERK was attenuated in vitro by both Sulf1 and Sulf2 expression. Sulf1/2 expression resulted in more ECM (collagen fibril deposition) than control tumors, which may be another mechanism by which Sulfs slow down tumor growth.[32] The authors also find Sulf1/2 specifically acts on HS-GAGs on the surface of tumor cells and not in the surrounding stroma, which consequently acts to block FGF-2/FGFR/HS ternary complex formation and inhibition of a downstream signal.[32]
Squamous cell head and neck carcinoma (SCCHN) has three cell lines lacking Sulf1 expression.[33] Transfected-in Sulf1 expression reduces FGF-2 and HGF-mediated phosphorylation and activation of ERK and phosphatidylinositol 3'-kinase (PI3K)/Akt pathways. Without these active pathways, a marked decreased in proliferation and mitogenecity is observed. Sulf1 expression even attenuates cell motility and invasion mediated by HGF, implicating Sulf1 loss in metastasis.[33]
# Animal models
In addition to cancer, Sulf1 and Sulf2 were studied with respect to normal development including neural, muscle, vasculogenesis and skeletal development. Recently, much of what is known was from studies on Sulf1/2 knockout mice.
## Skeletal Development
Through common genetrapping mechanisms, homozygous MSulf2 mice were created to assess the in vivo phenotypic traits.[34] Strain specific nonpenetrant lethality resulted (48% fewer than expected), pups were smaller, and some lung defects were observed, but MSulf2-/- were largely as healthy and viable as wild type litter mates.[34] MSulf2 nulls indicate MSulf1 and MSulf2 may have overlapping functions in regulating sulfation patterns in HSPGs.[34] Given that MSulf2 null mice did not present major abnormal phenotypes double MSulf1/2 knockouts were generated.[35] Again, MSulf1 and MSulf2 nulls individually did not display damaging phenotypes; however MSulf-/-;MSulf2-/- mice showed highly penetrant perinatal lethality. However, some double null mice survived into adulthood, and displayed smaller stature, skeletal lesions, and unusually small but functioning kidneys.[35] The skeletal lesions (axial and appendicular skeleton showing decreases in ossified bone volume; sternal fusion and defective basisphenoid patterning) display similar phenotype to heparan sulfate 2-O-transferase (Hs2st)-deficient mice, BMP deficient mice and hypermorphic Fgfr1 and 3 mice.[35] This provides evidence that Sulf1 and 2 is linked to HS modulation effecting BMP and FGF. In addition, this confirms that Sulf1 and 2 perform overlapping functions, but are needed for survival.[35] Further studies on MSulf1-/-;MSulf2-/- mice extended the role of Sulfs in skeletal development.[36] Double nulls displayed reduced bone length, premature ossification, and sternum and tail vertebrae fusion (Ratzka, Kalus et al. 2008). Also, the zone of proliferating chondrocytes was reduced by 90%, indicating defects in chondrogenesis.[36]
The important role Sulf1 and Sulf2 in skeletal development is not surprising given its regulation of bone-related growth factors. For example, QSulf1 reduces specific HS 6-O sulfation which releases Noggin, an inhibitor of bone morphogenetic protein (BMP), allowing cells to become BMP-4 responsive.[10] Therefore, this directly links Sulf1 to the complex developmental patterning mediated by BMPs.[10] Wnt signaling also is regulated by QSulf1. Investigators found lowered Wnt activation through the Frizzled receptor in the absence of QSulf1 expression in non-expressing embryonic cells.[37] 6-O sulfate HS binds with highly affinity to Wnt, abrogating receptor activation.[37] QSulf1 is required to desulfate 6-O chains, not entirely releasing Wnt but lowering the affinity with HS. This low affinity complex then binds and activates the Frizzled receptor.[37]
Additional studies emphasized the role of Sulfs in chondrogenesis. The role of QSulf1 was determined in quail cartilage development and joint formation because of its association with chondrogenic growth factor signaling (Wnt and BMP). Sulf1 was expressed highly in condensing mesenchyme and, in cell culture, caused prechondrocytes to differentiate into chondrocytes, indicating QSulf1 is needed for early chondrogenesis.[38] QSulf1 displayed perichondrial staining during early development but was downregulated during later stages of development.[38] In addition, QSulf1 shows transient expression in the early joint line followed by its rapid loss of expression in later stages of joint development, suggesting it would have an inhibitory effect in later joint development.[38] Because Sulfs were important in normal chondrogenesis, they were investigated in cartilage diseases. Expression patterns of Sulf1 and Sulf2 were determined in normal and osteoarthritic (AO) cartilage. Both Sulf1 and Sulf2 showed enhanced expression in OA and aging cartilage.[39] Given several HSPGs (perlecan, syndecan 1/3, glypican) are upregulated and growth factor signaling through FGF-2, Wnt, BMP, and Noggin are modulated in OA, Sulfs and the modifications of HS may mediate an entirely new level of control over OA development.[39]
## Nervous System Development
Sulf null mice and other model systems implicated Sulfs in other developmental and disease systems. For example, studies detected esophageal defects in surviving MSulf-/-;MSulf2-/- adult mice.[40] Specifically, esophagi had impaired smooth muscle contractility with reduced neuronal innervation and enteric glial cell numbers.[40] It was postulated to be mediated by decreased glial-derived neurotrophic factor (GDNF), which is responsible for neurite sprouting in the embryonic esophagus. Sulf expression is not obligatory for GDNF signaling, but it does enhance the signal greatly.[40] MSulf1 and 2 are believed to decrease 6-O sulfation, releasing GDNF from HS to bind and activate its receptor, thereby mediating its effects on esophageal innervation.[40] Sulf1 even functions in basic neural development. Sulf1 modulation of HS chains sulfation is critical in nervous system development. Specifically, Sufl1 expression leads to the switch of ventral neural progenitor cells toward an oligodendroglial fate by modulating Shh distribution and increasing signaling on apical neuroepithelial cells.[41]
## Muscle Development and Other Regulation
Sulf1 and 2 also display regulation over muscle development, angiogenesis, leukocyte rolling and wound healing. In adult mice, Sulf1 and Sulf2 have overlapping functions in regulating muscle regeneration.[42] Functionally, Sulfs cooperatively desulfate HS 6-O present on activated satellite cells to suppress FGF2 signaling and therefore promote myogenic differentiation to regenerate muscle.[42] Because of this role, Sulfs may have a direct role in diseases such as muscular dystrophy.[42] QSulf1 was used as a tool to either decrease sulfation of HS or increase sulfation by employing a dominant negative QSulf1 (DNQSulf1).[43] Vascular smooth muscle cells (VSMC) are highly influenced by degrees of HS sulfation. Overexpression of QSulf1 decreased adhesion, and increased proliferation and apoptosis of VSMC, while DNQSulf1 also decreased adhesion and increased proliferation, apoptosis, migration and chemotaxis of VSMC.[43] Displaying cell specific effects, both overexpression of Sulf1 and DNQSulf1 increased ERK1/2 phosphorylation in VSMCs, a different response from cancer cell lines.[43] Essentially, these experiments display that a fine-tuned 6-O sulfation pattern is needed for proper function of VSMCs.[43]
Sulf2 was investigated with respect to angiogenesis in a chick model. In contrast to Sulf1, Sulf2 actually induced angiogenesis in a chick chorioallantoic membrane assay.[44] Sulf2 was measured for its ability to modulate binding of growth factors to trisulfated disaccharide motif heparin and HS. Sulf2 inhibited both pre- and post-binding of VEGF165, FGF-1, and SDF-1, a HS-binding chemokine, to both heparin and HS.[44] Investigators hypothesize that Sulf-2 may mobilize ECM-sequestered angiogenic factors, increasing their bioavailability to endothelial cells that express the appropriate receptors.[44]
Investigators found that HSPGs such as perlecan and collagen type XVIII are modified during human renal ischemia/reperfusion, which is associated with severe endothelial damage.[45] Vascular basement membrane (BM) HSPGs are modified to bind L-selectin and monocyte chemoattractant protein-1 (MCP-1) during leukocyte infiltration.[45] Specifically, they require 6-0 sulfation to bind HS chains.[46] The authors show evidence and propose that Sulf1 is usually present on microvascular BM but is downregulated to allow resulfation of 6-O HS for binding of L-selectin and MCP-1.[45] This in turn implicates Sulf1 in human renal allograft rejection which is highly dependent upon HSPG function in peritubular capillaries.[45]
Finally, in a transcriptome wide assay in chronic wound, fortyfold higher expression Sulf1 was noted in wound-site vessels.[47] This increase was attributed to its ability to inhibit angiogenesis as it had in breast cancer models.[47] | https://www.wikidoc.org/index.php/SULF1 | |
b0d7d7bba5680e3a6d0f29ba3ebd37cdbd0477c3 | wikidoc | SUMO3 | SUMO3
Small ubiquitin-related modifier 3 is a protein that in humans is encoded by the SUMO3 gene.
# Function
SUMO proteins, such as SUMO3, and ubiquitin (see MIM 191339) posttranslationally modify numerous cellular proteins and affect their metabolism and function. However, unlike ubiquitination, which targets proteins for degradation, sumoylation participates in a number of cellular processes, such as nuclear transport, transcriptional regulation, apoptosis, and protein stability (Su and Li, 2002).
# Interactions
SUMO3 has been shown to interact with ARNTL and Thymine-DNA glycosylase. | SUMO3
Small ubiquitin-related modifier 3 is a protein that in humans is encoded by the SUMO3 gene.[1][2]
# Function
SUMO proteins, such as SUMO3, and ubiquitin (see MIM 191339) posttranslationally modify numerous cellular proteins and affect their metabolism and function. However, unlike ubiquitination, which targets proteins for degradation, sumoylation participates in a number of cellular processes, such as nuclear transport, transcriptional regulation, apoptosis, and protein stability (Su and Li, 2002).[supplied by OMIM][2]
# Interactions
SUMO3 has been shown to interact with ARNTL[3] and Thymine-DNA glycosylase.[4] | https://www.wikidoc.org/index.php/SUMO3 | |
300c293aa5342e9a26b106d0b3a8a523628b0214 | wikidoc | SURF1 | SURF1
Surfeit locus protein 1 (SURF1) is a protein that in humans is encoded by the SURF1 gene. The protein encoded by SURF1 is a component of the mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex (MITRAC complex), which is involved in the regulation of cytochrome c oxidase assembly. Defects in this gene are a cause of Leigh syndrome, a severe neurological disorder that is commonly associated with systemic cytochrome c oxidase (complex IV) deficiency, and Charcot-Marie-Tooth disease 4K (CMT4K).
# Structure
SURF1 is located on the q arm of chromosome 9 in position 34.2 and has 9 exons. The SURF1 gene produces a 33.3 kDa protein composed of 300 amino acids. The protein is a member of the SURF1 family, which includes the related yeast protein SHY1 and rickettsial protein RP733. The gene is located in the surfeit gene cluster, a group of very tightly linked genes that do not share sequence similarity, where it shares a bidirectional promoter with SURF2 on the opposite strand. SURF1 is a multi-pass protein that contains two transmembrane regions, one 19 amino acids in length from positions 61-79 and the other 17 amino acids in length from positions 274-290.
# Function
This gene encodes a protein localized to the inner mitochondrial membrane and thought to be involved in the biogenesis of the cytochrome c oxidase complex. SURF1 is a multi-pass membrane protein component of the mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex (MITRAC complex). The MITRAC complex regulates cytochrome c oxidase assembly by acting as a central assembly intermediate, receiving subunits imported to the inner mitochondrial membrane and regulating COX1 mRNA translation.
# Clinical significance
Mutations in SURF1 have been associated with mitochondrial complex IV (cytochrome c oxidase) deficiency with clinical manifestations of Leigh syndrome and Charcot-Marie-Tooth disease 4K (CMT4K).
## Mitochondrial complex IV deficiency
Mitochondrial complex IV deficiency is a disorder of the mitochondrial respiratory chain with heterogeneous clinical manifestations, ranging from isolated myopathy to severe multisystem disease affecting several tissues and organs. Features include hypertrophic cardiomyopathy, hepatomegaly and liver dysfunction, hypotonia, muscle weakness, exercise intolerance, developmental delay, delayed motor development and mental retardation. Some affected individuals manifest a fatal hypertrophic cardiomyopathy resulting in neonatal death. A subset of patients manifest Leigh syndrome. In patients presenting with pathogenic mutations resulting in dysfunctioning SURF1, cytochrome c oxidase activity is likely to be diminished in one or more types of tissues.
## Leigh syndrome
Leigh syndrome is an early-onset progressive neurodegenerative disorder characterized by the presence of focal, bilateral lesions in one or more areas of the central nervous system including the brainstem, thalamus, basal ganglia, cerebellum and spinal cord. Clinical features depend on which areas of the central nervous system are involved and include subacute onset of psychomotor retardation, hypotonia, ataxia, weakness, vision loss, eye movement abnormalities, seizures, and dysphagia. There have been over 30 different mutations in SURF1 that have been associated with Leigh syndrome. These mutations, which comprise at least 10 missense or nonsense, 8 splice site, and 12 insertion or deletion mutations, are believed to be the result of dysfunctional SURF1 that results in Leigh syndrome and cytochrome c oxidase deficiency. The most common mutation is believed to be 312_321del 311_312insAT.
## Charcot-Marie-Tooth disease 4K (CMT4K)
Charcot-Marie-Tooth disease 4K (CMT4K) is an autosomal recessive, demyelinating form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Demyelinating neuropathies are characterized by severely reduced nerve conduction velocities (less than 38 m/sec), segmental demyelination and remyelination with onion bulb formations on nerve biopsy, slowly progressive distal muscle atrophy and weakness, absent deep tendon reflexes, and hollow feet. By convention, autosomal recessive forms of demyelinating Charcot-Marie-Tooth disease are designated CMT4. CMT4K patients manifest upper and lower limbs involvement. Some affected individuals have nystagmus, polyneuropathy, putaminal and periaqueductal lesions, and late-onset cerebellar ataxia. This disease, when associated with mutations in SURF1, has been found to be linked to cytochrome c oxidase deficiency. Variants associated with this CMT4K have included a homozygous splice site mutation, c.107-2A>G, a missense mutation, c.574C>T, and a deletion, c.799_800del.
# Interactions
SURF1 has been shown to have 11 binary protein-protein interactions including 8 co-complex interactions. SURF1 interacts with COA3 as part of the mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex (MITRAC complex). PTGES3, SLC25A5, COX6C, COX14, COA1 have all also been found to interact with SURF1. | SURF1
Surfeit locus protein 1 (SURF1) is a protein that in humans is encoded by the SURF1 gene.[1][2] The protein encoded by SURF1 is a component of the mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex (MITRAC complex), which is involved in the regulation of cytochrome c oxidase assembly.[3][4] Defects in this gene are a cause of Leigh syndrome, a severe neurological disorder that is commonly associated with systemic cytochrome c oxidase (complex IV) deficiency, and Charcot-Marie-Tooth disease 4K (CMT4K).[5][6]
# Structure
SURF1 is located on the q arm of chromosome 9 in position 34.2 and has 9 exons.[5] The SURF1 gene produces a 33.3 kDa protein composed of 300 amino acids.[7][8] The protein is a member of the SURF1 family, which includes the related yeast protein SHY1 and rickettsial protein RP733. The gene is located in the surfeit gene cluster, a group of very tightly linked genes that do not share sequence similarity, where it shares a bidirectional promoter with SURF2 on the opposite strand.[5] SURF1 is a multi-pass protein that contains two transmembrane regions, one 19 amino acids in length from positions 61-79 and the other 17 amino acids in length from positions 274-290.[3][4]
# Function
This gene encodes a protein localized to the inner mitochondrial membrane and thought to be involved in the biogenesis of the cytochrome c oxidase complex.[5] SURF1 is a multi-pass membrane protein component of the mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex (MITRAC complex). The MITRAC complex regulates cytochrome c oxidase assembly by acting as a central assembly intermediate, receiving subunits imported to the inner mitochondrial membrane and regulating COX1 mRNA translation.[3][4][9]
# Clinical significance
Mutations in SURF1 have been associated with mitochondrial complex IV (cytochrome c oxidase) deficiency with clinical manifestations of Leigh syndrome and Charcot-Marie-Tooth disease 4K (CMT4K).[3][4][10]
## Mitochondrial complex IV deficiency
Mitochondrial complex IV deficiency is a disorder of the mitochondrial respiratory chain with heterogeneous clinical manifestations, ranging from isolated myopathy to severe multisystem disease affecting several tissues and organs. Features include hypertrophic cardiomyopathy, hepatomegaly and liver dysfunction, hypotonia, muscle weakness, exercise intolerance, developmental delay, delayed motor development and mental retardation. Some affected individuals manifest a fatal hypertrophic cardiomyopathy resulting in neonatal death. A subset of patients manifest Leigh syndrome. In patients presenting with pathogenic mutations resulting in dysfunctioning SURF1, cytochrome c oxidase activity is likely to be diminished in one or more types of tissues.[11][3][4]
## Leigh syndrome
Leigh syndrome is an early-onset progressive neurodegenerative disorder characterized by the presence of focal, bilateral lesions in one or more areas of the central nervous system including the brainstem, thalamus, basal ganglia, cerebellum and spinal cord. Clinical features depend on which areas of the central nervous system are involved and include subacute onset of psychomotor retardation, hypotonia, ataxia, weakness, vision loss, eye movement abnormalities, seizures, and dysphagia. There have been over 30 different mutations in SURF1 that have been associated with Leigh syndrome. These mutations, which comprise at least 10 missense or nonsense, 8 splice site, and 12 insertion or deletion mutations, are believed to be the result of dysfunctional SURF1 that results in Leigh syndrome and cytochrome c oxidase deficiency. The most common mutation is believed to be 312_321del 311_312insAT.[10][3][4]
## Charcot-Marie-Tooth disease 4K (CMT4K)
Charcot-Marie-Tooth disease 4K (CMT4K) is an autosomal recessive, demyelinating form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Demyelinating neuropathies are characterized by severely reduced nerve conduction velocities (less than 38 m/sec), segmental demyelination and remyelination with onion bulb formations on nerve biopsy, slowly progressive distal muscle atrophy and weakness, absent deep tendon reflexes, and hollow feet. By convention, autosomal recessive forms of demyelinating Charcot-Marie-Tooth disease are designated CMT4. CMT4K patients manifest upper and lower limbs involvement. Some affected individuals have nystagmus, polyneuropathy, putaminal and periaqueductal lesions, and late-onset cerebellar ataxia. This disease, when associated with mutations in SURF1, has been found to be linked to cytochrome c oxidase deficiency. Variants associated with this CMT4K have included a homozygous splice site mutation, c.107-2A>G, a missense mutation, c.574C>T, and a deletion, c.799_800del.[6][3][4]
# Interactions
SURF1 has been shown to have 11 binary protein-protein interactions including 8 co-complex interactions. SURF1 interacts with COA3 as part of the mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex (MITRAC complex). PTGES3, SLC25A5, COX6C, COX14, COA1 have all also been found to interact with SURF1.[3][4][12] | https://www.wikidoc.org/index.php/SURF1 | |
c67ffe71cfab4bf90c41e1e2c3d751ecf32ef0cf | wikidoc | SUZ12 | SUZ12
Polycomb protein SUZ12 is a protein that in humans is encoded by the SUZ12 gene.
# Function
This zinc finger gene has been identified at the breakpoints of a recurrent chromosomal translocation reported in endometrial stromal sarcoma. Recombination of these breakpoints results in the fusion of this gene and JAZF1. The protein encoded by this gene contains a zinc finger domain in the C terminus of the coding region. The specific function of this gene has not yet been determined.
SUZ12, as part of Polycomb Repressive Complex 2 (PRC2), may be involved with chromatin silencing in conjunction with HOTAIR ncRNA, using its zinc-finger domain to bind the RNA molecule. | SUZ12
Polycomb protein SUZ12 is a protein that in humans is encoded by the SUZ12 gene.[1][2][3][4]
# Function
This zinc finger gene has been identified at the breakpoints of a recurrent chromosomal translocation reported in endometrial stromal sarcoma. Recombination of these breakpoints results in the fusion of this gene and JAZF1. The protein encoded by this gene contains a zinc finger domain in the C terminus of the coding region. The specific function of this gene has not yet been determined.[4]
SUZ12, as part of Polycomb Repressive Complex 2 (PRC2), may be involved with chromatin silencing in conjunction with HOTAIR ncRNA, using its zinc-finger domain to bind the RNA molecule.[5] | https://www.wikidoc.org/index.php/SUZ12 | |
24b84bbc3fa45317b4f3f7a75d91d5e600befb8c | wikidoc | SYMPK | SYMPK
Symplekin is a protein that in humans is encoded by the SYMPK gene.
# Function
This gene encodes a nuclear protein that functions in the regulation of polyadenylation and promotes gene expression. The protein forms a high-molecular weight complex with components of the polyadenylation machinery. It is thought to serve as a scaffold for recruiting regulatory factors to the polyadenylation complex. It also participates in 3'-end maturation of histone mRNAs, which do not undergo polyadenylation. The protein also localizes to the cytoplasmic plaques of tight junctions in some cell types.
# Model organisms
Model organisms have been used in the study of SYMPK function. A conditional knockout mouse line, called Sympktm1a(EUCOMM)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty five tests were carried out on mutant mice and two significant abnormalities were observed. No homozygous mutant embryos were identified during gestation, and thus none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice; no additional significant abnormalities were observed in these animals.
# Interactions
SYMPK has been shown to interact with CSTF2 and HSF1. | SYMPK
Symplekin is a protein that in humans is encoded by the SYMPK gene.[1][2]
# Function
This gene encodes a nuclear protein that functions in the regulation of polyadenylation and promotes gene expression. The protein forms a high-molecular weight complex with components of the polyadenylation machinery. It is thought to serve as a scaffold for recruiting regulatory factors to the polyadenylation complex. It also participates in 3'-end maturation of histone mRNAs, which do not undergo polyadenylation. The protein also localizes to the cytoplasmic plaques of tight junctions in some cell types.[2]
# Model organisms
Model organisms have been used in the study of SYMPK function. A conditional knockout mouse line, called Sympktm1a(EUCOMM)Wtsi[7][8] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[9][10][11]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[5][12] Twenty five tests were carried out on mutant mice and two significant abnormalities were observed.[5] No homozygous mutant embryos were identified during gestation, and thus none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice; no additional significant abnormalities were observed in these animals.[5]
# Interactions
SYMPK has been shown to interact with CSTF2[13] and HSF1.[14] | https://www.wikidoc.org/index.php/SYMPK | |
910cc1ff4b03ef8cea640796adcfd6d3e19eae78 | wikidoc | SYT14 | SYT14
Synaptotagmin XIV is a protein that in humans is encoded by the SYT14 gene.
# Function
This gene is a member of the synaptotagmin gene family and encodes a protein similar to other family members that mediate membrane trafficking in synaptic transmission. The encoded protein is a calcium-independent synaptotagmin.
# Clinical relevance
Mutations in this gene have been shown to cause autosomal recessive spinocerebellar ataxia with psychomotor retardation. | SYT14
Synaptotagmin XIV is a protein that in humans is encoded by the SYT14 gene.[1]
# Function
This gene is a member of the synaptotagmin gene family and encodes a protein similar to other family members that mediate membrane trafficking in synaptic transmission. The encoded protein is a calcium-independent synaptotagmin.[1]
# Clinical relevance
Mutations in this gene have been shown to cause autosomal recessive spinocerebellar ataxia with psychomotor retardation.[2] | https://www.wikidoc.org/index.php/SYT14 | |
ffed306f9ad45f6d43ed6441f3d3b72ee218fd73 | wikidoc | SYTL1 | SYTL1
Synaptotagmin-like protein 1 is a protein that in humans is encoded by the SYTL1 gene.
# Model organisms
Model organisms have been used in the study of SYTL1 function. A conditional knockout mouse line, called Sytl1tm1a(KOMP)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty four tests were carried out on homozygous mutant mice and six significant abnormalities were observed. Females had abnormal locomotor coordination, caudal vertebral transformation, decreased circulating amylase levels and increased mean platelet volume. Both sexes displayed decreased IgG2b levels and abnormal peripheral blood lymphocyte parameters.
# Interactions
SYTL1 has been shown to interact with RAB27A. | SYTL1
Synaptotagmin-like protein 1 is a protein that in humans is encoded by the SYTL1 gene.[1][2]
# Model organisms
Model organisms have been used in the study of SYTL1 function. A conditional knockout mouse line, called Sytl1tm1a(KOMP)Wtsi[11][12] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[13][14][15]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[9][16] Twenty four tests were carried out on homozygous mutant mice and six significant abnormalities were observed.[9] Females had abnormal locomotor coordination, caudal vertebral transformation, decreased circulating amylase levels and increased mean platelet volume. Both sexes displayed decreased IgG2b levels and abnormal peripheral blood lymphocyte parameters.[9]
# Interactions
SYTL1 has been shown to interact with RAB27A.[17][18][19] | https://www.wikidoc.org/index.php/SYTL1 | |
34ce48d3abbf80f4562ee20e20d1f02646dafcaa | wikidoc | Salix | Salix
Willows, sallows and osiers form the genus Salix, around 400 species of deciduous trees and shrubs, found primarily on moist soils in cold and temperate regions of the Northern Hemisphere. Most species are known as willow, but some narrow-leaved shrub species are called osier, and some broader-leaved species are called sallow (the latter name is derived from the Latin word salix, willow). Some willows (particularly arctic and alpine species), are low-growing or creeping shrubs; for example the dwarf willow (Salix herbacea) rarely exceeds 6 cm in height, though spreading widely across the ground.
Willows are very cross-fertile and numerous hybrids occur, both naturally and in cultivation. A well known example is the weeping willow (Salix × sepulcralis), very widely planted as an ornamental tree, which is a hybrid of a Chinese species and a European species – Peking willow and white willow.
# Uses
## Medicinal uses
The leaves and bark of the willow tree have been mentioned in ancient texts from Assyria, Sumer and Egypt as a remedy for aches and fever, and the Ancient Greek physician Hippocrates wrote about its medicinal properties in the 5th century BC. Native Americans across the American continent relied on it as a staple of their medical treatments. This is because they contain salicylic acid, the precursor to aspirin.
In 1763 its medicinal properties were observed by the Reverend Edward Stone in England. He notified the Royal Society who published his findings. The active extract of the bark, called salicin, was isolated to its crystalline form in 1828 by Henri Leroux, a French pharmacist, and Raffaele Piria, an Italian chemist, who then succeeded in separating out the acid in its pure state. Salicin is acidic when in a saturated solution in water (pH = 2.4), and is called salicylic acid for that reason.
In 1897 Felix Hoffmann created a synthetically altered version of salicin (in his case derived from the Spiraea plant), which caused less digestive upset than pure salicylic acid. The new drug, formally Acetylsalicylic acid, was named aspirin by Hoffmann's employer Bayer AG. This gave rise to the hugely important class of drugs known as non-steroidal anti-inflammatory drugs (NSAIDs). | Salix
Willows, sallows and osiers form the genus Salix, around 400 species[1] of deciduous trees and shrubs, found primarily on moist soils in cold and temperate regions of the Northern Hemisphere. Most species are known as willow, but some narrow-leaved shrub species are called osier, and some broader-leaved species are called sallow (the latter name is derived from the Latin word salix, willow). Some willows (particularly arctic and alpine species), are low-growing or creeping shrubs; for example the dwarf willow (Salix herbacea) rarely exceeds 6 cm in height, though spreading widely across the ground.
Willows are very cross-fertile and numerous hybrids occur, both naturally and in cultivation. A well known example is the weeping willow (Salix × sepulcralis), very widely planted as an ornamental tree, which is a hybrid of a Chinese species and a European species – Peking willow and white willow.
# Uses
## Medicinal uses
The leaves and bark of the willow tree have been mentioned in ancient texts from Assyria, Sumer and Egypt[2] as a remedy for aches and fever,[3] and the Ancient Greek physician Hippocrates wrote about its medicinal properties in the 5th century BC. Native Americans across the American continent relied on it as a staple of their medical treatments. This is because they contain salicylic acid, the precursor to aspirin.
In 1763 its medicinal properties were observed by the Reverend Edward Stone in England. He notified the Royal Society who published his findings. The active extract of the bark, called salicin, was isolated to its crystalline form in 1828 by Henri Leroux, a French pharmacist, and Raffaele Piria, an Italian chemist, who then succeeded in separating out the acid in its pure state. Salicin is acidic when in a saturated solution in water (pH = 2.4), and is called salicylic acid for that reason.
In 1897 Felix Hoffmann created a synthetically altered version of salicin (in his case derived from the Spiraea plant), which caused less digestive upset than pure salicylic acid. The new drug, formally Acetylsalicylic acid, was named aspirin by Hoffmann's employer Bayer AG. This gave rise to the hugely important class of drugs known as non-steroidal anti-inflammatory drugs (NSAIDs).
# External links
- Salix alba at plants for a future
- Salix purpurea at plants for a future
- 1911 Encyclopaedia Britannica (but see Encyclop%C3%A6dia_Britannica_Eleventh_Edition#Versions_of_this_public_domain_work_claiming_copyright|this)
- Salix caroliniana images at bioimages.vanderbilt.edu
- Salix nigra images at bioimages.vanderbilt.edu | https://www.wikidoc.org/index.php/Salix | |
0362de95bc5286930a4ee2756453e669a00d0387 | wikidoc | Sarin | Sarin
Sarin, also known by its NATO designation of GB, (O-Isopropyl methylphosphonofluoridate) is an extremely toxic substance whose sole application is as a nerve agent. As a chemical weapon, it is classified as a weapon of mass destruction by the United Nations in UN Resolution 687. Production and stockpiling of Sarin was outlawed by the Chemical Weapons Convention of 1993.
# Chemical characteristics
Sarin is similar in structure and biological activity to some commonly used insecticides, such as Malathion, and is similar in biological activity to carbamates used as insecticides such as Sevin, and medicines such as Mestinon, Neostigmine, and Antilirium.
At room temperature, sarin is a colorless, odorless liquid. Its low vapor pressure (2.9 mmHg at 20 degrees C)makes it relatively ineffective as a terrorist inhalation weapon. Its vapor is also colorless and odorless. It can be made more persistent through the addition of certain oils or petroleum products.
Sarin can be used as a binary chemical weapon; its two precursors are methylphosphonyl difluoride and a mixture of isopropyl alcohol and isopropyl amine. The isopropyl amine binds the hydrogen fluoride generated during the chemical reaction.
## Shelf life
Sarin has a relatively short shelf life, and will degrade after a period of several weeks to several months. The shelf life may be greatly shortened by impurities in precursor materials. According to the CIA, in 1989 the Iraqis destroyed 40 or more tons of sarin that had decomposed, and that some Iraqi sarin had a shelf life of only a few weeks owing mostly to impure precursors.
Like other nerve agents, Sarin can be chemically deactivated with a strong alkali. Sodium hydroxide can be used in a hydrolysis reaction to destroy sarin converting it to effectively harmless sodium salts..
### Efforts to lengthen shelf life
Nations stockpiling sarin have tried to overcome the problem of its short shelf life in three ways:
- The shelf life of unitary (i.e., pure) sarin may be lengthened by increasing the purity of the precursor and intermediate chemicals and refining the production process.
- Incorporating a stabilizer chemical called tributylamine. Later this was replaced by diisopropylcarbodiimide (di-c-di), which allowed for GB nerve agent to be stored in aluminium casings.
- Developing binary chemical weapons, where the two precursor chemicals are stored separately in the same shell, and mixed to form the agent immediately before or when the shell is in flight. This approach has the dual benefit of making the issue of shelf life irrelevant and greatly increasing the safety of sarin munitions. However, experts still refuse to put the shelf life of this type of weapon past 5 years.
# Biological effects
Like other nerve agents, sarin attacks the nervous system of a living organism. It is an irreversible cholinesterase inhibitor.
When a functioning motor neuron or parasympathetic neuron is stimulated it releases the neurotransmitter acetylcholine to transmit the impulse to a muscle or organ. Once the impulse has been sent, the enzyme acetylcholinesterase breaks down the acetylcholine in order to allow the muscle or organ to relax.
Sarin is an extremely potent organophosphate compound that disrupts the nervous system by inhibiting the cholinesterase enzyme by forming a covalent bond with the particular serine residue in the enzyme which forms the site where acetylcholine normally undergoes hydrolysis; the fluorine of the phosphonyl fluoride group reacts with the hydroxyl group on the serine side-chain, forming a phosphoester and releasing HF. With the enzyme inhibited, acetylcholine builds up in the synapse and continues to act so that any nerve impulses are, in effect, continually transmitted.
Initial symptoms following exposure to sarin are a runny nose, tightness in the chest and constriction of the pupils. Soon after, the victim has difficulty breathing and experiences nausea and drooling. As the victim continues to lose control of bodily functions, he vomits, defecates and urinates. This phase is followed by twitching and jerking. Ultimately, the victim becomes comatose and suffocates in a series of convulsive spasms.
Sarin is a highly volatile liquid. Inhalation and absorption through the skin pose a great threat. Even vapour concentrations immediately penetrate the skin. People who absorb a nonlethal dose but do not receive immediate appropriate medical treatment may suffer permanent neurological damage.
Even at very low concentrations, sarin can be fatal. Death may follow in one minute after direct ingestion of about 0.01 milligram per kilogram of body weight if antidotes, typically atropine and pralidoxime, are not quickly administered. Atropine, an antagonist to acetylcholine receptors of muscarinic type, is given to treat the physiological symptoms of poisoning (since muscular response to acetylcholine is mediated through nicotinic acetylcholine receptors, atropine does not counteract muscular symptoms). Pralidoxime can regenerate cholinesterases if administered within approximately five hours.
It is estimated that sarin is more than 500 times as toxic as cyanide.
The short- and long-term symptoms experienced by those affected included:
- bleeding from the nose and mouth
- coma
- convulsions
- death
- difficulty breathing
- disturbed sleep and nightmares
- extreme sensitivity to light
- foaming at the mouth
- high fevers
- influenza-like symptoms
- loss of consciousness
- loss of memory
- nausea and vomiting
- paralysis
- post-traumatic stress disorder
- respiratory problems
- seizures
- uncontrollable trembling
- vision problems, both temporary and permanent
# History
The following is the specific history of sarin, which is closely linked to the history of similar nerve agents also discovered in Germany during or soon after World War II. That broader history is detailed in Nerve Agent: History .
## Origin
Sarin was discovered in 1938 in Wuppertal-Elberfeld in Germany by two German scientists attempting to create stronger pesticides; it is the most toxic of the four G-agents made by Germany. The compound, which followed the discovery of the nerve agent tabun, was named in honor of its discoverers: Gerhard Schrader, Ambros, Rüdiger and Van der LINde.
## Sarin in Nazi Germany during World War II
In mid-1939, the formula for the agent was passed to the chemical warfare section of the German Army Weapons Office, which ordered that it be brought into mass production for wartime use. A number of pilot plants were built, and a high-production facility was under construction (but was not finished) by the end of World War II. Estimates for total sarin production by Nazi Germany range from 500 kg to 10 tons.
Though sarin, tabun and soman were incorporated into artillery shells, Germany ultimately decided not to use nerve agents against Allied targets. German intelligence was unaware that the Allies had not developed similar compounds, but they understood that unleashing these compounds would lead the Allies to develop and use chemical weapons of their own, and they were concerned that the Allies' ability to reach German targets would prove devastating in a chemical war.
## Sarin after World War II
- 1950s (early): NATO adopts sarin as a standard chemical weapon, and both the U.S.S.R and the United States produce sarin for military purposes.
- 1953: 20-year-old Ronald Maddison, a Royal Air Force engineer from Consett, County Durham, died in human testing of sarin at the Porton Down chemical warfare testing facility in Wiltshire. Maddison had been told that he was participating in a test to "cure the common cold." Ten days after his death an inquest was held in secret which returned a verdict of "misadventure". In 2004 the inquest was reopened and, after a 64-day inquest hearing, the jury ruled that Maddison had been unlawfully killed by the "application of a nerve agent in a non-therapeutic experiment."
- 1956: Regular production of sarin ceased in the United States, though existing stocks of bulk Sarin were re-distilled until 1970.
- 1978: Michael Townley in a sworn declaration indicates that Sarin was produced by the secret police of Chile's Pinochet regime DINA, by Eugenio Berríos, it indicates that it was used to assassinate the state archives custodian Renato León Zenteno and the Army Corporal Manuel Leyton.
- 1980-1988: Iraq used Sarin against Iran during the 1980-88 war. During the 1990-91 Gulf War, Iraq still had large stockpiles available which were found as coalition forces advanced north.
- 1988: Over the span of two days in March, the ethnic Kurd city of Halabja in northern Iraq (population 70,000) was bombarded with chemical and cluster bombs, which included Sarin, in the Halabja poison gas attack. An estimated 5,000 people died.
- 1991: UN Resolution 687 establishes the term "weapon of mass destruction" and calls for the immediate destruction of chemical weapons in Iraq, and eventual destruction of all chemical weapons globally.
- 1993: The United Nations Chemical Weapons Convention is signed by 162 member countries, banning the production and stockpiling of many chemical weapons, including Sarin. It goes into effect on 29 April 1997, and calls for the complete destruction of all specified stockpiles of chemical weapons by April 2007.
- 1994: The Japanese religious sect Aum Shinrikyo releases an impure form of Sarin in Matsumoto, Nagano. (see Matsumoto incident)
- 1995: Aum Shinrikyo sect releases an impure form of Sarin in the Tokyo Subway. (see Sarin gas attack on the Tokyo subway)
- 1998: In its June 15 issue, Time Magazine runs a story entitled "Did The U.S. Drop Nerve Gas?". The story is broadcast on June 7 on the CNN program NewsStand. The Time article alleges that U.S. Air Force A-1E Skyraiders engaged in a covert operation called Operation Tailwind, in which they deliberately dropped CBU-15 Cluster Bomb Units containing submunitions that were filled with Sarin on defected U.S. troops in Laos. The report causes a scandal, and The Pentagon launches a study that concludes no nerve gas use took place. After an internal investigation, CNN and Time magazine (both owned by the media conglomerate Time Warner) retract the story and fired the two producers primarily responsible for it.
- 2004: On May 14 Iraqi insurgency fighters in Iraq detonate a 155 mm shell containing several litres of binary precursors for Sarin. The shell is designed to mix the chemicals as it spins during flight. The detonated shell released only a small amount of sarin gas, either because the explosion failed to mix the binary agents properly or because the chemicals inside the shell had degraded significantly with age. Two United States soldiers were treated for exposure after displaying the early symptoms. | Sarin
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Template:Chembox new
Sarin, also known by its NATO designation of GB, (O-Isopropyl methylphosphonofluoridate) is an extremely toxic substance whose sole application is as a nerve agent. As a chemical weapon, it is classified as a weapon of mass destruction by the United Nations in UN Resolution 687. Production and stockpiling of Sarin was outlawed by the Chemical Weapons Convention of 1993.
# Chemical characteristics
Sarin is similar in structure and biological activity to some commonly used insecticides, such as Malathion, and is similar in biological activity to carbamates used as insecticides such as Sevin, and medicines such as Mestinon, Neostigmine, and Antilirium.
At room temperature, sarin is a colorless, odorless liquid. Its low vapor pressure (2.9 mmHg at 20 degrees C)makes it relatively ineffective as a terrorist inhalation weapon. Its vapor is also colorless and odorless. It can be made more persistent through the addition of certain oils or petroleum products.
Sarin can be used as a binary chemical weapon; its two precursors are methylphosphonyl difluoride and a mixture of isopropyl alcohol and isopropyl amine. The isopropyl amine binds the hydrogen fluoride generated during the chemical reaction.
## Shelf life
Sarin has a relatively short shelf life, and will degrade after a period of several weeks to several months. The shelf life may be greatly shortened by impurities in precursor materials. According to the CIA[1], in 1989 the Iraqis destroyed 40 or more tons of sarin that had decomposed, and that some Iraqi sarin had a shelf life of only a few weeks owing mostly to impure precursors.
Like other nerve agents, Sarin can be chemically deactivated with a strong alkali. Sodium hydroxide can be used in a hydrolysis reaction to destroy sarin converting it to effectively harmless sodium salts.[2].
### Efforts to lengthen shelf life
Nations stockpiling sarin have tried to overcome the problem of its short shelf life in three ways:
- The shelf life of unitary (i.e., pure) sarin may be lengthened by increasing the purity of the precursor and intermediate chemicals and refining the production process.
- Incorporating a stabilizer chemical called tributylamine. Later this was replaced by diisopropylcarbodiimide (di-c-di), which allowed for GB nerve agent to be stored in aluminium casings.
- Developing binary chemical weapons, where the two precursor chemicals are stored separately in the same shell, and mixed to form the agent immediately before or when the shell is in flight. This approach has the dual benefit of making the issue of shelf life irrelevant and greatly increasing the safety of sarin munitions. However, experts still refuse to put the shelf life of this type of weapon past 5 years.
# Biological effects
Like other nerve agents, sarin attacks the nervous system of a living organism. It is an irreversible cholinesterase inhibitor.
When a functioning motor neuron or parasympathetic neuron is stimulated it releases the neurotransmitter acetylcholine to transmit the impulse to a muscle or organ. Once the impulse has been sent, the enzyme acetylcholinesterase breaks down the acetylcholine in order to allow the muscle or organ to relax.
Sarin is an extremely potent organophosphate compound that disrupts the nervous system by inhibiting the cholinesterase enzyme by forming a covalent bond with the particular serine residue in the enzyme which forms the site where acetylcholine normally undergoes hydrolysis; the fluorine of the phosphonyl fluoride group reacts with the hydroxyl group on the serine side-chain, forming a phosphoester and releasing HF. With the enzyme inhibited, acetylcholine builds up in the synapse and continues to act so that any nerve impulses are, in effect, continually transmitted.
Initial symptoms following exposure to sarin are a runny nose, tightness in the chest and constriction of the pupils. Soon after, the victim has difficulty breathing and experiences nausea and drooling. As the victim continues to lose control of bodily functions, he vomits, defecates and urinates. This phase is followed by twitching and jerking. Ultimately, the victim becomes comatose and suffocates in a series of convulsive spasms.
Sarin is a highly volatile liquid. Inhalation and absorption through the skin pose a great threat. Even vapour concentrations immediately penetrate the skin. People who absorb a nonlethal dose but do not receive immediate appropriate medical treatment may suffer permanent neurological damage.
Even at very low concentrations, sarin can be fatal. Death may follow in one minute after direct ingestion of about 0.01 milligram per kilogram of body weight if antidotes, typically atropine and pralidoxime, are not quickly administered. Atropine, an antagonist to acetylcholine receptors of muscarinic type, is given to treat the physiological symptoms of poisoning (since muscular response to acetylcholine is mediated through nicotinic acetylcholine receptors, atropine does not counteract muscular symptoms). Pralidoxime can regenerate cholinesterases if administered within approximately five hours.
It is estimated that sarin is more than 500 times as toxic as cyanide[3].
The short- and long-term symptoms experienced by those affected included:
- bleeding from the nose and mouth
- coma
- convulsions
- death
- difficulty breathing
- disturbed sleep and nightmares
- extreme sensitivity to light
- foaming at the mouth
- high fevers
- influenza-like symptoms
- loss of consciousness
- loss of memory
- nausea and vomiting
- paralysis
- post-traumatic stress disorder
- respiratory problems
- seizures
- uncontrollable trembling
- vision problems, both temporary and permanent
# History
The following is the specific history of sarin, which is closely linked to the history of similar nerve agents also discovered in Germany during or soon after World War II. That broader history is detailed in Nerve Agent: History .
## Origin
Sarin was discovered in 1938 in Wuppertal-Elberfeld in Germany by two German scientists attempting to create stronger pesticides; it is the most toxic of the four G-agents made by Germany. The compound, which followed the discovery of the nerve agent tabun, was named in honor of its discoverers: Gerhard Schrader, Ambros, Rüdiger and Van der LINde.
## Sarin in Nazi Germany during World War II
In mid-1939, the formula for the agent was passed to the chemical warfare section of the German Army Weapons Office, which ordered that it be brought into mass production for wartime use. A number of pilot plants were built, and a high-production facility was under construction (but was not finished) by the end of World War II. Estimates for total sarin production by Nazi Germany range from 500 kg to 10 tons.
Though sarin, tabun and soman were incorporated into artillery shells, Germany ultimately decided not to use nerve agents against Allied targets. German intelligence was unaware that the Allies had not developed similar compounds, but they understood that unleashing these compounds would lead the Allies to develop and use chemical weapons of their own, and they were concerned that the Allies' ability to reach German targets would prove devastating in a chemical war.
## Sarin after World War II
- 1950s (early): NATO adopts sarin as a standard chemical weapon, and both the U.S.S.R and the United States produce sarin for military purposes.
- 1953: 20-year-old Ronald Maddison, a Royal Air Force engineer from Consett, County Durham, died in human testing of sarin at the Porton Down chemical warfare testing facility in Wiltshire. Maddison had been told that he was participating in a test to "cure the common cold." Ten days after his death an inquest was held in secret which returned a verdict of "misadventure". In 2004 the inquest was reopened and, after a 64-day inquest hearing, the jury ruled that Maddison had been unlawfully killed by the "application of a nerve agent in a non-therapeutic experiment."[4]
- 1956: Regular production of sarin ceased in the United States, though existing stocks of bulk Sarin were re-distilled until 1970.
- 1978: Michael Townley in a sworn declaration indicates that Sarin was produced by the secret police of Chile's Pinochet regime DINA, by Eugenio Berríos, it indicates that it was used to assassinate the state archives custodian Renato León Zenteno and the Army Corporal Manuel Leyton.[5]
- 1980-1988: Iraq used Sarin against Iran during the 1980-88 war. During the 1990-91 Gulf War, Iraq still had large stockpiles available which were found as coalition forces advanced north.
- 1988: Over the span of two days in March, the ethnic Kurd city of Halabja in northern Iraq (population 70,000) was bombarded with chemical and cluster bombs, which included Sarin, in the Halabja poison gas attack. An estimated 5,000 people died.
- 1991: UN Resolution 687 establishes the term "weapon of mass destruction" and calls for the immediate destruction of chemical weapons in Iraq, and eventual destruction of all chemical weapons globally. [2]
- 1993: The United Nations Chemical Weapons Convention is signed by 162 member countries, banning the production and stockpiling of many chemical weapons, including Sarin. It goes into effect on 29 April 1997, and calls for the complete destruction of all specified stockpiles of chemical weapons by April 2007. [6]
- 1994: The Japanese religious sect Aum Shinrikyo releases an impure form of Sarin in Matsumoto, Nagano. (see Matsumoto incident)
- 1995: Aum Shinrikyo sect releases an impure form of Sarin in the Tokyo Subway. (see Sarin gas attack on the Tokyo subway)
- 1998: In its June 15 issue, Time Magazine runs a story entitled "Did The U.S. Drop Nerve Gas?". The story is broadcast on June 7 on the CNN program NewsStand. The Time article alleges that U.S. Air Force A-1E Skyraiders engaged in a covert operation called Operation Tailwind, in which they deliberately dropped CBU-15 Cluster Bomb Units containing submunitions that were filled with Sarin on defected U.S. troops in Laos. The report causes a scandal, and The Pentagon launches a study that concludes no nerve gas use took place. After an internal investigation, CNN and Time magazine (both owned by the media conglomerate Time Warner) retract the story and fired the two producers primarily responsible for it.[7]
- 2004: On May 14 Iraqi insurgency fighters in Iraq detonate a 155 mm shell containing several litres of binary precursors for Sarin. The shell is designed to mix the chemicals as it spins during flight. The detonated shell released only a small amount of sarin gas, either because the explosion failed to mix the binary agents properly or because the chemicals inside the shell had degraded significantly with age. Two United States soldiers were treated for exposure after displaying the early symptoms.[8] | https://www.wikidoc.org/index.php/Sarin | |
28903d1e9395fc40719be3d5838ff32f7dfde060 | wikidoc | Scalp | Scalp
# Overview
The scalp is the anatomical area bordered by the face anteriorly and the neck to the sides and posteriorly.
# Layers
It is usually described as having five layers, which can be remembered with the mnemonic "SCALP":
- S: The skin on the head from which head hair grows. It is richly supplied with blood vessels and can be subject to such conditions as dandruff and cutis verticis gyrata.
- C: Connective tissue. a thin layer of fat and fibrous tissue lies beneath the skin
- A: The aponeurosis (or galea aponeurotica) is the next layer. It is a tough layer of dense fibrous tissue which runs from the frontalis muscle anteriorly to the occipitalis posteriorly
- L: The loose areolar connective tissue layer provides an easy plane of separation between the upper three layers and the pericranium. In scalping the scalp is torn off through this layer. It also provides a plane of access in craniofacial surgery and neurosurgery. This layer is sometimes referred to as the "Danger Zone" because of the ease by which infectious agents can spread through it to emissary veins which then drain into the cranium. The loose areolar tissue in this layer is made up of random collagen I bundles, collagen III and is highly vascular and cellular. It will also be rich in glycosaminoglycans (GAGs) and will be constituted of more matrix than fibers.
- P: The pericranium is the periosteum of the skull bones and provides nutrition to the bone and the capacity for repair. It may be lifted from the bone to allow removal of bone windows (craniotomy).
# Blood supply
The blood supply of the scalp is via four pairs of arteries, two from the external carotid and two from the internal carotid:
- internal carotid
the supratrochlear artery to the midline forehead
the supraorbital artery to the lateral forehead and scalp as far up as the vertex
- the supratrochlear artery to the midline forehead
- the supraorbital artery to the lateral forehead and scalp as far up as the vertex
- external carotid
the superficial temporal artery which gives frontal and parietal branches to supply much of the scalp
the occipital artery which runs from posteriorly to supply much of the back of the scalp.
- the superficial temporal artery which gives frontal and parietal branches to supply much of the scalp
- the occipital artery which runs from posteriorly to supply much of the back of the scalp.
# Innervation
The scalp is innervated by the following:
- Supratrochlear nerve and the supraorbital nerve from the ophthalmic division of the trigeminal nerve
- Greater occipital nerve (C2) posteriorly up to the vertex
- Lesser occipital nerve (C3) behind the ear.
- Zygomaticotemporal nerve from the maxillary division of the trigeminal nerve supplying the hairless temple
- Auriculotemporal nerve from the mandibular division of the trigeminal nerve
# Role in aesthetics
The scalp plays an important role in the aesthetics of the face. Androgenic alopecia, or male pattern hair loss, is a common cause of concern to men. It may be treated by medication (eg finasteride) or hair transplantation with variable success. If the scalp is heavy and loose, a common change with aging, the forehead may be low, heave and deeply lined. The brow lift procedure aims to address these concerns.
# Pathology
The scalp is a common site for the development of tumours including:
- epidermoid cyst
- pilar cyst
- actinic keratosis and squamous cell carcinoma
- basal cell carcinoma
- merkel cell tumours | Scalp
Template:Infobox Anatomy
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
# Overview
The scalp is the anatomical area bordered by the face anteriorly and the neck to the sides and posteriorly.
# Layers
It is usually described as having five layers, which can be remembered with the mnemonic "SCALP":[1]
- S: The skin on the head from which head hair grows. It is richly supplied with blood vessels and can be subject to such conditions as dandruff and cutis verticis gyrata.
- C: Connective tissue. a thin layer of fat and fibrous tissue lies beneath the skin
- A: The aponeurosis (or galea aponeurotica) is the next layer. It is a tough layer of dense fibrous tissue which runs from the frontalis muscle anteriorly to the occipitalis posteriorly
- L: The loose areolar connective tissue layer provides an easy plane of separation between the upper three layers and the pericranium. In scalping the scalp is torn off through this layer. It also provides a plane of access in craniofacial surgery and neurosurgery. This layer is sometimes referred to as the "Danger Zone" because of the ease by which infectious agents can spread through it to emissary veins which then drain into the cranium. The loose areolar tissue in this layer is made up of random collagen I bundles, collagen III and is highly vascular and cellular. It will also be rich in glycosaminoglycans (GAGs) and will be constituted of more matrix than fibers.
- P: The pericranium is the periosteum of the skull bones and provides nutrition to the bone and the capacity for repair. It may be lifted from the bone to allow removal of bone windows (craniotomy).
# Blood supply
The blood supply of the scalp is via four pairs of arteries, two from the external carotid and two from the internal carotid:
- internal carotid
the supratrochlear artery to the midline forehead
the supraorbital artery to the lateral forehead and scalp as far up as the vertex
- the supratrochlear artery to the midline forehead
- the supraorbital artery to the lateral forehead and scalp as far up as the vertex
- external carotid
the superficial temporal artery which gives frontal and parietal branches to supply much of the scalp
the occipital artery which runs from posteriorly to supply much of the back of the scalp.
- the superficial temporal artery which gives frontal and parietal branches to supply much of the scalp
- the occipital artery which runs from posteriorly to supply much of the back of the scalp.
# Innervation
The scalp is innervated by the following:[2]
- Supratrochlear nerve and the supraorbital nerve from the ophthalmic division of the trigeminal nerve
- Greater occipital nerve (C2) posteriorly up to the vertex
- Lesser occipital nerve (C3) behind the ear.
- Zygomaticotemporal nerve from the maxillary division of the trigeminal nerve supplying the hairless temple
- Auriculotemporal nerve from the mandibular division of the trigeminal nerve
# Role in aesthetics
The scalp plays an important role in the aesthetics of the face. Androgenic alopecia, or male pattern hair loss, is a common cause of concern to men. It may be treated by medication (eg finasteride) or hair transplantation with variable success. If the scalp is heavy and loose, a common change with aging, the forehead may be low, heave and deeply lined. The brow lift procedure aims to address these concerns.
# Pathology
The scalp is a common site for the development of tumours including:
- epidermoid cyst
- pilar cyst
- actinic keratosis and squamous cell carcinoma
- basal cell carcinoma
- merkel cell tumours | https://www.wikidoc.org/index.php/Scalp | |
1c25f1b433ce8ff5cd60661d0a26fd17d2c2b0d8 | wikidoc | Semen | Semen
Semen is an organic fluid (also known as seminal fluid) that usually contains spermatozoa. It is secreted by the gonads (sexual glands) and other sexual organs of male or hermaphroditic animals for fertilization of female ova. The process of discharge is called ejaculation.
# Physiological aspects
## Internal and external fertilization
Depending on the species, spermatozoa can fertilize ova externally or internally. In external fertilization, the spermatozoa fertilize the ova directly, outside of the female's sexual organs. Female fish, for example, spawn ova into their aquatic environment, where they are fertilized by the semen of the male fish.
During internal fertilization, however, fertilization occurs inside the female's sexual organs. Internal fertilization takes place after insemination of a female by a male through copulation. In low vertebrates (amphibians, reptiles, birds and monotreme mammals), copulation is achieved through the physical mating of the cloaca of the male and female. In marsupial and placental mammals, copulation occurs through the vagina.
## Composition of human semen
The components of semen come from two sources: sperm, and "seminal plasma". Seminal plasma, in turn, is produced by contributions from the seminal vesicle, prostate, and bulbourethral glands.
Seminal plasma of humans contains a complex range of organic and inorganic constituents.
The seminal plasma provides a nutritive and protective medium for the spermatozoa during their journey through the female reproductive tract. The normal environment of the vagina is a hostile one for sperm cells, as it is very acidic (from the native microflora producing lactic acid), viscous, and patrolled by immune cells. The components in the seminal plasma attempt to compensate for this hostile environment. Basic amines such as putrescine, spermine, spermidine and cadaverine are responsible for the smell and flavor of semen. These alkaline bases counteract the acidic environment of the vaginal canal, and protect DNA inside the sperm from acidic denaturation.
The components and contributions of semen are as follows:
A 1992 World Health Organization report described normal human semen as having a volume of 2 ml or greater, pH of 7.2 to 8.0, sperm concentration of 20x106 spermatozoa/ml or more, sperm count of 40x106 spermatozoa per ejaculate or more and motility of 50% or more with forward progression (categories a and b) of 25% or more with rapid progression (category a) within 60 minutes of ejaculation.
## Appearance and consistency of human semen
Most semen is white in colour, but grey or even yellowish semen can be normal as well. Blood in the semen can cause a pink or reddish colour and may indicate a medical problem which should be evaluated by a doctor.
After ejaculation, semen first goes through a clotting process and then becomes more liquid. It is postulated that the initial clotting helps keep the semen in the vaginal canal, but liquefaction frees the sperm to make their longer journey to the ova. Immediately after ejaculation semen is typically a sticky, jelly-like liquid often forming globules. Within 5 to 40 minutes it will become more watery and liquid before finally drying.
## Semen quality
Semen quality is a measure of the ability of semen to accomplish fertilisation. Thus, it is a measure of fertility in a man. It is the sperm in the semen that are of importance, and therefore semen quality involves both sperm quantity and sperm quality.
## Semen and transmission of disease
Semen can be the vehicle for many sexually transmitted diseases, including HIV, the virus that causes AIDS.
It is also hypothesized that components of semen, such as the spermatozoa as well as the seminal plasma, can cause immunosuppression in the body when introduced to the bloodstream or lymph. Evidence for this dates back to 1898, when Elie Metchnikoff injected a guinea pig with its own and foreign guinea pig sperm, finding that an antibody was produced in response; however the antibody was inactive, pointing to a suppression response by the immune system.
Further research, such as that by S. Mathur and J.M. Goust, demonstrated that non-preexisting antibodies were produced in humans in response to the sperm. These antibodies mistakenly recognized native T lymphocytes as foreign antigens, and consequently the T lymphocytes would fall under attack by the body's B lymphocytes.
Other semen components shown to spur an immunosuppressive effect are seminal plasma and seminal lymphocytes.
## Blood in the semen (hematospermia)
The presence of blood in the semen may be undetectable (it only can be seen microscopically) or visible in the fluid. Its cause could be the result of inflammation, infection, blockage, or injury of the male reproductive tract or a problem within the urethra, testicles, epididymis and prostate.
Further semen analysis and other urogenital system tests might be needed to find out the cause of blood in the semen.
## Semen allergy
In rare cases people have been known to experience allergic reactions to seminal fluids, known as human seminal plasma hypersensitivity. Symptoms can be either localized or systemic, and may include vaginal itching, redness, swelling, or blisters within 30 minutes of contact. They may also include generalized itching, hives, and even difficulty breathing.
The best way to test for human seminal plasma sensitivity is to use a condom during intercourse. If symptoms dissipate with the use of a condom, it is possible that a sensitivity to semen is present. Mild cases of semen allergy can often be overcome by repeated exposure to seminal fluid. In more severe cases, it is important to seek the advice of a physician, particularly in the event that a couple is trying to conceive, in which case, artificial insemination may be indicated.
# Cultural aspects
## Semen and martial arts
Chi Kung and Chinese medicine places huge emphasis on a form of energy called 精(pinyin: jing1, also a morpheme denoting "essence" or "spirit") - which one attempts to develop and accumulate, jing is sexual energy and is considered to dissipate with ejaculation so masturbation is considered "Energy Suicide" amongst those who practice this art. According to Chi Kung theory, energy from many pathways/meridians becomes diverted and transfers itself to the sexual organs during sexual excitement, the ensuing orgasm and ejaculation will then finally expel the energy from the system completely. The Chinese proverb 一滴精，十滴血(pinyin: yi4 di1 jing1, shi2 di1 xue3, literally: a drop of semen is equal to ten drops of blood) illustrates this point.
The scientific term for semen in Chinese is 精液(pinyin: jing1 ye4, literally: fluid of essence/jing) and the term for sperm is 精子(pinyin: jing1 zi3, literally: basic element of essence/jing), two modern terms with classical reference.
## Cultural views
In some cultures, semen is attributed with special properties of masculinity. For instance, among the Etoro people of Papua New Guinea, it is believed that young boys must fellate their elders and ingest their sperm to achieve proper sexual maturation. This act may also be attributed to the culturally active homosexuality throughout these and other tribes.
### Aristotle
Aristotle wrote on the importance of semen as follows:
"For Aristotle, semen is the residue derived from nourishment, that is of blood, that has been highly concocted to the optimum temperature and substance. This can only be emitted by the male as only the male, by nature of his very being, has the requisite heat to concoct blood into semen."
"Sperms are the excretion of our food, or to put it more clearly, as the most perfect component of our food"
If men start to engage in sexual activity at too early an age... this will affect the growth of their bodies. Nourishment that would otherwise make the body grow is diverted to the production of semen. ... Aristotle is saying that at this stage the body is still growing; it is best for sexual activity to begin when its growth is 'no longer abundant', for when the body is more or less at full height, the transformation of nourishment into semen does not drain the body of needed material.
## Sacred semen
In some pre-industrial societies, semen and other body fluids were revered because they were believed to be magical. Blood is an example of such a fluid, but semen was also widely believed to be of supernatural origin and effect and was, as a result, considered holy or sacred.
Semen is currently and has long been revered by Buddhist, and Daoist traditions as a very important constituent of human physiology.
Dew was once thought to be a sort of rain that fertilized the earth and, in time, became a metaphor for semen. The Bible employs the term “dew” in this sense in such verses as Song of Solomon 5:2 and Psalm 110:3, declaring, in the latter verse, for example, that the people should follow only a king who was virile enough to be full of the “dew” of youth.
It was widely believed, in ancient times, that gemstones were drops of divine semen which had coagulated after having fertilized the earth. There is an ancient Chinese belief that jade, in particular, was the dried semen of the celestial dragon.
Based upon the resemblance of dandelion juice to human semen, it was believed that the flower magically promoted the flow of sperm.
The orchid’s twin bulbs were thought to resemble the testicles, and there was an ancient Roman belief that the flower sprang from the spilled semen of copulating satyrs.
Barbara G. Walker recounts these examples of sacred semen in The Woman’s Dictionary of Symbols and Sacred Objects, the thesis of which is that myth and folklore show a pre-patriarchic rule by women that was later supplanted by masculine culture.
In primitive mythology semen is considered to be the returning or refunding of the milk of the mother in an alimentary metaphor. The wife feeds her husband who returns to her his semen, the milk of human kindness, as it were.
## Semen in popular culture
Depiction of semen in art and popular culture has, for a long time, been considered a taboo subject.
The Japanese artist Takashi Murakami is famous for a manga style piece entitled My Lonesome Cowboy, which features a naked cowboy superhero wielding his own semen as a lasso.
Andres Serrano, whose photos depict bodily fluids such as "Blood and Semen II" (Semen y Sangre II) (1990), became a controversial figure for featuring semen in his work. He was criticized by some for producing offensive art, while others defended him in the name of artistic freedom. His photos were featured on the cover art of two Metallica albums, Load and ReLoad, which feature images made by shining light through a piece of clear plastic on which semen, blood and urine have been splattered and swirled around.
Only recently has semen been depicted (albeit controversially) in movies such as Kika (1993), There's Something About Mary (1998) ("a hard-core staple making its debut in a mainstream Hollywood comedy"), Happiness (1998), American Pie (1999), Scary Movie (2000), Scary Movie 2 (2001), and National Lampoon's Van Wilder (2002). Jackass Number Two (2006) features a scene where Chris Pontius drinks horse semen. It has also appeared in the anime movie End of Evangelion, which is not otherwise an adult-oriented film.
## Euphemisms
A huge variety of euphemisms and dysphemisms have been invented to describe semen. For a complete list of terms, see Sexual slang. | Semen
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]
Semen is an organic fluid (also known as seminal fluid) that usually contains spermatozoa. It is secreted by the gonads (sexual glands) and other sexual organs of male or hermaphroditic animals for fertilization of female ova. The process of discharge is called ejaculation.
# Physiological aspects
## Internal and external fertilization
Depending on the species, spermatozoa can fertilize ova externally or internally. In external fertilization, the spermatozoa fertilize the ova directly, outside of the female's sexual organs. Female fish, for example, spawn ova into their aquatic environment, where they are fertilized by the semen of the male fish.
During internal fertilization, however, fertilization occurs inside the female's sexual organs. Internal fertilization takes place after insemination of a female by a male through copulation. In low vertebrates (amphibians, reptiles, birds and monotreme mammals), copulation is achieved through the physical mating of the cloaca of the male and female. In marsupial and placental mammals, copulation occurs through the vagina.
## Composition of human semen
The components of semen come from two sources: sperm, and "seminal plasma". Seminal plasma, in turn, is produced by contributions from the seminal vesicle, prostate, and bulbourethral glands.
Seminal plasma of humans contains a complex range of organic and inorganic constituents.
The seminal plasma provides a nutritive and protective medium for the spermatozoa during their journey through the female reproductive tract. The normal environment of the vagina is a hostile one for sperm cells, as it is very acidic (from the native microflora producing lactic acid), viscous, and patrolled by immune cells. The components in the seminal plasma attempt to compensate for this hostile environment. Basic amines such as putrescine, spermine, spermidine and cadaverine are responsible for the smell and flavor of semen. These alkaline bases counteract the acidic environment of the vaginal canal, and protect DNA inside the sperm from acidic denaturation.
The components and contributions of semen are as follows:
A 1992 World Health Organization report described normal human semen as having a volume of 2 ml or greater, pH of 7.2 to 8.0, sperm concentration of 20x106 spermatozoa/ml or more, sperm count of 40x106 spermatozoa per ejaculate or more and motility of 50% or more with forward progression (categories a and b) of 25% or more with rapid progression (category a) within 60 minutes of ejaculation.[2]
## Appearance and consistency of human semen
Most semen is white in colour, but grey or even yellowish semen can be normal as well. Blood in the semen can cause a pink or reddish colour and may indicate a medical problem which should be evaluated by a doctor.
After ejaculation, semen first goes through a clotting process and then becomes more liquid. It is postulated that the initial clotting helps keep the semen in the vaginal canal, but liquefaction frees the sperm to make their longer journey to the ova. Immediately after ejaculation semen is typically a sticky, jelly-like liquid often forming globules. Within 5 to 40 minutes it will become more watery and liquid before finally drying. [3]
## Semen quality
Semen quality is a measure of the ability of semen to accomplish fertilisation. Thus, it is a measure of fertility in a man. It is the sperm in the semen that are of importance, and therefore semen quality involves both sperm quantity and sperm quality.
## Semen and transmission of disease
Semen can be the vehicle for many sexually transmitted diseases, including HIV, the virus that causes AIDS.
It is also hypothesized that components of semen, such as the spermatozoa as well as the seminal plasma, can cause immunosuppression in the body when introduced to the bloodstream or lymph.[citation needed] Evidence for this dates back to 1898, when Elie Metchnikoff injected a guinea pig with its own and foreign guinea pig sperm, finding that an antibody was produced in response; however the antibody was inactive, pointing to a suppression response by the immune system.
Further research, such as that by S. Mathur and J.M. Goust, demonstrated that non-preexisting antibodies were produced in humans in response to the sperm. These antibodies mistakenly recognized native T lymphocytes as foreign antigens, and consequently the T lymphocytes would fall under attack by the body's B lymphocytes. [4]
Other semen components shown to spur an immunosuppressive effect are seminal plasma and seminal lymphocytes.
## Blood in the semen (hematospermia)
The presence of blood in the semen may be undetectable (it only can be seen microscopically) or visible in the fluid. Its cause could be the result of inflammation, infection, blockage, or injury of the male reproductive tract or a problem within the urethra, testicles, epididymis and prostate.
Further semen analysis and other urogenital system tests might be needed to find out the cause of blood in the semen.
## Semen allergy
In rare cases people have been known to experience allergic reactions to seminal fluids, known as human seminal plasma hypersensitivity.[5] Symptoms can be either localized or systemic, and may include vaginal itching, redness, swelling, or blisters within 30 minutes of contact. They may also include generalized itching, hives, and even difficulty breathing.
The best way to test for human seminal plasma sensitivity is to use a condom during intercourse. If symptoms dissipate with the use of a condom, it is possible that a sensitivity to semen is present. Mild cases of semen allergy can often be overcome by repeated exposure to seminal fluid.[6] In more severe cases, it is important to seek the advice of a physician, particularly in the event that a couple is trying to conceive, in which case, artificial insemination may be indicated.
# Cultural aspects
## Semen and martial arts
Chi Kung and Chinese medicine places huge emphasis on a form of energy called 精(pinyin: jing1, also a morpheme denoting "essence" or "spirit")[7] [8] - which one attempts to develop and accumulate, jing is sexual energy and is considered to dissipate with ejaculation so masturbation is considered "Energy Suicide" amongst those who practice this art. According to Chi Kung theory, energy from many pathways/meridians becomes diverted and transfers itself to the sexual organs during sexual excitement, the ensuing orgasm and ejaculation will then finally expel the energy from the system completely. The Chinese proverb 一滴精，十滴血(pinyin: yi4 di1 jing1, shi2 di1 xue3, literally: a drop of semen is equal to ten drops of blood) illustrates this point.
The scientific term for semen in Chinese is 精液(pinyin: jing1 ye4, literally: fluid of essence/jing) and the term for sperm is 精子(pinyin: jing1 zi3, literally: basic element of essence/jing), two modern terms with classical reference.
## Cultural views
In some cultures, semen is attributed with special properties of masculinity. For instance, among the Etoro people of Papua New Guinea, it is believed that young boys must fellate their elders and ingest their sperm to achieve proper sexual maturation. This act may also be attributed to the culturally active homosexuality throughout these and other tribes.[9]
### Aristotle
Aristotle wrote on the importance of semen as follows:
"For Aristotle, semen is the residue derived from nourishment, that is of blood, that has been highly concocted to the optimum temperature and substance. This can only be emitted by the male as only the male, by nature of his very being, has the requisite heat to concoct blood into semen."[10]
"Sperms are the excretion of our food, or to put it more clearly, as the most perfect component of our food"[11]
If men start to engage in sexual activity at too early an age... this will affect the growth of their bodies. Nourishment that would otherwise make the body grow is diverted to the production of semen. ... Aristotle is saying that at this stage the body is still growing; it is best for sexual activity to begin when its growth is 'no longer abundant', for when the body is more or less at full height, the transformation of nourishment into semen does not drain the body of needed material.[12]
## Sacred semen
In some pre-industrial societies, semen and other body fluids were revered because they were believed to be magical. Blood is an example of such a fluid, but semen was also widely believed to be of supernatural origin and effect and was, as a result, considered holy or sacred.
Semen is currently and has long been revered by Buddhist, and Daoist traditions as a very important constituent of human physiology.
Dew was once thought to be a sort of rain that fertilized the earth and, in time, became a metaphor for semen. The Bible employs the term “dew” in this sense in such verses as Song of Solomon 5:2 and Psalm 110:3, declaring, in the latter verse, for example, that the people should follow only a king who was virile enough to be full of the “dew” of youth.
It was widely believed, in ancient times, that gemstones were drops of divine semen which had coagulated after having fertilized the earth. There is an ancient Chinese belief that jade, in particular, was the dried semen of the celestial dragon.
Based upon the resemblance of dandelion juice to human semen, it was believed that the flower magically promoted the flow of sperm.
The orchid’s twin bulbs were thought to resemble the testicles, and there was an ancient Roman belief that the flower sprang from the spilled semen of copulating satyrs.
Barbara G. Walker recounts these examples of sacred semen in The Woman’s Dictionary of Symbols and Sacred Objects, the thesis of which is that myth and folklore show a pre-patriarchic rule by women that was later supplanted by masculine culture.[13]
In primitive mythology semen is considered to be the returning or refunding of the milk of the mother in an alimentary metaphor. The wife feeds her husband who returns to her his semen, the milk of human kindness, as it were.[14]
## Semen in popular culture
Depiction of semen in art and popular culture has, for a long time, been considered a taboo subject.
The Japanese artist Takashi Murakami is famous for a manga style piece entitled My Lonesome Cowboy, which features a naked cowboy superhero wielding his own semen as a lasso.
Andres Serrano, whose photos depict bodily fluids such as "Blood and Semen II" (Semen y Sangre II) (1990), became a controversial figure for featuring semen in his work. He was criticized by some for producing offensive art, while others defended him in the name of artistic freedom.[15] His photos were featured on the cover art of two Metallica albums, Load and ReLoad, which feature images made by shining light through a piece of clear plastic on which semen, blood and urine have been splattered and swirled around.
Only recently has semen been depicted (albeit controversially) in movies such as Kika (1993), There's Something About Mary (1998) ("a hard-core staple making its debut in a mainstream Hollywood comedy")[16], Happiness (1998), American Pie (1999), Scary Movie (2000), Scary Movie 2 (2001), and National Lampoon's Van Wilder (2002). Jackass Number Two (2006) features a scene where Chris Pontius drinks horse semen. It has also appeared in the anime movie End of Evangelion, which is not otherwise an adult-oriented film.
## Euphemisms
A huge variety of euphemisms and dysphemisms have been invented to describe semen. For a complete list of terms, see Sexual slang. | https://www.wikidoc.org/index.php/Semen |
Subsets and Splits