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NaK

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NaK NaK (often pronounced as such, rhyming with "sack") is an alloy of sodium (Na) and potassium (K), and particularly one that is liquid at room temperatures. It is a commercially available material in various grades. NaK is highly reactive with air or water, and must be handled with special precautions. Quantities as small as one gram can be a fire or explosion risk. # Physical properties Alloys with between about 40% and 90% potassium by weight are liquid at room temperature. The mixture with the lowest melting point (the eutectic mix), consisting of 78% potassium and 22% sodium, is liquid from −12.6 to 785 °C, and has a density of 866 kg/m³ at 21°C and 855 kg/m³ at 100°C. # Usage

d2c9ad160b9d9d3e3084895fc88a145252626a91

NaK

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# Usage ## As coolant One notable use is as the coolant in experimental fast neutron nuclear reactors. Unlike commercial plants, these are frequently shut down and defuelled. Use of lead or pure sodium, the other materials used in practical reactors, would require continual heating to maintain the coolant as a liquid. Use of NaK overcomes this. NaK is used in many other heat transfer applications for similar reasons. The Soviet RORSAT radar satellites were powered by a NaK-cooled reactor. Apart from the wide liquid temperature range, NaK has a very low vapor pressure, important in the vacuum of space. Some of the coolant has leaked and these NaK droplets constitute a significant space debris hazard. ## In catalysis NaK is also used as a catalyst for many reactions, including precursors of ibuprofen.

d2c9ad160b9d9d3e3084895fc88a145252626a91

NaK

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## In catalysis NaK is also used as a catalyst for many reactions, including precursors of ibuprofen. ## As desiccant Both sodium and potassium are used as desiccants in drying solvents prior to distillation. However, without heating, the solid metal is only able to react at the surface. Formation of crusts of oxide also helps to reduce the reactivity. As a liquid metal alloy at room temperature, the use of NaK as a desiccant helps to avoid these problems.

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Oat

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Oat The oat (Avena sativa) is a species of cereal grain, and the seeds of this plant. They are used for food for people and as fodder for animals, especially poultry and horses. Oat straw is used as animal bedding and sometimes as animal feed.

a1b7b03e1aa7d801bba2fd9e17c3bb4a279a8b0c

Oat

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Since oats are unsuitable for making bread on their own, due to their lack of gluten, they are often served as a porridge made from crushed or rolled oats (see oatmeal), and are also baked into cookies (oatcakes), which can have added wheat flour. As oat flour or oatmeal, they are also used in a variety of other baked goods (e.g. bread made from a mixture of oatmeal and wheat flour) and cold cereals, and as an ingredient in muesli and granola. Oats may also be consumed raw, and cookies with raw oats are becoming popular. Oats are also occasionally used in Britain for brewing beer. Oatmeal stout is one variety brewed using a percentage of oats for the wort. The more rarely used Oat Malt is produced by the Thomas Fawcett & Sons Maltings and was used in the Maclay Oat Malt Stout before Maclay ceased independent brewing operations.

a1b7b03e1aa7d801bba2fd9e17c3bb4a279a8b0c

Oat

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Oats also have non-food uses. Oat straw is also used in corn dolly making, and it is the favourite filling for home made lace pillows. Oat extract can be used to soothe the skin conditions, e.g. in baths, skin products, etc. A now obsolete Middle English name for the plant was haver (still used in most other Germanic languages), surviving in the name of the livestock feeding bag haversack. In contrast with the names of the other grains, "oat" is usually used in the plural.

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Oat

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# Origin The wild ancestor of Avena sativa and the closely-related minor crop, A. byzantina, is the hexaploid wild oat A. sterilis. Genetic evidence shows that the ancestral forms of A. sterilis grow in the Fertile Crescent of the Near East. Domesticated oats appear relatively late, and far from the Near East, in Bronze Age Europe. Oats, like rye, are usually considered a secondary crop, i.e. derived from a weed of the primary cereal domesticates wheat and barley. As these cereals spread westwards into cooler, wetter areas, this may have favoured the oat weed component, leading to its eventual domestication.

a1b7b03e1aa7d801bba2fd9e17c3bb4a279a8b0c

Oat

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# Cultivation Oats are grown throughout the temperate zones. They have a lower summer heat requirement and greater tolerance of rain than other cereals like wheat, rye or barley, so are particularly important in areas with cool, wet summers such as Northwest Europe, even being grown successfully in Iceland. Oats are an annual plant, and can be planted either in autumn (for late summer harvest) or in the spring (for early autumn harvest).

a1b7b03e1aa7d801bba2fd9e17c3bb4a279a8b0c

Oat

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Historical attitudes towards oats vary. Oat bread was first manufactured in England, where the first oat bread factory was established in 1899. In Scotland they were, and still are, held in high esteem, as a mainstay of the national diet. A traditional saying in England is that "oats are only fit to be fed to horses and Scotsmen", to which the Scottish riposte is "and England has the finest horses, and Scotland the finest men". Samuel Johnson notoriously defined oats in his Dictionary as "a grain, which in England is generally given to horses, but in Scotland supports the people". While frequently seen as derogatory, this is no less than the literal truth. Oats are so central to traditional Scottish cuisine that the Scottish English word "corn" refers to oats instead of wheat, as in England, and maize in North America and Australia. Oats grown in Scotland command a premium price throughout the United Kingdom as a result of these traditions.

a1b7b03e1aa7d801bba2fd9e17c3bb4a279a8b0c

Oat

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# Health Oats are generally considered "healthy", or a health food, being touted commercially as nutritious. The discovery of the healthy cholesterol-lowering properties has led to wider appreciation of oats as human food.

a1b7b03e1aa7d801bba2fd9e17c3bb4a279a8b0c

Oat

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## Soluble fiber Oat bran is the outer casing of the oat. Its consumption is believed to lower LDL ("bad") cholesterol, and possibly to reduce the risk of heart disease.

a1b7b03e1aa7d801bba2fd9e17c3bb4a279a8b0c

Oat

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After reports found that oats can help lower cholesterol, an "oat bran craze" swept the U.S. in the late 1980s, peaking in 1989, when potato chips with added oat bran were marketed. The food fad was short-lived and faded by the early 1990s. The popularity of oatmeal and other oat products again increased after the January 1998 decision by the Food and Drug Administration (FDA) when it issued its final rule allowing a health claim to be made on the labels of foods containing soluble fiber from whole oats (oat bran, oat flour and rolled oats), noting that 3 grams of soluble fiber daily from these foods, in conjunction with a diet low in saturated fat, cholesterol, and fat may reduce the risk of heart disease. In order to qualify for the health claim, the whole oat-containing food must provide at least 0.75 grams of soluble fiber per serving. The soluble fiber in whole oats comprise a class of polysaccharides known as Beta-D-glucan.

a1b7b03e1aa7d801bba2fd9e17c3bb4a279a8b0c

Oat

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Beta-D-glucans, usually referred to as beta-glucans, comprise a class of non-digestible polysaccharides widely found in nature in sources such as grains, barley, yeast, bacteria, algae and mushrooms. In oats, barley and other cereal grains, they are located primarily in the endosperm cell wall.

a1b7b03e1aa7d801bba2fd9e17c3bb4a279a8b0c

Oat

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Oat beta-glucan is a soluble fiber. It is a viscous polysaccharide made up of units of the sugar D-glucose. Oat beta-glucan is comprised of mixed-linkage polysaccharides. This means that the bonds between the D-glucose or D-glucopyranosyl units are either beta-1, 3 linkages or beta-1, 4 linkages. This type of beta-glucan is also referred to as a mixed-linkage (1→3), (1→4)-beta-D-glucan. The (1→3)-linkages break up the uniform structure of the beta-D-glucan molecule and make it soluble and flexible. In comparison, the non-digestible polysaccharide cellulose is also a beta-glucan but is non-soluble. The reason that it is non-soluble is that cellulose consists only of (1→4)-beta-D-linkages. The percentages of beta-glucan in the various whole oat products are: oat bran, greater than 5.5% and up to 23.0%; rolled oats, about 4%; whole oat flour about 4%.

a1b7b03e1aa7d801bba2fd9e17c3bb4a279a8b0c

Oat

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Oats after corn (maize) has the highest lipid content of any cereal, e.g., greater than 10 percent for oats and as high as 17 percent for some maize cultivars compared to about 2–3 percent for wheat and most other cereals. The polar lipid content of oats (about 8–17% glycolipid and 10–20% phospholipid or a total of about 33% ) is greater than that of other cereals since much of the lipid fraction is contained within the endosperm.

a1b7b03e1aa7d801bba2fd9e17c3bb4a279a8b0c

Oat

WikiDoc

## Protein Oat is the only cereal containing a globulin or legume-like protein, avenalin, as the major (80%) storage protein. Globulins are characterized by water solubility; because of this property, oats may be turned into milk but not into bread. The more typical cereal proteins such as gluten and zein are prolamines(prolamins). The minor protein of oat is a prolamine: avenin. Oat protein is nearly equivalent in quality to soy protein, which has been shown by the World Health Organization to be the equal to meat, milk, and egg protein. The protein content of the hull-less oat kernel (groat) ranges from 12–24%, the highest among cereals.

a1b7b03e1aa7d801bba2fd9e17c3bb4a279a8b0c

Oat

WikiDoc

## Celiac Disease Coeliac disease, or celiac disease, from Greek "koiliakos", meaning "suffering in the bowels", is a disease often associated with ingestion of wheat, or more specifically a group of proteins labelled prolamines, or more commonly, gluten. Oats lack many of the prolamines found in wheat; however, oats do contain avenin. Avenin is a prolamine that is toxic to the intestinal submucosa and can trigger a reaction in some celiacs. Although oats do contain avenin, there are several studies suggesting that oats can be a part of a gluten free diet if it is pure. The first such study was published in 1995. A follow-up study indicated that it is safe to use oats even in a longer period

a1b7b03e1aa7d801bba2fd9e17c3bb4a279a8b0c

Oat

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Additionally, oats are frequently processed near wheat, barley and other grains such that they become contaminated with other glutens. Because of this, the FAO's Codex Alimentarius Commission officially lists them as a crop containing gluten. Oats from Ireland and Scotland, where less wheat is grown, are less likely to be contaminated in this way. Oats are part of a gluten free diet in, for example, Finland and Sweden. In both of these countries there are "pure oat" products on the market.

a1b7b03e1aa7d801bba2fd9e17c3bb4a279a8b0c

Oat

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# Agronomy Oats are sown in the spring, as soon as the soil can be worked. An early start is crucial to good yields as oats will go dormant during the summer heat. Oats are cold-tolerant and will be unaffected by late frosts or snow. Typically about 100 kg/hectare (about 2 bushels per acre) are sown, either broadcast or drilled in 150 mm (6 inch) rows. Lower rates are used when underseeding with a legume. Somewhat higher rates can be used on the best soils. Excessive sowing rates will lead to problems with lodging and may reduce yields. Winter oats may be grown as an off-season groundcover and plowed under in the spring as a green fertilizer.

a1b7b03e1aa7d801bba2fd9e17c3bb4a279a8b0c

Oat

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Winter oats may be grown as an off-season groundcover and plowed under in the spring as a green fertilizer. Oats remove substantial amounts of nitrogen from the soil. They also remove phosphorus in the form of P2O5 at the rate of .25 pounds per bushel per acre (1 bushel = 32 pounds at 14% moisture). Oats remove potash (K2O) at a rate of .19 pounds per bushel per acre. If the straw is removed from the soil rather than being ploughed back, the removal rate of phosphorus is 8 pounds per ton per acre and the rate of potash removal is 40 pounds per ton per acre. Usually 50–100 kg/hectare (50–100 pounds per acre) of nitrogen in the form of urea or ammonium sulphate is sufficient. A sufficient amount of nitrogen is particularly important for plant height and hence straw quality and yield. When the prior-year crop was a legume, or where ample manure is applied, nitrogen rates can be reduced somewhat.

a1b7b03e1aa7d801bba2fd9e17c3bb4a279a8b0c

Oat

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The vigorous growth habit of oats will tend to choke out most weeds. A few tall broadleaf weeds, such as ragweed, goosegrass and buttonweed (velvetleaf), can occasionally be a problem as they complicate harvest. These can be controlled with a modest application of a broadleaf herbicide such as 2,4-D while the weeds are still small. Modern harvest technique is a matter of available equipment, local tradition, and priorities. Best yields are attained by swathing, cutting the plants at about 10 cm (4 inches) above ground and putting them into windrows with the grain all oriented the same way, just before the grain is completely ripe. The windrows are left to dry in the sun for several days before being combined using a dummy head. Then the straw is baled.

a1b7b03e1aa7d801bba2fd9e17c3bb4a279a8b0c

Oat

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Oats can also be left standing until completely ripe and then combined with a grain head. This will lead to greater field losses as the grain falls from the heads and to harvesting losses as the grain is threshed out by the reel. Without a draper head, there will also be somewhat more damage to the straw since it will not be properly oriented as it enters the throat of the combine. Overall yield loss is 10–15% compared to proper swathing. Historical harvest methods involved cutting with a scythe or sickle, and threshing under the feet of cattle. Late 19th and early 20th century harvesting was performed using a binder. Oats were gathered into shocks and then collected and run through a stationary threshing machine. A good yield is typically about 3,000 kg/hectare (100 bushels/acre) of grain and two tonnes of straw.

a1b7b03e1aa7d801bba2fd9e17c3bb4a279a8b0c

Oat

WikiDoc

# Trivia - The eruption of Mount Tambora caused a change in world climate resulting in a volcanic winter and the "year without a summer" in 1816, during which time the price of oats rose dramatically, for example in the USA from 12 to 92 cents per bushel. This led to the starvation of many horses, which in turn led to transportation problems, which Baron Karl von Drais attempted to solve by inventing the dandy horse, the direct precursor to the bicycle. - Oats are sometimes marketed, while in seed-form, as 'Cat Grass'. This is then grown and fed to the cat as a treat, or as aid to digestion.

1cb886dcf85d594e1726408b17e59bc5d69be583

p16

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p16 p16 (also known as p16INK4a, cyclin-dependent kinase inhibitor 2A, multiple tumor suppressor 1 and as several other synonyms), is a tumor suppressor protein, that in humans is encoded by the CDKN2A gene. p16 plays an important role in cell cycle regulation by decelerating the cell's progression from G1 phase to S phase, and therefore acts as a tumor suppressor that is implicated in the prevention of cancers, notably melanoma, oropharyngeal squamous cell carcinoma, cervical cancer, and esophageal cancer. p16 can be used as a biomarker to improve the histological diagnostic accuracy of CIN3. Expression of the CDKN2A gene is frequently changed in a wide variety of tumors. p16 was originally found in an “open reading frame of 148 amino acids encoding a protein with a molecular weight of 16 kDa that comprises four ankyrin repeats.” The name of p16 is derived from its molecular weight, while the alternative name p16INK4a additionally refers to its role in inhibiting CDK4.

1cb886dcf85d594e1726408b17e59bc5d69be583

p16

WikiDoc

# Nomenclature p16 is also known as: - p16INK4A - p16Ink4 - Cyclin-dependent kinase inhibitor 2A (CDKN2A) - CDKN2 - CDK 4 Inhibitor - Multiple Tumor Suppressor 1 (MTS1) - TP16 - ARF - MLM - P14

1cb886dcf85d594e1726408b17e59bc5d69be583

p16

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# Gene

1cb886dcf85d594e1726408b17e59bc5d69be583

p16

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In humans, p16 is encoded by the CDKN2A gene, located on chromosome 9 (9p21.3). This gene generates several transcript variants that differ in their first exons. At least three alternatively spliced variants encoding distinct proteins have been reported, two of which encode structurally related isoforms known to function as inhibitors of CDK4. The remaining transcript includes an alternate exon 1 located 20 kb upstream of the remainder of the gene; this transcript contains an alternate open reading frame (ARF) that specifies a protein that is structurally unrelated to the products of the other variants. The ARF product functions as a stabilizer of the tumor suppressor protein p53, as it can interact with and sequester MDM2, a protein responsible for the degradation of p53. In spite of their structural and functional differences, the CDK inhibitor isoforms and the ARF product encoded by this gene, through the regulatory roles of CDK4 and p53 in cell cycle G1 progression, share a

1cb886dcf85d594e1726408b17e59bc5d69be583

p16

WikiDoc

of their structural and functional differences, the CDK inhibitor isoforms and the ARF product encoded by this gene, through the regulatory roles of CDK4 and p53 in cell cycle G1 progression, share a common functionality in controlling the G1 phase of the cell cycle. This gene is frequently mutated or deleted in a wide variety of tumors and is known to be an important tumor suppressor gene.

1cb886dcf85d594e1726408b17e59bc5d69be583

p16

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When organisms age, the expression of p16 increases to reduce the proliferation of stem cells. This reduction in the division and production of stem cells protects against cancer while increasing the risks associated with cellular senescence.

1cb886dcf85d594e1726408b17e59bc5d69be583

p16

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# Function p16 is an inhibitor of cyclin-dependent kinases (CDK). It slows down the cell cycle by prohibiting progression from G1 phase to S phase. Otherwise, CDK4/6 binds cyclin D and forms an active protein complex that phosphorylates retinoblastoma protein (pRB). Once phosphorylated, pRB dissociates from the transcription factor E2F1. This liberates E2F1 from its bound state in the cytoplasm and allows it to enter the nucleus. Once in the nucleus, E2F1 promotes the transcription of target genes that are essential for transition from G1 to S phase.

1cb886dcf85d594e1726408b17e59bc5d69be583

p16

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This pathway connects the processes of tumor oncogenesis and senescence, fixing them on opposite ends of a spectrum. On one end, the hypermethylation, mutation, or deletion of p16 leads to downregulation of the gene and can lead to cancer through the dysregulation of cell cycle progression. Conversely, activation of p16 through reactive oxygen species, DNA damage, or senescence leads to the buildup of p16 in tissues and is implicated in the aging of cells.

1cb886dcf85d594e1726408b17e59bc5d69be583

p16

WikiDoc

# Regulation Regulation of p16 is complex and involves the interaction of several transcription factors, as well as several proteins involved in epigenetic modification through methylation and repression of the promoter region. PRC1 and PRC2 are two protein complexes that modify the expression of p16 through the interaction of various transcription factors that execute methylation patterns that can repress transcription of p16. These pathways are activated in the cellular response to reduce senescence. # Clinical significance

1cb886dcf85d594e1726408b17e59bc5d69be583

p16

WikiDoc

## Role in cancer Mutations resulting in deletion or reduction of function of the CDKN2A gene are associated with increased risk of a wide range of cancers, and alterations of the gene are frequently seen in cancer cell lines. Examples include: Pancreatic adenocarcinoma is often associated with mutations in the CDKN2A gene. Carriers of germline mutations in CDKN2A have, besides their high risks of melanoma, also increased risks of pancreatic, lung, laryngeal and oropharyngeal cancers. Tobacco smoking increases the carriers’ susceptibility for such non-melanoma cancers. Homozygous deletions of p16 are frequently found in esophageal cancer and gastric cancer cell lines. Germline mutations in CDKN2A are associated with an increased susceptibility to develop skin cancer.

1cb886dcf85d594e1726408b17e59bc5d69be583

p16

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Germline mutations in CDKN2A are associated with an increased susceptibility to develop skin cancer. Hypermethylation of tumor suppressor genes has been implicated in various cancers. In 2013, a meta-analysis revealed an increased frequency of DNA methylation of the p16 gene in esophageal cancer. As the degree of tumor differentiation increased, so did the frequency of p16 DNA methylation.

1cb886dcf85d594e1726408b17e59bc5d69be583

p16

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Tissue samples of primary oral squamous cell carcinoma (OSCC) often display hypermethylation in the promoter regions of p16. Cancer cells show a significant increase in the accumulation of methylation in CpG islands in the promoter region of p16. This epigenetic change leads to loss of the tumor suppressor gene function through two possible mechanisms: first, methylation can physically inhibit the transcription of the gene, and second, methylation can lead to the recruitment of transcription factors that repress transcription. Both mechanisms cause the same end result: downregulation of gene expression that leads to decreased levels of the p16 protein. It has been suggested that this process is responsible for the development of various forms of cancer serving as an alternative process to gene deletion or mutation.

1cb886dcf85d594e1726408b17e59bc5d69be583

p16

WikiDoc

p16 positivity has been shown to be favorably prognostic in oropharyngeal squamous cell carcinoma. In a retrospective trial analysis of patients with Stage III and IV oropharyngeal cancer, HPV status was assessed and it was found that the 3-year rates of overall survival were 82.4% (95% CI, 77.2 to 87.6) in the HPV-positive subgroup and 57.1% (95% CI, 48.1 to 66.1) in the HPV-negative subgroup, and the 3-year rates of progression-free survival were 73.7% (95% CI, 67.7 to 79.8) and 43.4% (95% CI, 34.4 to 52.4), respectively. p16 status is so prognostic that the AJCC staging system has been revised to include p16 status in oropharyngeal squamous cell cancer group staging.

1cb886dcf85d594e1726408b17e59bc5d69be583

p16

WikiDoc

# Clinical use ## Biomarker for cancer types Expression of p16 is used as a prognostic biomarker for certain types of cancer. The reason for this is different types of cancer can have different effects on p16 expression: cancers that overexpress p16 are usually caused by the human papillomavirus (HPV), whereas cancers in which p16 is downregulated will usually have other causes. For patients with oropharyngeal squamous cell carcinoma, using immunohistochemistry to detect the presence of the p16 biomarker has been shown to be the strongest indicator of disease course. Presence of the biomarker is associated with a more favorable prognosis as measured by cancer-specific survival (CSS), recurrence-free survival (RFS), locoregional control (LRC), as well as other measurements. The appearance of hypermethylation of p16 is also being evaluated as a potential prognostic biomarker for prostate cancer.

1cb886dcf85d594e1726408b17e59bc5d69be583

p16

WikiDoc

## p16 FISH p16 deletion detected by FISH in surface epithelial mesothelial proliferations is predictive of underlying invasive mesothelioma. ## p16 immunochemistry As consensus grows regarding the strength of p16 as a biomarker for detecting and determining prognoses of cancer, p16 immunohistochemistry is growing in importance. ### gynecologic cancers p16 is a widely used immunohistochemical marker in gynecologic pathology. Strong and diffuse cytoplasmic and nuclear expression of p16 in squamous cell carcinomas (SCC) of the female genital tract is strongly associated with high-risk human papilloma virus (HPV) infection and neoplasms of cervical origin. The majority of SCCs of uterine cervix express p16. However, p16 can be expressed in other neoplasms and in several normal human tissues.

1cb886dcf85d594e1726408b17e59bc5d69be583

p16

WikiDoc

## Urinary bladder SCCs More than a third of urinary bladder SCCs express p16. SCCs of urinary bladder express p16 independent of gender. p16 immunohistochemical expression alone cannot be used to discriminate between SCCs arising from uterine cervix versus urinary bladder. ## Role in senescence Concentrations of p16INK4a increase dramatically as tissue ages. p16INK4a, along with senescence-associated beta-galactosidase, is regarded to be a biomarker of cellular senescence. Therefore, p16INK4a could potentially be used as a blood test that measures how fast the body's tissues are aging at a molecular level. Notably, a recent survey of cellular senescence induced by multiple treatments to several cell lines does not identify p16 as belonging to a "core signature" of senescence markers. It has been used as a target to delay some aging changes in mice.

1cb886dcf85d594e1726408b17e59bc5d69be583

p16

WikiDoc

# Discovery Researchers Manuel Serrano, Gregory J. Hannon and David Beach discovered p16 in 1993 and correctly characterized the protein as a cyclin-dependent kinase inhibitor. Since its discovery, p16 has become significant in the field of cancer research. The protein was suspected to be involved in carcinogenesis due to the observation that mutation or deletion in the gene was implicated in human cancer cell lines. The detection of p16 inactivation in familial melanoma supplied further evidence. p16 deletion, mutation, hypermethylation, or overexpression is now associated with various cancers. Whether mutations in p16 can be considered to be driver mutations requires further investigation. # Interactions p16 has been shown to interact with: - CCNG1, - CDK4, - CDK6, - DAXX, - E4F1, - MDM2, - P53, - PPP1R9B, - RPL11, and - SERTAD1.

a9aadc1e332f39503a1ccf374d47f758984cdc82

p21

WikiDoc

p21 p21Cip1 (alternatively p21Waf1), also known as cyclin-dependent kinase inhibitor 1 or CDK-interacting protein 1, is a cyclin-dependent kinase inhibitor (CKI) that is capable of inhibiting all cyclin/CDK complexes, though is primarily associated with inhibition of CDK2. p21 represents a major target of p53 activity and thus is associated with linking DNA damage to cell cycle arrest. This protein is encoded by the CDKN1A gene located on chromosome 6 (6p21.2) in humans. # Function

a9aadc1e332f39503a1ccf374d47f758984cdc82

p21

WikiDoc

## CDK inhibition p21 is a potent cyclin-dependent kinase inhibitor (CKI). The p21 (CIP1/WAF1) protein binds to and inhibits the activity of cyclin-CDK2, -CDK1, and -CDK4/6 complexes, and thus functions as a regulator of cell cycle progression at G1 and S phase. The binding of p21 to CDK complexes occurs through p21's N-terminal domain, which is homologous to the other CIP/KIP CDK inhibitors p27 and p57. Specifically it contains a Cy1 motif in the N-terminal half, and weaker Cy2 motif in the C-terminal domain that allow it to bind CDK in a region that blocks its ability to complex with cyclins and thus prevent CDK activation.

a9aadc1e332f39503a1ccf374d47f758984cdc82

p21

WikiDoc

Experiments looking at CDK2 activity within single cells have also shown p21 to be responsible for a bifurcation in CDK2 activity following mitosis, cells with high p21 enter a G0/quiescent state, whilst those with low p21 continue to proliferate. Follow up work, found evidence that this bistability is underpinned by double negative feedback between p21 and CDK2, where CDK2 inhibits p21 activity via ubiquitin ligase activity.

a9aadc1e332f39503a1ccf374d47f758984cdc82

p21

WikiDoc

## PCNA inhibition p21 interacts with proliferating cell nuclear antigen (PCNA), a DNA polymerase accessory factor, and plays a regulatory role in S phase DNA replication and DNA damage repair. Specifically, p21 has a high affinity for the PIP-box binding region on PCNA, binding of p21 to this region is proposed to block the binding of processivity factors necessary for PCNA dependent S-phase DNA synthesis, but not PCNA dependent nucleotide excision repair (NER). As such, p21 acts as an effective inhibitor of DNA S-phase DNA synthesis though permits NER, leading to the proposal that p21 acts to preferentially select polymerase processivity factors depending on the context of DNA synthesis.

a9aadc1e332f39503a1ccf374d47f758984cdc82

p21

WikiDoc

## Apoptosis inhibition This protein was reported to be specifically cleaved by CASP3-like caspases, which thus leads to a dramatic activation of CDK2, and may be instrumental in the execution of apoptosis following caspase activation. However p21 may inhibit apoptosis and does not induce cell death on its own. The ability of p21 to inhibit apoptosis in response to replication fork stress has also been reported. # Regulation

a9aadc1e332f39503a1ccf374d47f758984cdc82

p21

WikiDoc

## p53 dependent response Studies of p53 dependent cell cycle arrest in response to DNA damage identified p21 as the primary mediator of downstream cell cycle arrest. Notably, El-Deiry et al. identified a protein p21 (WAF1) which was present in cells expressing wild type p53 but not those with mutant p53, moreover constitutive expression of p21 led to cell cycle arrest in a number of cell types. Dulcic et al. also found that γ-irradiation of fibroblasts induced a p53 and p21 dependent cell cycle arrest, here p21 was found bound to inactive cyclin E/CDK2 complexes. Working in mouse models, it was also shown that whilst mice lacking p21 were healthy, spontaneous tumours developed and G1 checkpoint control was compromised in cells derived from these mice. Taken together, these studies thus defined p21 as the primary mediator of p53-dependent cell cycle arrest in response to DNA damage.

a9aadc1e332f39503a1ccf374d47f758984cdc82

p21

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Recent work exploring p21 activation in response to DNA damage at a single-cell level have demonstrated that pulsatile p53 activity leads to subsequent pulses of p21, and that the strength of p21 activation is cell cycle phase dependent. Moreover, studies of p21-levels in populations of cycling cells, not exposed to DNA damaging agents, have shown that DNA damage occurring in mother cell S-phase can induce p21 accumulation over both mother G2 and daughter G1 phases which subsequently induces cell cycle arrest; this responsible for the bifurcation in CDK2 activity observed in Spencer et al..

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p21

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## Degradation p21 is negatively regulated by ubiquitin ligases both over the course of the cell cycle and in response to DNA damage. Specifically, over the G1/S transition it has been demonstrated that the E3 ubiquitin ligase complex SCFSkp2 induces degradation of p21. Studies have also demonstrated that the E3 ubiquitin ligase complex CRL4Cdt2 degrades p21 in a PCNA dependent manner over S-phase, necessary to prevent p21 dependent re-replication, as well as in response to UV irradiation. Recent work has now found that in human cell lines SCFSkp2 degrades p21 towards the end of G1 phase, allowing cells to exit a quiescent state, whilst CRL4Cdt2 acts to degrade p21 at a much higher rate than SCFSkp2 over the G1/S transition and subsequently maintain low levels of p21 throughout S-phase.

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p21

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# Clinical significance Cytoplasmic p21 expression can be significantly correlated with lymph node metastasis, distant metastases, advanced TNM stage (a classification of cancer staging that stands for: tumor size, describing nearby lymph nodes, and distant metastasis), depth of invasion and OS (overall survival rate). A study on immunohistochemical markers in malignant thymic epithelial tumors shows that p21 expression has a negatively influenced survival and significantly correlated with WHO (World Health Organization) type B2/B3. When combined with low p27 and high p53, DFS (Disease-Free Survival) decreases.

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p21

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p21 mediates the resistance of hematopoietic cells to an infection with HIV by complexing with the HIV integrase and thereby aborting chromosomal integration of the provirus. HIV infected individuals who naturally suppress viral replication have elevated levels of p21 and its associated mRNA. p21 expression affects at least two stages in the HIV life cycle inside CD4 T cells, significantly limiting production of new viruses. Metastatic canine mammary tumors display increased levels of p21 in the primary tumors but also in their metastases, despite increased cell proliferation. Mice that lack the p21 gene gain the ability to regenerate lost appendages.

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p21

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# Interactions P21 has been shown to interact with: - Nrf2 - BCCIP, - CIZ1, - CUL4A, - CCNE1, - CDK, - DDB1, - DTL, - GADD45A, - GADD45G, - HDAC, - PCNA, - PIM1, - TK1, and - TSG101.

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p53

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p53 Lua error in Module:Effective_protection_level at line 60: attempt to index field 'TitleBlacklist' (a nil value). Tumor protein p53, also known as p53, cellular tumor antigen p53 (UniProt name), phosphoprotein p53, tumor suppressor p53, antigen NY-CO-13, or transformation-related protein 53 (TRP53), is any isoform of a protein encoded by homologous genes in various organisms, such as TP53 (humans) and Trp53 (mice). This homolog (originally thought to be, and often spoken of as, a single protein) is crucial in multicellular organisms, where it prevents cancer formation, thus, functions as a tumor suppressor. As such, p53 has been described as "the guardian of the genome" because of its role in conserving stability by preventing genome mutation. Hence TP53 is classified as a tumor suppressor gene. (Italics are used to denote the TP53 gene name and distinguish it from the protein it encodes.)

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p53

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The name p53 was given in 1979 describing the apparent molecular mass; SDS-PAGE analysis indicates that it is a 53-kilodalton (kDa) protein. However, the actual mass of the full-length p53 protein (p53α) based on the sum of masses of the amino acid residues is only 43.7 kDa. This difference is due to the high number of proline residues in the protein, which slow its migration on SDS-PAGE, thus making it appear heavier than it actually is. In addition to the full-length protein, the human TP53 gene encodes at least 15 protein isoforms, ranging in size from 3.5 to 43.7 kDa. All these p53 proteins are called the p53 isoforms. The TP53 gene is the most frequently mutated gene (>50%) in human cancer, indicating that the TP53 gene plays a crucial role in preventing cancer formation. TP53 gene encodes proteins that bind to DNA and regulate gene expression to prevent mutations of the genome.

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p53

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# Gene In humans, the TP53 gene is located on the short arm of chromosome 17 (17p13.1). The gene spans 20 kb, with a non-coding exon 1 and a very long first intron of 10 kb. The coding sequence contains five regions showing a high degree of conservation in vertebrates, predominantly in exons 2, 5, 6, 7 and 8, but the sequences found in invertebrates show only distant resemblance to mammalian TP53. TP53 orthologs have been identified in most mammals for which complete genome data are available.

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p53

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In humans, a common polymorphism involves the substitution of an arginine for a proline at codon position 72. Many studies have investigated a genetic link between this variation and cancer susceptibility; however, the results have been controversial. For instance, a meta-analysis from 2009 failed to show a link for cervical cancer. A 2011 study found that the TP53 proline mutation did have a profound effect on pancreatic cancer risk among males. A study of Arab women found that proline homozygosity at TP53 codon 72 is associated with a decreased risk for breast cancer. One study suggested that TP53 codon 72 polymorphisms, MDM2 SNP309, and A2164G may collectively be associated with non-oropharyngeal cancer susceptibility and that MDM2 SNP309 in combination with TP53 codon 72 may accelerate the development of non-oropharyngeal cancer in women. A 2011 study found that TP53 codon 72 polymorphism was associated with an increased risk of lung cancer.

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p53

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Meta-analyses from 2011 found no significant associations between TP53 codon 72 polymorphisms and both colorectal cancer risk and endometrial cancer risk. A 2011 study of a Brazilian birth cohort found an association between the non mutant arginine TP53 and individuals without a family history of cancer. Another 2011 study found that the p53 homozygous (Pro/Pro) genotype was associated with a significantly increased risk for renal cell carcinoma.

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p53

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# Structure - an acidic N-terminus transcription-activation domain (TAD), also known as activation domain 1 (AD1), which activates transcription factors. The N-terminus contains two complementary transcriptional activation domains, with a major one at residues 1–42 and a minor one at residues 55–75, specifically involved in the regulation of several pro-apoptotic genes. - activation domain 2 (AD2) important for apoptotic activity: residues 43-63. - proline rich domain important for the apoptotic activity of p53 by nuclear exportation via MAPK: residues 64-92. - central DNA-binding core domain (DBD). Contains one zinc atom and several arginine amino acids: residues 102-292. This region is responsible for binding the p53 co-repressor LMO3. - Nuclear Localization Signaling (NLS) domain, residues 316-325. - homo-oligomerisation domain (OD): residues 307-355. Tetramerization is essential for the activity of p53 in vivo.

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p53

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- Nuclear Localization Signaling (NLS) domain, residues 316-325. - homo-oligomerisation domain (OD): residues 307-355. Tetramerization is essential for the activity of p53 in vivo. - C-terminal involved in downregulation of DNA binding of the central domain: residues 356-393. A tandem of nine-amino-acid transactivation domains (9aaTAD) was identified in the AD1 and AD2 regions of transcription factor p53. KO mutations and position for p53 interaction with TFIID are listed below: The competence of the p53 transactivation domains 9aaTAD to activate transcription as small peptides was reported. File:Piskacek p53b.jpg p53 transactivation Piskacek M, Havelka M, Rezacova M, Knight A. "The 9aaTAD Transactivation Domains: From Gal4 to p53". PLOS One. 11 (9): e0162842. doi:10.1371/journal.pone.0162842. PMC 5019370. PMID 27618436.

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p53

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9aaTADs mediate p53 interaction with general coactivators – TAF9, CBP/p300 (all four domains KIX, TAZ1, TAZ2 and IBiD), GCN5 and PC4, regulatory protein MDM2 and replication protein A (RPA). File:Piskacek p53a.jpg p53 conversion Piskacek M, Havelka M, Rezacova M, Knight A. "The 9aaTAD Transactivation Domains: From Gal4 to p53". PLOS One. 11 (9): e0162842. doi:10.1371/journal.pone.0162842. PMC 5019370. PMID 27618436. Mutations that deactivate p53 in cancer usually occur in the DBD. Most of these mutations destroy the ability of the protein to bind to its target DNA sequences, and thus prevents transcriptional activation of these genes. As such, mutations in the DBD are recessive loss-of-function mutations. Molecules of p53 with mutations in the OD dimerise with wild-type p53, and prevent them from activating transcription. Therefore, OD mutations have a dominant negative effect on the function of p53.

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p53

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Wild-type p53 is a labile protein, comprising folded and unstructured regions that function in a synergistic manner.

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p53

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# Function p53 has many mechanisms of anticancer function and plays a role in apoptosis, genomic stability, and inhibition of angiogenesis. In its anti-cancer role, p53 works through several mechanisms: - It can activate DNA repair proteins when DNA has sustained damage. Thus, it may be an important factor in aging. - It can arrest growth by holding the cell cycle at the G1/S regulation point on DNA damage recognition (if it holds the cell here for long enough, the DNA repair proteins will have time to fix the damage and the cell will be allowed to continue the cell cycle). - It can initiate apoptosis (i.e., programmed cell death) if DNA damage proves to be irreparable. - It is essential for the senescence response to short telomeres.

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p53

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- It can initiate apoptosis (i.e., programmed cell death) if DNA damage proves to be irreparable. - It is essential for the senescence response to short telomeres. Activated p53 binds DNA and activates expression of several genes including microRNA miR-34a , WAF1/CIP1 encoding for p21 and hundreds of other down-stream genes. p21 (WAF1) binds to the G1-S/CDK (CDK4/CDK6, CDK2, and CDK1) complexes (molecules important for the G1/S transition in the cell cycle) inhibiting their activity.

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p53

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When p21(WAF1) is complexed with CDK2, the cell cannot continue to the next stage of cell division. A mutant p53 will no longer bind DNA in an effective way, and, as a consequence, the p21 protein will not be available to act as the "stop signal" for cell division. Studies of human embryonic stem cells (hESCs) commonly describe the nonfunctional p53-p21 axis of the G1/S checkpoint pathway with subsequent relevance for cell cycle regulation and the DNA damage response (DDR). Importantly, p21 mRNA is clearly present and upregulated after the DDR in hESCs, but p21 protein is not detectable. In this cell type, p53 activates numerous microRNAs (like miR-302a, miR-302b, miR-302c, and miR-302d) that directly inhibit the p21 expression in hESCs. Research has also linked the p53 and RB1 pathways, via p14ARF, raising the possibility that the pathways may regulate each other. p53 by regulating LIF has been shown to facilitate implantation in the mouse model and possibly in humans.

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p53

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p53 by regulating LIF has been shown to facilitate implantation in the mouse model and possibly in humans. p53 expression can be stimulated by UV light, which also causes DNA damage. In this case, p53 can initiate events leading to tanning. The p21 protein binds directly to cyclin-CDK complexes that drive forward the cell cycle and inhibits their kinase activity thereby causing cell cycle arrest to allow repair to take place. p21 can also mediate growth arrest associated with differentiation and a more permanent growth arrest associated with cellular senescence. The p21 gene contains several p53 response elements that mediate direct binding of the p53 protein, resulting in transcriptional activation of the gene encoding the p21 protein.

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p53

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## Stem cells Levels of p53 play an important role in the maintenance of stem cells throughout development and the rest of human life. ### Embryonic stem cells p53 is maintained at low inactive levels in human embryonic stem cells (hESCs). This is because activation of p53 leads to rapid differentiation of hESCs. Studies have shown that knocking out p53 delays differentiation and that adding p53 causes spontaneous differentiation, showing how p53 promotes differentiation of hESCs and plays a key role in cell cycle as a differentiation regulator. When p53 becomes stabilized and activated in hESCs, it increases p21 to establish a longer G1. This typically leads to abolition of S-phase entry, which stops the cell cycle in G1, leading to differentiation. p53 also activates miR-34a and miR-145, which then repress the hESCs pluripotency factors, further instigating differentiation.

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p53

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### Adult stem cells

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p53

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In adult stem cells, p53 regulation is important for maintenance of stemness in adult stem cell niches. Mechanical signals such as hypoxia affect levels of p53 in these niche cells through the hypoxia inducible factors, HIF-1α and HIF-2α. While HIF-1α stabilizes p53, HIF-2α suppresses it. Suppression of p53 plays important roles in cancer stem cell phenotype, induced pluripotent stem cells and other stem cell roles and behaviors, such as blastema formation. Cells with decreased levels of p53 have been shown to reprogram into stem cells with a much greater efficiency than normal cells. Papers suggest that the lack of cell cycle arrest and apoptosis gives more cells the chance to be reprogrammed. Decreased levels of p53 were also shown to be a crucial aspect of blastema formation in the legs of salamanders. p53 regulation is very important in acting as a barrier between stem cells and a differentiated stem cell state, as well as a barrier between stem cells being functional and being

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p53

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of salamanders. p53 regulation is very important in acting as a barrier between stem cells and a differentiated stem cell state, as well as a barrier between stem cells being functional and being cancerous.

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p53

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# Regulation p53 becomes activated in response to myriad stressors, including but not limited to DNA damage (induced by either UV, IR, or chemical agents such as hydrogen peroxide), oxidative stress, osmotic shock, ribonucleotide depletion, and deregulated oncogene expression. This activation is marked by two major events. First, the half-life of the p53 protein is increased drastically, leading to a quick accumulation of p53 in stressed cells. Second, a conformational change forces p53 to be activated as a transcription regulator in these cells. The critical event leading to the activation of p53 is the phosphorylation of its N-terminal domain. The N-terminal transcriptional activation domain contains a large number of phosphorylation sites and can be considered as the primary target for protein kinases transducing stress signals.

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p53

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The protein kinases that are known to target this transcriptional activation domain of p53 can be roughly divided into two groups. A first group of protein kinases belongs to the MAPK family (JNK1-3, ERK1-2, p38 MAPK), which is known to respond to several types of stress, such as membrane damage, oxidative stress, osmotic shock, heat shock, etc. A second group of protein kinases (ATR, ATM, CHK1 and CHK2, DNA-PK, CAK, TP53RK) is implicated in the genome integrity checkpoint, a molecular cascade that detects and responds to several forms of DNA damage caused by genotoxic stress. Oncogenes also stimulate p53 activation, mediated by the protein p14ARF.

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p53

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In unstressed cells, p53 levels are kept low through a continuous degradation of p53. A protein called Mdm2 (also called HDM2 in humans), binds to p53, preventing its action and transports it from the nucleus to the cytosol. Also Mdm2 acts as ubiquitin ligase and covalently attaches ubiquitin to p53 and thus marks p53 for degradation by the proteasome. However, ubiquitylation of p53 is reversible. MI-63 binds to MDM2 making the action of p53 again possible in situations were p53's function has become inhibited. A ubiquitin specific protease, USP7 (or HAUSP), can cleave ubiquitin off p53, thereby protecting it from proteasome-dependent degradation via the ubiquitin ligase pathway. This is one means by which p53 is stabilized in response to oncogenic insults. USP42 has also been shown to deubiquitinate p53 and may be required for the ability of p53 to respond to stress.

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p53

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Recent research has shown that HAUSP is mainly localized in the nucleus, though a fraction of it can be found in the cytoplasm and mitochondria. Overexpression of HAUSP results in p53 stabilization. However, depletion of HAUSP does not result to a decrease in p53 levels but rather increases p53 levels due to the fact that HAUSP binds and deubiquitinates Mdm2. It has been shown that HAUSP is a better binding partner to Mdm2 than p53 in unstressed cells. USP10 however has been shown to be located in the cytoplasm in unstressed cells and deubiquitinates cytoplasmic p53, reversing Mdm2 ubiquitination. Following DNA damage, USP10 translocates to the nucleus and contributes to p53 stability. Also USP10 does not interact with Mdm2.

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p53

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Phosphorylation of the N-terminal end of p53 by the above-mentioned protein kinases disrupts Mdm2-binding. Other proteins, such as Pin1, are then recruited to p53 and induce a conformational change in p53, which prevents Mdm2-binding even more. Phosphorylation also allows for binding of transcriptional coactivators, like p300 and PCAF, which then acetylate the carboxy-terminal end of p53, exposing the DNA binding domain of p53, allowing it to activate or repress specific genes. Deacetylase enzymes, such as Sirt1 and Sirt7, can deacetylate p53, leading to an inhibition of apoptosis. Some oncogenes can also stimulate the transcription of proteins that bind to MDM2 and inhibit its activity.

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p53

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# Role in disease If the TP53 gene is damaged, tumor suppression is severely compromised. People who inherit only one functional copy of the TP53 gene will most likely develop tumors in early adulthood, a disorder known as Li-Fraumeni syndrome. The TP53 gene can also be modified by mutagens (chemicals, radiation, or viruses), increasing the likelihood for uncontrolled cell division. More than 50 percent of human tumors contain a mutation or deletion of the TP53 gene. Loss of p53 creates genomic instability that most often results in an aneuploidy phenotype.

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p53

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Increasing the amount of p53 may seem a solution for treatment of tumors or prevention of their spreading. This, however, is not a usable method of treatment, since it can cause premature aging. Restoring endogenous normal p53 function holds some promise. Research has shown that this restoration can lead to regression of certain cancer cells without damaging other cells in the process. The ways by which tumor regression occurs depends mainly on the tumor type. For example, restoration of endogenous p53 function in lymphomas may induce apoptosis, while cell growth may be reduced to normal levels. Thus, pharmacological reactivation of p53 presents itself as a viable cancer treatment option. The first commercial gene therapy, Gendicine, was approved in China in 2003 for the treatment of head and neck squamous cell carcinoma. It delivers a functional copy of the p53 gene using an engineered adenovirus.

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p53

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Certain pathogens can also affect the p53 protein that the TP53 gene expresses. One such example, human papillomavirus (HPV), encodes a protein, E6, which binds to the p53 protein and inactivates it. This mechanism, in synergy with the inactivation of the cell cycle regulator pRb by the HPV protein E7, allows for repeated cell division manifested clinically as warts. Certain HPV types, in particular types 16 and 18, can also lead to progression from a benign wart to low or high-grade cervical dysplasia, which are reversible forms of precancerous lesions. Persistent infection of the cervix over the years can cause irreversible changes leading to carcinoma in situ and eventually invasive cervical cancer. This results from the effects of HPV genes, particularly those encoding E6 and E7, which are the two viral oncoproteins that are preferentially retained and expressed in cervical cancers by integration of the viral DNA into the host genome.

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p53

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The p53 protein is continually produced and degraded in cells of healthy people, resulting in damped oscillation. The degradation of the p53 protein is associated with binding of MDM2. In a negative feedback loop, MDM2 itself is induced by the p53 protein. Mutant p53 proteins often fail to induce MDM2, causing p53 to accumulate at very high levels. Moreover, the mutant p53 protein itself can inhibit normal p53 protein levels. In some cases, single missense mutations in p53 have been shown to disrupt p53 stability and function. Suppression of p53 in human breast cancer cells is shown to lead to increased CXCR5 chemokine receptor gene expression and activated cell migration in response to chemokine CXCL13. One study found that p53 and Myc proteins were key to the survival of Chronic Myeloid Leukaemia (CML) cells. Targeting p53 and Myc proteins with drugs gave positive results on mice with CML.

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p53

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# Experimental analysis of p53 mutations Most p53 mutations are detected by DNA sequencing. However, it is known that single missense mutations can have a large spectrum from rather mild to very severe functional affects. The large spectrum of cancer phenotypes due to mutations in the TP53 gene is also supported by the fact that different isoforms of p53 proteins have different cellular mechanisms for prevention against cancer. Mutations in TP53 can give rise to different isoforms, preventing their overall functionality in different cellular mechanisms and thereby extending the cancer phenotype from mild to severe. Recents studies show that p53 isoforms are differentially expressed in different human tissues, and the loss-of-function or gain-of-function mutations within the isoforms can cause tissue-specific cancer or provides cancer stem cell potential in different tissues. TP53 mutation also hits energy metabolism and increases glycolysis in breast cancer cells.

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p53

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The dynamics of p53 proteins, along with its antagonist Mdm2, indicate that the levels of p53, in units of concentration, oscillate as a function of time. This "damped" oscillation is both clinically documented and mathematically modelled. Mathematical models also indicate that the p53 concentration oscillates much faster once teratogens, such as double-stranded breaks (DSB) or UV radiation, are introduced to the system. This supports and models the current understanding of p53 dynamics, where DNA damage induces p53 activation (see p53 regulation for more information). Current models can also be useful for modelling the mutations in p53 isoforms and their effects on p53 oscillation, thereby promoting de novo tissue-specific pharmacological drug discovery.

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p53

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# Discovery p53 was identified in 1979 by Lionel Crawford, David P. Lane, Arnold Levine, and Lloyd Old, working at Imperial Cancer Research Fund (UK) Princeton University/UMDNJ (Cancer Institute of New Jersey), and Memorial Sloan-Kettering Cancer Center, respectively. It had been hypothesized to exist before as the target of the SV40 virus, a strain that induced development of tumors. The TP53 gene from the mouse was first cloned by Peter Chumakov of the Russian Academy of Sciences in 1982, and independently in 1983 by Moshe Oren in collaboration with David Givol (Weizmann Institute of Science). The human TP53 gene was cloned in 1984 and the full length clone in 1985. It was initially presumed to be an oncogene due to the use of mutated cDNA following purification of tumor cell mRNA. Its role as a tumor suppressor gene was revealed in 1989 by Bert Vogelstein at the Johns Hopkins School of Medicine and Arnold Levine at Princeton University.

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p53

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Warren Maltzman, of the Waksman Institute of Rutgers University first demonstrated that TP53 was responsive to DNA damage in the form of ultraviolet radiation. In a series of publications in 1991–92, Michael Kastan of Johns Hopkins University, reported that TP53 was a critical part of a signal transduction pathway that helped cells respond to DNA damage. In 1993, p53 was voted molecule of the year by Science magazine.

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p53

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# Isoforms As with 95% of human genes, TP53 encodes more than one protein. In 2005 several isoforms were discovered and until now, 12 human p53 isoforms were identified (p53α, p53β, p53γ, ∆40p53α, ∆40p53β, ∆40p53γ, ∆133p53α, ∆133p53β, ∆133p53γ, ∆160p53α, ∆160p53β, ∆160p53γ). Furthermore, p53 isoforms are expressed in a tissue dependent manner and p53α is never expressed alone.

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p53

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The full length p53 isoform proteins can be subdivided into different protein domains. Starting from the N-terminus, there are first the amino-terminal transactivation domains (TAD 1, TAD 2), which are needed to induce a subset of p53 target genes. This domain is followed by the Proline rich domain (PXXP), whereby the motif PXXP is repeated (P is a Proline and X can be any amino acid). It is required among others for p53 mediated apoptosis. Some isoforms lack the Proline rich domain, such as Δ133p53β,γ and Δ160p53α,β,γ; hence some isoforms of p53 are not mediating apoptosis, emphasizing the diversifying roles of the TP53 gene. Afterwards there is the DNA binding domain (DBD), which enables the proteins to sequence specific binding. The carboxyl terminal domain completes the protein. It includes the nuclear localization signal (NLS), the nuclear export signal (NES) and the oligomerisation domain (OD). The NLS and NES are responsible for the subcellular regulation of p53. Through the

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p53

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includes the nuclear localization signal (NLS), the nuclear export signal (NES) and the oligomerisation domain (OD). The NLS and NES are responsible for the subcellular regulation of p53. Through the OD, p53 can form a tetramer and then bind to DNA. Among the isoforms, some domains can be missing, but all of them share most of the highly conserved DNA-binding domain.

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p53

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The isoforms are formed by different mechanisms. The beta and the gamma isoforms are generated by multiple splicing of intron 9, which leads to a different C-terminus. Furthermore, the usage of an internal promoter in intron 4 causes the ∆133 and ∆160 isoforms, which lack the TAD domain and a part of the DBD. Moreover, alternative initiation of translation at codon 40 or 160 bear the ∆40p53 and ∆160p53 isoforms. Due to the isoformic nature of p53 proteins, there have been several sources of evidence showing that mutations within the TP53 gene giving rise to mutated isoforms are causative agents of various cancer phenotypes, from mild to severe, due to single mutation in the TP53 gene (refer to section Experimental analysis of p53 mutations for more details).

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p53

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# Interactions p53 has been shown to interact with: - AIMP2, - ANKRD2, - APTX, - ATM, - ATR, - ATF3, - AURKA, - BAK1, - BARD1, - BLM, - BRCA1, - BRCA2, - BRCC3, - BRE, - CEBPZ, - CDC14A, - Cdk1, - CFLAR, - CHEK1, - CCNG1, - CREBBP, - CREB1, - Cyclin H, - CDK7, - DNA-PKcs, - E4F1, - EFEMP2, - EIF2AK2, - ELL, - EP300, - ERCC6, - GNL3, - GPS2, - GSK3B, - HSP90AA1, - HIF1A, - HIPK1, - HIPK2, - HMGB1, - HSPA9, - Huntingtin, - ING1, - ING4, - ING5, - IκBα, - KPNB1, - LMO3, - Mdm2, - MDM4, - MED1, - MAPK9, - MNAT1, - NDN, - NCL, - NUMB, - NF-κB, - P16, - PARC, - PARP1, - PIAS1, - CDC14B, - PIN1, - PLAGL1, - PLK3, - PRKRA, - PHB, - PML, - PSME3, - PTEN, - PTK2, - PTTG1, - RAD51, - RCHY1, - RELA, - Reprimo - RPA1, - RPL11, - S100B, - SUMO1, - SMARCA4, - SMARCB1, - SMN1, - STAT3, - TBP, - TFAP2A, - TFDP1, - TIGAR, - TOP1, - TOP2A, - TP53BP1, - TP53BP2, - TOP2B, - TP53INP1, - TSG101, - UBE2A, - UBE2I, - UBC, - USP7, - WRN, - WWOX, - XPB, - YBX1, - YPEL3, - YWHAZ, - Zif268, - ZNF148. - SIRT1.

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p73

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p73 p73 is a protein related to the p53 tumor protein. Because of its structural resemblance to p53, it has also been considered a tumor suppressor. It is involved in cell cycle regulation, and induction of apoptosis. Like p53, p73 is characterized by the presence of different isoforms of the protein. This is explained by splice variants, and an alternative promoter in the DNA sequence. p73, also known as tumor protein 73 (TP73), protein was the first identified homologue of the tumor suppressor gene, p53. Like p53, p73 has several variants. It is expressed as distinct forms differing at either at the C- or the N-terminus. Currently, six different C-terminus splicing variants have been found in normal cells. The p73 gene encodes a protein with a significant sequence homology and a functional similarity with the tumor suppressor p53. The over-expression of p73 in cultured cells promotes a growth arrest and/or apoptosis similarly to p53.

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p73

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The p73 gene has been mapped to a chromosome region (1p36. 2-3) a locus commonly deleted in various tumor entities and human cancers. Similar to p53 the protein product of p73 induces cell cycle arrest or apoptosis, hence its classification as a tumor suppressor. However unlike its counterpart, p73 is infrequently mutated in cancers. Perhaps, even more shocking is the fact that p73 – deficient mice do not show a tumorigenic phenotype. A deficiency of p53 almost certainly leads to unchecked cell proliferation and is noted in 60% of cancers.

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p73

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Analyses of many tumors typically found in humans including breast and ovarian cancer show a high expression of p73 when compared to normal tissues in corresponding areas. Adenoviruses that cause cellular transformations have also been found to result in increased p73 expression. Furthermore, recent finding are suggesting that over-expression of transcription factors involved in cell cycle regulation and synthesis of DNA in mammalian cells (e.g.: E2F-1) induces the expression of p73. Many researchers believe that these results imply that p73 may not be a tumor suppressor but rather an oncoprotein. Some suggest that the TP73 locus encodes both a tumor suppressor (TAp73) and a putative oncogene (ΔNp73). This is a strong theory and causes much confusion, as it is unknown which of the two p73 variants is over-expressed and ultimately plays a role in tumorigenesis.

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p73

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Genes of the p53 family are known to be complex. The viral oncoproteins (e.g. Adenovirus E1B) that efficiently inhibit p53 function are unable to inactivate p73, and those that seem to inhibit p73 have no effect on p53. Debate persists about the exact function of p73. Recently it has been reported that p73 is enriched in the nervous system and that the p73-deficient mice, which do not exhibit an increased susceptibility to spontaneous tumorigenesis, have neurological and immunological defects. These results have been expanded and it has also been shown that p73 is present in early stages of neurological development and neuronal apoptosis by blocking the proapoptotic function of p53. This strongly implicates p73 as playing a large role in cellular differentiation.

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PGY

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PGY PGY, short for post-graduate year, refers to a North American numerical scheme denoting the progress of post-medical school graduation medical residents in their residency program. It is used to stratify responsibility in most training programs and to determine salary. The length of residency depends mostly on the field a medical school graduate chooses to take. Specialties such as family medicine and internal medicine often require only three years, whereas surgery usually requires a minimum of five. Subspecialization (vascular or orthopedic spine surgery as a branch of surgery, for example) in any field will add time to post-graduate training. For more information on specific medical residency programs, see the American Medical Association's Fellowship and Residency Electronic Interactive Database.

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PGY

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For more information on specific medical residency programs, see the American Medical Association's Fellowship and Residency Electronic Interactive Database. Pharmacy residencies, which are becoming more popular, also use the PGY nomenclature. Here, PGY-1 is the usual general pharmacy practice residency, and PGY-2 can be completed, often as an option, for pharmacy specialties such as critical care, cardiology, oncology, etc. In some teaching institutions, trainees are required to indicate level of training on all signatures (John Doe, M.D., PGY-1 or R-1).

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Paw

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Paw A paw is the soft foot of a mammal, generally a quadruped, that has claws or nails. A hard foot is called a hoof. Paws are used to pad feet for walking and reduce friction.

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Paw

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# Common characteristics The paw is characterised by thick, pigmented, keratinised, hairless epidermis covering subcutaneous, collagenous, adipose tissue which make up the pads. These pads act as a cushion for the load-bearing limbs of the animal. The paw consists of the large, heart-shaped metacarpal pad (forelimb) or metatarsal pad (rear limb), and generally four load bearing digital pads, although there can be five or six toes in the case of bears and the Giant Panda. A carpal pad is also found on the forelimb which is used for additional traction when stopping or descending a slope in digitigrade species. Additional dew claws can also be present. The paw also includes a horny, beak shaped claw on each digit. Though usually hairless, certain animals do have fur on the soles of their paws. An example being the Red Panda, whose furry soles help insulate them in their snowy habitat.

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Paw

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# Animals with paws - Members of the Canidae family, such as dogs and foxes - Felines, such as cats and tigers, some of these animals may have toe tufts - Bears and Raccoons - Weasels and other mustelids - Rodents - A dog's paw resting on a hard concrete surface. A dog's paw resting on a hard concrete surface. - A tiger's paw, showing pads. A tiger's paw, showing pads. - A cat's paw, showing pads. A cat's paw, showing pads.

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QKI

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QKI Quaking homolog, KH domain RNA binding (mouse), also known as QKI, is a protein which in humans is encoded by the QKI gene. QKI belongs to a family of RNA-binding proteins called STAR proteins for Signal Transduction and Activation of RNA. They have an HNRNPK homology (KH) domain embedded in a 200-amino acid region called the GSG domain. Other members of this family include SAM68 (KHDRBS1) and SF1 . Two more new members are KHDRBS3 and KHDRBS2. The QKI gene is implicated as being important in schizophrenia, and QKI controls translation of many oligodendrocyte-related genes.

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RP9

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RP9 Retinitis pigmentosa 9 (autosomal dominant), also known as RP9 or PAP-1, is a protein which in humans is encoded by the RP9 gene. # Function The removal of introns from nuclear pre-mRNAs occurs on a complex called a spliceosome, which is made up of 4 small nuclear ribonucleoprotein (snRNP) particles and an undefined number of transiently associated splicing factors. The exact role of PAP-1 in splicing is not fully understood, but it is thought that PAP-1 localizes in nuclear speckles containing the splicing factor SC35 and interacts directly with another splicing factor, U2AF35. # Clinical significance Mutations in PAP1 underlie autosomal dominant retinitis pigmentosa mapped to the RP9 gene locus. # Interactions RP9 has been shown to interact with U2 small nuclear RNA auxiliary factor 1.

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RRH

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RRH Peropsin, a visual pigment-like receptor, is a protein that in humans is encoded by the RRH gene. Peropsin is an opsin and so belongs to the guanine nucleotide-binding protein (G protein)-coupled receptors. Peropsin genes have seven-exons as neuropsin and RGR-opsin genes. # Phylogeny The peropsins are one of the four subgroups of the Go/RGR opsins, also known as RGR/Go or Group 4 opsins. Go/RGR opsins are one of the four major groups of type-II opsins, also known as metazoan or animal opsins. The Go/RGR opsins consist of four groups: The Go-opsins, the RGR-opsins, the peropsins, and the neuropsins. Animal opsins belong to four classes: C-opsins (ciliary), R-opsins (rhabdomeric), Cnidops (cnidarian), and Go/RGR-opsins. Three of these subclades occur only in Bilateria (all but Cnidops). However, the bilaterian clades constitute a parphyletic taxon without the Cnidops.

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RUQ

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RUQ # Overview RUQ refers to the right-upper quadrant of the human abdomen. The term allows a doctor to localise pain and tenderness, scars, lumps and other items of interest. The RUQ extends from the median plane to the right of the patient, and from the umbilical plane to the right ribcage. The RUQ may be painful and/or tender in such conditions as hepatitis, cholecystitis, and peptic ulcer. The term is not used in comparative anatomy, since most other animals do not stand erect. The equivalent term for animals is 'right anterior quadrant'.

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Ras

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Ras # Overview In molecular biology, Ras is the name of a protein, the gene that encodes it, and the family and superfamily of proteins to which it belongs. The Ras superfamily of small GTPases includes the Ras, Rho, Arf, Rab, and Ran families. # History Ras gene was the first human oncogene discovered by Robert A. Weinberg of MIT in early 80's from a bladder cancer cell line. # Functions Proteins in the Ras family are very important molecular switches for a wide variety of signal pathways that control such processes as cytoskeletal integrity, proliferation, cell adhesion, apoptosis, and cell migration. Ras and ras-related proteins are often deregulated in cancers, leading to increased invasion and metastasis, and decreased apoptosis. RAS activates a number of pathways but an especially important one seems to be the mitogen-activated protein (MAP) kinases, which themselves transmit signals downstream to other protein kinases and gene regulatory proteins.