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82-679: 7157 22059 ENSG00000141510 ENSMUSG00000059552 P04637 P02340 NM_001126115 NM_001126116 NM_001126117 NM_001126118 NM_001276695 NM_001276696 NM_001276697 NM_001276698 NM_001276699 NM_001276760 NM_001127233 NM_011640 NP_001119588 NP_001119589 NP_001119590 NP_001263624 NP_001263625 NP_001263626 NP_001263627 NP_001263628 NP_001263689 NP_001263690 NP_001120705 NP_035770 p53 , also known as Tumor protein P53 , cellular tumor antigen p53 ( UniProt name), or transformation-related protein 53 (TRP53)

164-435: A balance or equilibrium between morphs. The mechanisms that conserve it are types of balancing selection . Most genes have more than one effect on the phenotype of an organism ( pleiotropism ). Some of these effects may be visible, and others cryptic, so it is often important to look beyond the most obvious effects of a gene to identify other effects. Cases occur where a gene affects an unimportant visible characteristic, yet

246-470: A certain type of tissue. Mutant protein antigens are likely to be much more specific to cancer cells because normal cells shouldn't contain these proteins. Normal cells will display the normal protein antigen on their MHC molecules, whereas cancer cells will display the mutant version. Some viral proteins are implicated in forming cancer ( oncogenesis ), and some viral antigens are also cancer antigens. Cancer-testis antigens are antigens expressed primarily in

328-432: A change in fitness is recorded. In such cases, the gene's subsurface effects may be responsible for the change in fitness. Pleiotropism is posing continual challenges for many clinical dysmorphologists in their attempt to explain birth defects which affect one or more organ system, with only a single underlying causative agent. For many pleiotropic disorders, the connection between the genetic abnormality and its manifestations

410-452: A common polymorphism involves the substitution of an arginine for a proline at codon position 72 of exon 4. 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

492-452: A couple of decades the work of Fisher, Ford, Arthur Cain , Philip Sheppard and Cyril Clarke promoted natural selection as the primary explanation of variation in natural populations, instead of genetic drift. Evidence can be seen in Mayr's famous book Animal Species and Evolution , and Ford's Ecological Genetics . Similar shifts in emphasis can be seen in most of the other participants in

574-404: 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. p53 plays a role in regulation or progression through the cell cycle, apoptosis , and genomic stability by means of several mechanisms: WAF1/CIP1 encodes for p21 and hundreds of other down-stream genes. p21 (WAF1) binds to

656-505: A founder of niche research, commented "It is very likely from an ecological point of view that all species, or at least all common species, consist of populations adapted to more than one niche". He gave as examples sexual size dimorphism and mimicry. In many cases where the male is short-lived and smaller than the female, he does not compete with her during her late pre-adult and adult life. Size difference may permit both sexes to exploit different niches. In elaborate cases of mimicry , such as

738-628: A large number of phosphorylation sites and can be considered as the primary target for protein kinases transducing stress signals. 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 )

820-480: A longer G1. This typically leads to abolition of S-phase entry, which stops the cell cycle in G1, leading to differentiation. Work in mouse embryonic stem cells has recently shown however that the expression of P53 does not necessarily lead to differentiation. p53 also activates miR-34a and miR-145 , which then repress the hESCs pluripotency factors, further instigating differentiation. In adult stem cells, p53 regulation

902-401: A more formal term is morphotype. Form and phase are sometimes used, but are easily confused in zoology with, respectively, "form" in a population of animals, and "phase" as a color or other change in an organism due to environmental conditions (temperature, humidity, etc.). Phenotypic traits and characteristics are also possible descriptions, though that would imply just a limited aspect of

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984-475: 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 cancerous. Apart from

1066-416: 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

1148-440: A protein is the enzyme tyrosinase , which is required for melanin production. Normally tyrosinase is produced in minute quantities but its levels are very much elevated in melanoma cells. Oncofetal antigens are another important class of tumor antigens. Examples are alphafetoprotein (AFP) and carcinoembryonic antigen (CEA). These proteins are normally produced in the early stages of embryonic development and disappear by

1230-491: A species from each other. Presently, geneticists use the term genetic polymorphism to describe the functionally silent differences in DNA sequence between individuals that make each human genome unique. Genetic polymorphism is actively and steadily maintained in populations by natural selection, in contrast to transient polymorphisms where a form is progressively replaced by another. By definition, genetic polymorphism relates to

1312-447: A species. It is heritable and is modified by natural selection . In polyphenism, an individual's genetic makeup allows for different morphs, and the switch mechanism that determines which morph is shown is environmental. In genetic polymorphism, the genetic makeup determines the morph. The term polymorphism also refers to the occurrence of structurally and functionally more than two different types of individuals, called zooids , within

1394-458: 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. Phosphorylation of the N-terminal end of p53 by

1476-677: Is a long-standing debate as to how this situation could have arisen, and the question is not yet resolved. Whereas a gene family (several tightly linked genes performing similar or identical functions) arises by duplication of a single original gene, this is usually not the case with supergenes. In a supergene some of the constituent genes have quite distinct functions, so they must have come together under selection. This process might involve suppression of crossing-over, translocation of chromosome fragments and possibly occasional cistron duplication. That crossing-over can be suppressed by selection has been known for many years. Debate has centered round

1558-434: Is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often spoken of as, a single protein) are crucial in vertebrates , where they prevent cancer formation. 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 . The TP53 gene

1640-449: Is called the switch . This switch may be genetic, or it may be environmental. Taking sex determination as the example, in humans the determination is genetic, by the XY sex-determination system . In Hymenoptera ( ants , bees and wasps ), sex determination is by haplo-diploidy: the females are all diploid , the males are haploid . However, in some animals an environmental trigger determines

1722-430: Is imperfect because many antigens thought to be tumor-specific turned out to be expressed on some normal cells as well. The modern classification of tumor antigens is based on their molecular structure and source. Accordingly, they can be classified as; Any protein produced in a tumor cell that has an abnormal structure due to mutation can act as a tumor antigen. Such abnormal proteins are produced due to mutation of

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1804-432: 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 . 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

1886-518: 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

1968-484: Is known that single missense mutations can have a large spectrum from rather mild to very severe functional effects. 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

2050-431: Is maintained at low inactive levels. 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

2132-423: 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

2214-467: Is more than one possible trait in terms of a jaguar's skin colouring; they can be light morph or dark morph. Due to having more than one possible variation for this gene, it is termed 'polymorphism'. However, if the jaguar has only one possible trait for that gene, it would be termed "monomorphic". For example, if there was only one possible skin colour that a jaguar could have, it would be termed monomorphic. The term polyphenism can be used to clarify that

2296-472: Is neither apparent nor understood. Epistasis occurs when the expression of one gene is modified by another gene. For example, gene A only shows its effect when allele B1 (at another locus ) is present, but not if it is absent. This is one of the ways in which two or more genes may combine to produce a coordinated change in more than one characteristic (for instance, in mimicry). Unlike the supergene, epistatic genes do not need to be closely linked or even on

2378-477: Is related to biodiversity , genetic variation , and adaptation . Polymorphism usually functions to retain a variety of forms in a population living in a varied environment. The most common example is sexual dimorphism , which occurs in many organisms. Other examples are mimetic forms of butterflies (see mimicry ), and human hemoglobin and blood types . According to the theory of evolution, polymorphism results from evolutionary processes, as does any aspect of

2460-400: 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. Most p53 mutations are detected by DNA sequencing. However, it

2542-448: Is strongly tied to the adaptation of a species to its environment, which may vary in colour, food supply, and predation and in many other ways including sexual harassment avoidance. Polymorphism is one good way the opportunities get to be used; it has survival value, and the selection of modifier genes may reinforce the polymorphism. In addition, polymorphism seems to be associated with a higher rate of speciation . G. Evelyn Hutchinson ,

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2624-403: 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. In addition to the full-length protein, the human TP53 gene encodes at least 12 protein isoforms . In humans, the TP53 gene is located on

2706-410: Is the occurrence of two or more clearly different morphs or forms , also referred to as alternative phenotypes , in the population of a species. To be classified as such, morphs must occupy the same habitat at the same time and belong to a panmictic population (one with random mating). Put simply, polymorphism is when there are two or more possibilities of a trait on a gene. For example, there

2788-586: The G1 - S / CDK ( CDK4 / CDK6 , CDK2 , and CDK1 ) complexes (molecules important for the G1/S transition in the cell cycle) inhibiting their activity. 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

2870-889: The ICN . Horticulturists sometimes confuse this usage of "variety" both with cultivar ("variety" in viticultural usage, rice agriculture jargon, and informal gardening lingo) and with the legal concept " plant variety " (protection of a cultivar as a form of intellectual property ). Three mechanisms may cause polymorphism: Endler's survey of natural selection gave an indication of the relative importance of polymorphisms among studies showing natural selection. The results, in summary: Number of species demonstrating natural selection: 141. Number showing quantitative traits: 56. Number showing polymorphic traits: 62. Number showing both Q and P traits: 23. This shows that polymorphisms are found to be at least as common as continuous variation in studies of natural selection, and hence just as likely to be part of

2952-522: The Mesolithic Holocene . Non-human apes have similar blood groups to humans; this strongly suggests that this kind of polymorphism is ancient, at least as far back as the last common ancestor of the apes and man, and possibly even further. The relative proportions of the morphs may vary; the actual values are determined by the effective fitness of the morphs at a particular time and place. The mechanism of heterozygote advantage assures

3034-458: The germ cells of the testes , but also in fetal ovaries and the trophoblast . Some cancer cells aberrantly express these proteins and therefore present these antigens, allowing attack by T-cells specific to these antigens. Example antigens of this type are CTAG1B and MAGEA1 . Proteins that are normally produced in very low quantities but whose production is dramatically increased in tumor cells, trigger an immune response. An example of such

3116-438: The nucleus to the cytosol . Mdm2 also acts as an ubiquitin ligase and covalently attaches ubiquitin to p53 and thus marks p53 for degradation by the proteasome . However, ubiquitylation of p53 is reversible. On activation of p53, Mdm2 is also activated, setting up a feedback loop . p53 levels can show oscillations (or repeated pulses) in response to certain stresses, and these pulses can be important in determining whether

3198-722: The African butterfly Papilio dardanus , female morphs mimic a range of distasteful models called Batesian mimicry, often in the same region. The fitness of each type of mimic decreases as it becomes more common, so the polymorphism is maintained by frequency-dependent selection. Thus the efficiency of the mimicry is maintained in a much increased total population. However it can exist within one gender. Female-limited polymorphism and sexual assault avoidance Female-limited polymorphism in Papilio dardanus can be described as an outcome of sexual conflict. Cook et al. (1994) argued that

3280-550: 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

3362-433: The ability of p53 to respond to stress. 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 in 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

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3444-685: 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 C-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

3526-492: The body are not antigenic because of self-tolerance , a process in which self-reacting cytotoxic T lymphocytes (CTLs) and autoantibody -producing B lymphocytes are culled "centrally" in primary lymphatic tissue (BM) and "peripherally" in secondary lymphatic tissue (mostly thymus for T-cells and spleen /lymph nodes for B cells). Thus any protein that is not exposed to the immune system triggers an immune response. This may include normal proteins that are well sequestered from

3608-521: The body. In the taxonomic nomenclature of zoology , the word "morpha" plus a Latin name for the morph can be added to a binomial or trinomial name. However, this invites confusion with geographically variant ring species or subspecies , especially if polytypic. Morphs have no formal standing in the ICZN . In botanical taxonomy , the concept of morphs is represented with the terms " variety ", " subvariety " and " form ", which are formally regulated by

3690-482: The cancer phenotype from mild to severe. Recent 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 provide cancer stem cell potential in different tissues. TP53 mutation also hits energy metabolism and increases glycolysis in breast cancer cells. The dynamics of p53 proteins, along with its antagonist Mdm2 , indicate that

3772-415: 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

3854-467: The cells survive the stress, or die. MI-63 binds to MDM2, reactivating p53 in situations where 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

3936-417: The cellular and molecular effects above, p53 has a tissue-level anticancer effect that works by inhibiting angiogenesis . As tumors grow they need to recruit new blood vessels to supply them, and p53 inhibits that by (i) interfering with regulators of tumor hypoxia that also affect angiogenesis, such as HIF1 and HIF2, (ii) inhibiting the production of angiogenic promoting factors, and (iii) directly increasing

4018-706: The concerned gene . Mutation of protooncogenes and tumor suppressors which lead to abnormal protein production are the cause of the tumor and thus such abnormal proteins are called tumor-specific antigens . Examples of tumor-specific antigens include the abnormal products of ras and p53 genes. In contrast, mutation of other genes unrelated to the tumor formation may lead to synthesis of abnormal proteins which are called tumor-associated antigens . Other examples include tissue differentiation antigens, mutant protein antigens, oncogenic viral antigens , cancer-testis antigens and vascular or stromal specific antigens. Tissue differentiation antigens are those that are specific to

4100-444: 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. 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

4182-400: The different forms arise from the same genotype . Genetic polymorphism is a term used somewhat differently by geneticists and molecular biologists to describe certain mutations in the genotype, such as single nucleotide polymorphisms that may not always correspond to a phenotype, but always corresponds to a branch in the genetic tree. See below . Polymorphism is common in nature; it

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4264-402: 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. The p53 protein is continually produced and degraded in cells of healthy people, resulting in damped oscillation (see a stochastic model of this process in ). The degradation of

4346-404: The evolutionary process. Since all polymorphism has a genetic basis, genetic polymorphism has a particular meaning: The definition has three parts: a) sympatry : one interbreeding population; b) discrete forms; and c) not maintained just by mutation. In simple words, the term polymorphism was originally used to describe variations in shape and form that distinguish normal individuals within

4428-433: The field: And in the laboratory: Without proper field-work, the significance of the polymorphism to the species is uncertain and without laboratory breeding the genetic basis is obscure. Even with insects, the work may take many years; examples of Batesian mimicry noted in the nineteenth century are still being researched. Polymorphism was crucial to research in ecological genetics by E. B. Ford and his co-workers from

4510-724: The genes start on the same chromosome. They argue that supergenes arose in situ . This is known as Turner's sieve hypothesis. John Maynard Smith agreed with this view in his authoritative textbook, but the question is still not definitively settled. Selection, whether natural or artificial, changes the frequency of morphs within a population; this occurs when morphs reproduce with different degrees of success. A genetic (or balanced) polymorphism usually persists over many generations, maintained by two or more opposed and powerful selection pressures. Diver (1929) found banding morphs in Cepaea nemoralis could be seen in prefossil shells going back to

4592-415: The histone profile at key target genes and act in a gene-specific manner. 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

4674-560: The immune system, proteins that are normally produced in extremely small quantities, proteins that are normally produced only in certain stages of development, or proteins whose structure is modified due to mutation. Initially tumor antigens were broadly classified into two categories based on their pattern of expression: Tumor-Specific Antigens (TSA), which are present only on tumor cells and not on any other cell and Tumor-Associated Antigens (TAA), which are present on some tumor cells and also some normal cells. This classification, however,

4756-438: The immune system. Tumor antigens, because of their relative abundance in tumor cells are useful in identifying specific tumor cells. Certain tumors have certain tumor antigens in abundance. Hepatocellular carcinoma Certain tumor antigens are thus used as tumor markers . More importantly, tumor antigens can be used in cancer therapy as tumor antigen vaccines . Polymorphism (biology) In biology , polymorphism

4838-448: The last quarter of the 20th century when ideas such as Kimura 's neutral theory of molecular evolution was given much attention. The significance of the work on ecological genetics is that it has shown how important selection is in the evolution of natural populations, and that selection is a much stronger force than was envisaged even by those population geneticists who believed in its importance, such as Haldane and Fisher . In just

4920-560: 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

5002-614: 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. 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

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5084-574: The male-like phenotype in some females in P. dardanus population on Pemba Island, Tanzania functions to avoid detection from a mate-searching male. The researchers found that male mate preference is controlled by frequency-dependent selection, which means that the rare morph suffers less from mating attempt than the common morph. The reasons why females try to avoid male sexual harassment are that male mating attempt can reduce female fitness in many ways such as fecundity and longevity. The mechanism which decides which of several morphs an individual displays

5166-416: The mid-1920s to the 1970s (similar work continues today, especially on mimicry ). The results had a considerable effect on the mid-century evolutionary synthesis , and on present evolutionary theory . The work started at a time when natural selection was largely discounted as the leading mechanism for evolution, continued through the middle period when Sewall Wright 's ideas on drift were prominent, to

5248-462: The mutations in p53 isoforms and their effects on p53 oscillation, thereby promoting de novo tissue-specific pharmacological drug 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

5330-595: 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. The p21 protein binds directly to cyclin-CDK complexes that drive forward

5412-444: The p21 protein. The p53 and RB1 pathways are linked via p14ARF, raising the possibility that the pathways may regulate each other. p53 expression can be stimulated by UV light, which also causes DNA damage. In this case, p53 can initiate events leading to tanning . Levels of p53 play an important role in the maintenance of stem cells throughout development and the rest of human life. In human embryonic stem cells (hESCs)s, p53

5494-710: 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. This image shows different patterns of p53 expression in endometrial cancers on chromogenic immunohistochemistry , whereof all except wild-type are variably termed abnormal/aberrant/mutation-type and are strongly predictive of an underlying TP53 mutation: Suppression of p53 in human breast cancer cells

5576-427: The population of some alternative alleles at the locus or loci involved. Only if competing selection disappears will an allele disappear. However, heterozygote advantage is not the only way a polymorphism can be maintained. Apostatic selection , whereby a predator consumes a common morph whilst overlooking rarer morphs is possible and does occur. This would tend to preserve rarer morphs from extinction. Polymorphism

5658-457: 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

5740-403: The production of angiogenesis inhibitors, such as arresten . p53 by regulating Leukemia Inhibitory Factor has been shown to facilitate implantation in the mouse and possibly human reproduction. The immune response to infection also involves p53 and NF-κB . Checkpoint control of the cell cycle and of apoptosis by p53 is inhibited by some infections such as Mycoplasma bacteria, raising

5822-439: The question of whether the component genes in a super-gene could have started off on separate chromosomes, with subsequent reorganization, or if it is necessary for them to start on the same chromosome. Originally, it was held that chromosome rearrangement would play an important role. This explanation was accepted by E. B. Ford and incorporated into his accounts of ecological genetics. However, many believe it more likely that

5904-476: The same chromosome . Both pleiotropism and epistasis show that a gene need not relate to a character in the simple manner that was once supposed. Although a polymorphism can be controlled by alleles at a single locus (e.g. human ABO blood groups), the more complex forms are controlled by supergenes consisting of several tightly linked genes on a single chromosome . Batesian mimicry in butterflies and heterostyly in angiosperms are good examples. There

5986-458: The same concept different names, and different concepts may be given the same name. For example, there are the terms established in ecological genetics by E.B. Ford (1975), and for classical genetics by John Maynard Smith (1998). The shorter term morphism was preferred by the evolutionary biologist Julian Huxley (1955). Various synonymous terms exist for the various polymorphic forms of an organism. The most common are morph and morpha, while

6068-626: The same organism. It is a characteristic feature of cnidarians . For example, Obelia has feeding individuals, the gastrozooids ; the individuals capable of asexual reproduction only, the gonozooids, blastostyles; and free-living or sexually reproducing individuals, the medusae . Balanced polymorphism refers to the maintenance of different phenotypes in population. Monomorphism means having only one form. Dimorphism means having two forms. Polymorphism crosses several discipline boundaries, including ecology, genetics, evolution theory, taxonomy, cytology, and biochemistry. Different disciplines may give

6150-494: The sex: alligators are a famous case in point. In ants the distinction between workers and guards is environmental, by the feeding of the grubs. Polymorphism with an environmental trigger is called polyphenism . The polyphenic system does have a degree of environmental flexibility not present in the genetic polymorphism. However, such environmental triggers are the less common of the two methods. Investigation of polymorphism requires use of both field and laboratory techniques. In

6232-565: 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, overlapping the Hp53int1 gene. 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. In humans,

6314-588: The specter of oncogenic infection . p53 acts as a cellular stress sensor. It is normally kept at low levels by being constantly marked for degradation by the E3 ubiquitin ligase protein MDM2 . p53 is activated in response to myriad stressors – including DNA damage (induced by either UV , IR , or chemical agents such as hydrogen peroxide), oxidative stress , osmotic shock , ribonucleotide depletion, viral lung infections and deregulated oncogene expression. This activation

6396-507: The target of the SV40 virus, a strain that induced development of tumors. The name p53 was given in 1979 describing the apparent molecular mass . The TP53 gene from the mouse was first cloned by Peter Chumakov of The Academy of Sciences of the USSR in 1982, and independently in 1983 by Moshe Oren in collaboration with David Givol ( Weizmann Institute of Science ). The human TP53 gene

6478-518: The time the immune system is fully developed. Thus self-tolerance does not develop against these antigens. Abnormal proteins are also produced by cells infected with oncoviruses , e.g. EBV and HPV . Cells infected by these viruses contain latent viral DNA which is transcribed and the resulting protein produces an immune response. In addition to proteins, other substances like cell surface glycolipids and glycoproteins may also have an abnormal structure in tumor cells and could thus be targets of

6560-415: The transcription of proteins that bind to MDM2 and inhibit its activity. Epigenetic marks like histone methylation can also regulate p53, for example, p53 interacts directly with a repressive Trim24 cofactor that binds histones in regions of the genome that are epigenetically repressed. Trim24 prevents p53 from activating its targets, but only in these regions, effectively giving p53 the ability to 'read out'

6642-429: The treatment of head and neck squamous cell carcinoma . It delivers a functional copy of the p53 gene using an engineered adenovirus . 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

6724-434: Was cloned in 1984 and the full length clone in 1985. Tumor antigen Tumor antigen is an antigenic substance produced in tumor cells , i.e., it triggers an immune response in the host . Tumor antigens are useful tumor markers in identifying tumor cells with diagnostic tests and are potential candidates for use in cancer therapy . The field of cancer immunology studies such topics. Normal proteins in

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