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74-676: 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)

148-452: A post-translational modification process called citrullination .This is important in fetal development, is part of the normal immune process, as well as the control of gene expression, but is also significant in autoimmune diseases . Another post-translational modification of arginine involves methylation by protein methyltransferases . Arginine is the immediate precursor of nitric oxide, an important signaling molecule which can act as

222-481: A second messenger , as well as an intercellular messenger which regulates vasodilation, and also has functions in the immune system's reaction to infection. Arginine is also a precursor for urea , ornithine , and agmatine ; is necessary for the synthesis of creatine ; and can also be used for the synthesis of polyamines (mainly through ornithine and to a lesser degree through agmatine, citrulline, and glutamate). The presence of asymmetric dimethylarginine (ADMA),

296-470: 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

370-468: A close relative, inhibits the nitric oxide reaction; therefore, ADMA is considered a marker for vascular disease , just as L -arginine is considered a sign of a healthy endothelium . The amino acid side-chain of arginine consists of a 3-carbon aliphatic straight chain, the distal end of which is capped by a guanidinium group, which has a p K a of 13.8, and is therefore always protonated and positively charged at physiological pH. Because of

444-448: 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

518-404: 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

592-625: 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 )

666-477: 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

740-475: 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

814-416: 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

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888-440: 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

962-501: Is encoded by the codons CGU, CGC, CGA, CGG, AGA, and AGG. The guanidine group in arginine is the precursor for the biosynthesis of nitric oxide . Like all amino acids, it is a white, water-soluble solid. The one-letter symbol R was assigned to arginine for its phonetic similarity. Arginine was first isolated in 1886 from yellow lupin seedlings by the German chemist Ernst Schulze and his assistant Ernst Steiger. He named it from

1036-452: 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

1110-420: Is a component of all protein-containing foods and can be synthesized in the body from glutamine via citrulline . Additional, dietary arginine is necessary for otherwise healthy individuals temporarily under physiological stress, for example during recovery from burns, injury or sepsis, or if either of the major sites of arginine biosynthesis, the small intestine and kidneys , have reduced function, because

1184-434: 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

1258-432: Is available for any of these observations". Further reviews conclude that "lysine's efficacy for herpes labialis may lie more in prevention than treatment." and that "the use of lysine for decreasing the severity or duration of outbreaks" is not supported, while further research is needed. A 2017 study concludes that "clinicians could consider advising patients that there is a theoretical role of lysine supplementation in

1332-430: 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

1406-433: 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

1480-518: 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

1554-484: 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

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1628-431: 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

1702-423: 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

1776-472: Is normally associated with exercising. However, a more recent trial reported that although oral arginine increased plasma levels of L -arginine it did not cause an increase in growth hormone. Research from 1964 into amino acid requirements of herpes simplex virus in human cells indicated that "...the lack of arginine or histidine , and possibly the presence of lysine , would interfere markedly with virus synthesis", but concludes that "no ready explanation

1850-420: Is not quantitative, however, because citrulline accumulates in nitric oxide producing cells along with nitrate and nitrite , the stable end-products of nitric oxide breakdown. Arginine plays an important role in cell division , wound healing , removing ammonia from the body, immune function , and the release of hormones. It is a precursor for the synthesis of nitric oxide (NO), making it important in

1924-470: Is obtained commercially by fermentation. In this way, 25-35 g/liter can be produced, using glucose as a carbon source. Arginine is classified as a semiessential or conditionally essential amino acid , depending on the developmental stage and health status of the individual. Preterm infants are unable to synthesize arginine internally, making the amino acid nutritionally essential for them. Most healthy people do not need to supplement with arginine because it

1998-409: Is returned to the blood. This means that impaired small bowel or renal function can reduce arginine synthesis and thus create a dietary requirement for arginine. For such a person, arginine would become "essential". Synthesis of arginine from citrulline also occurs at a low level in many other cells, and cellular capacity for arginine synthesis can be markedly increased under circumstances that increase

2072-400: 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

2146-522: Is still poorly understood, a number of factors, such as dopamine hyperfunction, glutamatergic hypofunction, GABAergic deficits, cholinergic system dysfunction, stress vulnerability and neurodevelopmental disruption, have been linked to the aetiology and/or pathophysiology of the disease. Oral L-arginine has been shown to reverse digital necrosis in Raynaud syndrome L-arginine is recognized as safe (GRAS-status) at intakes of up to 20 grams per day. L-arginine

2220-455: Is the amino acid with the formula (H 2 N)(HN)CN(H)(CH 2 ) 3 CH(NH 2 )CO 2 H. The molecule features a guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO 2 ) and both the amino and guanidino groups are protonated, resulting in a cation. Only the l -arginine (symbol Arg or R ) enantiomer is found naturally. Arg residues are common components of proteins . It

2294-403: 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

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2368-448: Is typically found on the outside of the protein, where the hydrophilic head group can interact with the polar environment, for example taking part in hydrogen bonding and salt bridges. For this reason, it is frequently found at the interface between two proteins. The aliphatic part of the side chain sometimes remains below the surface of the protein. Arginine residues in proteins can be deiminated by PAD enzymes to form citrulline, in

2442-580: 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

2516-431: The conjugation between the double bond and the nitrogen lone pairs , the positive charge is delocalized, enabling the formation of multiple hydrogen bonds . Intravenously administered arginine is used in growth hormone stimulation tests because it stimulates the secretion of growth hormone . A review of clinical trials concluded that oral arginine increases growth hormone, but decreases growth hormone secretion, which

2590-458: 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

2664-438: 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

2738-537: The Greek árgyros (ἄργυρος) meaning "silver" due to the silver-white appearance of arginine nitrate crystals. In 1897, Schulze and Ernst Winterstein (1865–1949) determined the structure of arginine. Schulze and Winterstein synthesized arginine from ornithine and cyanamide in 1899, but some doubts about arginine's structure lingered until Sørensen's synthesis of 1910. It is traditionally obtained by hydrolysis of various cheap sources of protein, such as gelatin . It

2812-544: 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

2886-433: 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

2960-676: 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

3034-492: 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

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3108-481: 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

3182-415: 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

3256-467: 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

3330-417: 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

3404-706: 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

3478-444: 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

3552-402: 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

3626-417: 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

3700-560: 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,

3774-403: 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 . Arginine Arginine

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3848-560: 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

3922-614: 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

3996-463: 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

4070-427: The net use or production of these amino acids is highly dependent on cell type and developmental stage. Arginine is made by the body as follows. The epithelial cells of the small intestine produce citrulline, primarily from glutamine and glutamate , which is secreted into the bloodstream which carries it to the proximal tubule cells of the kidney , which extract the citrulline and convert it to arginine, which

4144-589: 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

4218-446: 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

4292-710: 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

4366-994: The prevention of herpes simplex sores but the research evidence is insufficient to back this. Patients with cardiovascular or gallbladder disease should be cautioned and warned of the theoretical risks." A meta-analysis showed that L -arginine reduces blood pressure with pooled estimates of 5.4 mmHg for systolic blood pressure and 2.7 mmHg for diastolic blood pressure. Supplementation with l -arginine reduces diastolic blood pressure and lengthens pregnancy for women with gestational hypertension , including women with high blood pressure as part of pre-eclampsia . It did not lower systolic blood pressure or improve weight at birth . Both liquid chromatography and liquid chromatography/mass spectrometric assays have found that brain tissue of deceased people with schizophrenia shows altered arginine metabolism. Assays also confirmed significantly reduced levels of γ-aminobutyric acid (GABA), but increased agmatine concentration and glutamate/GABA ratio in

4440-453: 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

4514-497: The production of inducible nitric oxide synthase (NOS) . This allows citrulline, a byproduct of the NOS-catalyzed production of nitric oxide, to be recycled to arginine in a pathway known as the citrulline to nitric oxide (citrulline-NO) or arginine-citrulline pathway. This is demonstrated by the fact that, in many cell types, nitric oxide synthesis can be supported to some extent by citrulline, and not just by arginine. This recycling

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4588-403: 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

4662-439: The regulation of blood pressure . Arginine is necessary for T-cells to function in the body, and can lead to their deregulation if depleted. Arginine's side chain is amphipathic , because at physiological pH it contains a positively charged guanidinium group, which is highly polar, at the end of a hydrophobic aliphatic hydrocarbon chain. Because globular proteins have hydrophobic interiors and hydrophilic surfaces, arginine

4736-429: The schizophrenia cases. Regression analysis indicated positive correlations between arginase activity and the age of disease onset and between L-ornithine level and the duration of illness. Moreover, cluster analyses revealed that L-arginine and its main metabolites L-citrulline, L-ornithine and agmatine formed distinct groups, which were altered in the schizophrenia group. Despite this, the biological basis of schizophrenia

4810-560: 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,

4884-403: The small bowel does the first step of the synthesizing process and the kidneys do the second. Arginine is an essential amino acid for birds, as they do not have a urea cycle . For some carnivores, for example cats, dogs and ferrets, arginine is essential, because after a meal, their highly efficient protein catabolism produces large quantities of ammonia which need to be processed through

4958-581: 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

5032-500: 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

5106-518: 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

5180-416: 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'

5254-429: 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

5328-451: The urea cycle by the sequential action of the cytosolic enzymes argininosuccinate synthetase and argininosuccinate lyase . This is an energetically costly process, because for each molecule of argininosuccinate that is synthesized, one molecule of adenosine triphosphate (ATP) is hydrolyzed to adenosine monophosphate (AMP), consuming two ATP equivalents. The pathways linking arginine, glutamine , and proline are bidirectional. Thus,

5402-406: The urea cycle, and if not enough arginine is present, the resulting ammonia toxicity can be lethal. This is not a problem in practice, because meat contains sufficient arginine to avoid this situation. Animal sources of arginine include meat, dairy products, and eggs, and plant sources include seeds of all types, for example grains, beans, and nuts. Arginine is synthesized from citrulline in

5476-434: 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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