Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The initiation step of the carcinogenic process consists in an alteration of genes playing a central role in the cellular life. The next steps of promotion and progression result from anomalies in the response to growth factors, to hormones and/or from the action of tumor promotors leading to cellular hyperplasia. This process generally leads to genetic instability of the initiated cell which in turn allows selection of malignant and invasive clones. The production of DNA damage by physical or chemical agents is dose-dependent. The error-free enzymatic repair processes including excision resynthesis of base damage or of altered nucleotides allow the restitution of intact DNA. The error-prone repair systems permit survival in association with transmissible alterations (genes and chromosomal mutations). Absence of repair leads to cytotoxicity, programmed cell death or disruption of cell cycle control leading to a pretumoral state. The major role played by mutations in the initiation of carcinogenesis is evidenced by the existence of genetic syndromes associated to hypersensitivity to genotoxic agents, defects in DNA repair capacity, anomalies in the expression of certain genes (including the tumor suppressor p53 gene, etc.) and an elevated predisposition to cancer. Xeroderma pigmentosum which is defective in excision-repair, ataxia telangiectasia and Fanconi anemia which are associated to anomalies in DNA recombination and the familial type of colon cancer HPNCP due to inefficient mismatch repair constitute paradigm for this fundamental notion. Alterations in the capacity to rejoin radiation induced DNA strand breaks appears to be associated to over-reactions to radiotherapy of cancer patients. Also the predisposition to develop secondary thyroid tumors following treatment of a primary cancer in childhood seems to involve the same defect. The existence in the general population of heterozygotes for such DNA repair genes should be taken into account for risk evaluation to therapeutic and environmental exposures.
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PMID:[Molecular mechanisms of carcinogenesis: the role of systems of DNA repair]. 962 30

Mammalian cells in culture react to ultraviolet irradiation with the massive transcriptional activation of several genes and with the stabilization of the p53 protein. While U.V.-induced transcription of several immediate-response genes depends on U.V.-induced activation of signal transduction generated by non-nuclear mechanisms, stabilization of p53 and the transcription of several delayed-response genes are triggered by U.V.-induced DNA damage. By comparing dose responses for the activation by U.V. of delayed-responsive genes (collagenase 1, metallothionein IIA) in cells from patients with different DNA repair deficiencies (complementation groups of Xeroderma pigmentosum, Cockayne's syndrome and Trichothiodystrophy), we show here that U.V.-induced transcription of these genes does depend on pyrimidine dimers in transcribed regions of the genome (but not on damage in its silent part). Since all cells with defects in DNA repair that had been tested and which lack different enzymes, respond to U.V. with expression of these same genes, functional repair does not appear to be required for the induction of expression, and repair intermediates (which would not be identical in cells of different repair deficiency) cannot be responsible for signal generation.
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PMID:Photoproducts in transcriptionally active DNA induce signal transduction to the delayed U.V.-responsive genes for collagenase and metallothionein. 967 3

The purpose of this study is to better understand the roles of the p53 tumor suppressor protein and the product of the p53-regulated gene p21WAF1 in the response of diploid human dermal fibroblast cultures to 254 nm ultraviolet (UV) light. We report that Li-Fraumeni syndrome (LFS) fibroblast strains heterozygous for TP53 mutation at either codon 245 or 234 exhibit markedly reduced or no expression of p21WAF1 following UV irradiation, respectively. These strains also exhibit defective nucleotide excision repair and pronounced inhibition of RNA synthesis following UV exposure, both of which are molecular hallmarks of cells derived from patients with the UV-sensitive syndrome xeroderma pigmentosum. In sharp contrast to xeroderma pigmentosum cells, however, the repair-deficient LFS cells show abnormal resistance, rather than hypersensitivity, to the killing effect of UV light. We further demonstrate that exposure of normal human fibroblasts to biologically relevant fluences (< or = 15 J/m2) of UV does not induce apoptotic cell death, indicating that UV resistant phenotype displayed by LFS strains is not associated with deregulated apoptosis. In normal fibroblasts, such treatment results in a moderate ( threefold) up-regulation of p53 protein, induction of the p21WAF1 gene, and a senescence-like growth arrest. On the other hand, exposure to > or = 20 J/m2 UV results in a striking up-regulation of p53, inhibition of p21WAF1 expression, and activation of an apoptotic pathway. We conclude that: (i) p21WAF1-mediated senescence is the principal mode of cell death induced by < or = 15 J/m2 UV light in normal human fibroblasts; (ii) there is a threshold effect for p53-dependent apoptosis and that, in normal human cells, this threshold level is induced upon expsoure to 20 J/m2 UV; (iii) the p53 signaling pathway is malfunctional in the TP53 heterozygous LFS strains examined; and (iv) the enhanced resistance to UV-induced cell killing displayed by these LFS strains is a consequence of diminished growth arrest, which is presumably mediated by p21WAF1 and not abnormalities in an apoptotic pathway.
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PMID:Aberrant p21WAF1-dependent growth arrest as the possible mechanism of abnormal resistance to ultraviolet light cytotoxicity in Li-Fraumeni syndrome fibroblast strains heterozygous for TP53 mutations. 970 19

Fifty-eight skin biopsies and three primary internal tumors from patients affected by the rare hereditary disease xeroderma pigmentosum (XP) were studied by an improved PCR-single strand conformation polymorphism analysis to detect the mutations of the tumor suppressor gene p53. The results from cutaneous XP tumors, including 27 squamous cell carcinomas and 6 basal cell carcinomas, show a very high level (86%) of p53 mutations. The analysis of mutations found in XP skin cancers according to the complementation group of the patients shows that tandem CC-->TT transitions are a characteristic of XP-C patients with a frequency much higher in their skin tumors (85%) compared with tumors in XP patients who do not belong to group C (33%). In all XP-C biopsies, mutations were due to replication of unrepaired DNA lesions on the nontranscribed strand of the p53 gene, substantiating the preferential repair in vivo of the transcribed strand of this gene in human tissues. For the first time, we were able to analyze three primary internal tumors (a neuroendocrine tumor of the thyroid, a gastric adenocarcinoma, and a glioma of the brain) of young XP children. All of them contained one mutation on the p53 gene, which were different from the ones found in the XP skin tumors and could have resulted from unrepaired lesions caused by oxidative damage.
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PMID:p53 mutations in skin and internal tumors of xeroderma pigmentosum patients belonging to the complementation group C. 976 70

Among the major responses of human cells to DNA damage is accumulation of the p53 tumor suppressor protein, which plays a crucial role as a cell-cycle checkpoint. We have already shown that this response is different in cells from the UV-hypersensitive human syndromes xeroderma pigmentosum (XP) and trichothiodystrophy (TTD), which overlap with each other and arise from mutations in genes involved in nucleotide excision repair. In this paper we report that correction of the repair defect by retroviral-mediated transduction of the wild-type XPD gene in XP-D and TTD/XP-D untransformed primary fibroblasts leads to a normal p53 response in these cells. Thus, the complemented cells, like normal human fibroblasts, require higher UV doses (10 J/m2) for p53 induction than the parental repair-deficient XP-D or TTD/XP-D cells (both mapping at the XPD locus), which accumulate p53 protein at very low UV doses (2.5 and 5 J/m2). The p53 protein levels return to normal 24 h after irradiation when UV-induced lesions have been efficiently repaired by the restored NER activity. These data confirm our earlier results that p53 accumulation following UV treatment is directly related to the presence of unrepaired cyclobutane dimers on the transcribed strand of active genes.
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PMID:Recovery of the normal p53 response after UV treatment in DNA repair-deficient fibroblasts by retroviral-mediated correction with the XPD gene. 977 45

The mutational specificity of UV-light is characterized by an abundance of C to T transition mutations at dipyrimidines containing cytosine or 5-methylcytosine. A significant percentage of these mutations are CC to TT double transitions. Of the major types of UV-induced DNA lesions, the cis-syn cyclobutane pyrimidine dimers (CPDs) are thought to be the most mutagenic lesions, at least in mammalian cells. It has been proposed that the CPDs become mutagenic perhaps only after cytosine bases within these dimers deaminate to uracil and the resulting U-containing photolesions are correctly bypassed by DNA polymerases. In order to assess the significance of this proposed mutagenic mechanism, we have developed two methods to specifically measure deaminated CPDs in UV-irradiated human cells or DNA. The first method is based on enzymatic photoreversal of CPDs, followed by cleavage of the DNA with uracil DNA glycosylase, an AP lyase activity, and ligation-mediated PCR to map the resulting strand breaks. The second method, which can be used to detect double deamination events (CC to UU), is PCR amplification of photolyase-treated DNA using primers complemetary to the deaminated sequences. We have measured deamination events in the human p53 gene, which contains a large percentage of C to T transitions in skin cancers. The deamination reactions are specific for cytosine within CPDs, are negligible immediately after irradiation, and are time-dependent and DNA sequence context-dependent. Twenty four hours after irradiation of human fibroblasts with UVB light, between 10 and 60% of most CPD signals are converted to the deaminated form, depending on the sequence. Significant deamination occurs at skin cancer mutation sites in the p53 gene. Double deamination also occurs and this reaction can involve dimers containing 5-methylcytosine or cytosine. These double events are expected to occur more frequently in cells with a DNA repair defect because there is more time for deamination in unrepaired lesions. This may explain the relatively high frequency of CC to TT mutations in skin cancers from xeroderma pigmentosum patients. In summary, these novel detection techniques demonstrate that deamination of cytosine in pyrimidine dimers is a significant event that most likely contributes to the mutational specificity of UVB irradiation in human cells.
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PMID:Sequence and time-dependent deamination of cytosine bases in UVB-induced cyclobutane pyrimidine dimers in vivo. 981 19

In human cells, efficient global genomic repair of DNA damage induced by ultraviolet radiation requires the p53 tumor suppressor, but the mechanism has been unclear. The p48 gene is required for expression of an ultraviolet radiation-damaged DNA binding activity and is disrupted by mutations in the subset of xeroderma pigmentosum group E cells that lack this activity. Here, we show that p48 mRNA levels strongly depend on basal p53 expression and increase further after DNA damage in a p53-dependent manner. Furthermore, like p53(-/-) cells, xeroderma pigmentosum group E cells are deficient in global genomic repair. These results identify p48 as the link between p53 and the nucleotide excision repair apparatus.
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PMID:Expression of the p48 xeroderma pigmentosum gene is p53-dependent and is involved in global genomic repair. 989 49

The xeroderma pigmentosum group G (XP-G) gene (XPG) encodes a structure-specific DNA endonuclease that functions in nucleotide excision repair (NER). XP-G patients show various symptoms, ranging from mild cutaneous abnormalities to severe dermatological impairments. In some cases, patients exhibit growth failure and life-shortening and neurological dysfunctions, which are characteristics of Cockayne syndrome (CS). The known XPG protein function as the 3' nuclease in NER, however, cannot explain the development of CS in certain XP-G patients. To gain an insight into the functions of the XPG protein, we have generated and examined mice lacking xpg (the mouse counterpart of the human XPG gene) alleles. The xpg-deficient mice exhibited postnatal growth failure and underwent premature death. Since XPA-deficient mice, which are totally defective in NER, do not show such symptoms, our data indicate that XPG performs an additional function(s) besides its role in NER. Our in vitro studies showed that primary embryonic fibroblasts isolated from the xpg-deficient mice underwent premature senescence and exhibited the early onset of immortalization and accumulation of p53.
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PMID:Postnatal growth failure, short life span, and early onset of cellular senescence and subsequent immortalization in mice lacking the xeroderma pigmentosum group G gene. 1002 22

The xeroderma pigmentosum (XP) variant (XPV) is a form of XP that has normal excision repair but shows defective DNA replication after UV irradiation. In developing various transformed fibroblast cell lines from these patients, we have found that there are significant phenotypic changes in transformed cells that seem to correlate with inactivation of p53. After transformation with SV40, XPV cell lines are only slightly UV sensitive, like their primary counterparts, but their sensitization with caffeine and the induction of sister chromatid exchanges (SCEs) by UV irradiation are greatly enhanced. After transformation by HPV16 E7, which targets the retinoblastoma cell cycle regulatory gene, there is no change in the UV sensitivity of XPV cells; but, when transformed by HPV16 E6 or E6 and E7 combined, there is a large increase in UV sensitivity and in the induction of SCEs. These changes are not associated with any detectable changes in the reactivation of an externally irradiated luciferase expression vector, the excision of cyclobutane pyrimidine dimers from bulk DNA, or unscheduled DNA synthesis and, therefore, do not involve excision repair. We suggest that if SCEs represent homologous recombination between sister chromatids, then in the absence of p53 function, the DNA chain arrest typical of UV-damaged XPV cells initiates strand exchange during recovery. In untransformed cells with normal p53, the preferred mode of recovery would then be replication bypass. The symptoms of elevated solar carcinogenesis in XPV patients may, therefore, be associated with increased genomic instability in cells of the skin in which p53 is inactivated by UV-induced mutations.
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PMID:Increased ultraviolet sensitivity and chromosomal instability related to P53 function in the xeroderma pigmentosum variant. 1007 Sep 69

Microinjection of the restriction endonuclease HaeIII, which causes DNA double-strand breaks with blunt ends, induces nuclear accumulation of p53 protein in normal and xeroderma pigmentosum (XP) primary fibroblasts. In contrast, this induction of p53 accumulation is not observed in ataxia telangiectasia (AT) fibroblasts. HaeIII-induced p53 protein in normal fibroblasts is phosphorylated at serine 15, as determined by immunostaining with an antibody specific for phosphorylated serine 15 of p53. This phosphorylation correlates well with p53 accumulation. Treatment with lactacystin (an inhibitor of the proteasome) or heat shock leads to similar levels of p53 accumulation in normal and AT fibroblasts, but the p53 protein lacks a phosphorylated serine 15. Following microinjection of HaeIII into lactacystin-treated normal fibroblasts, lactacystin-induced p53 protein is phosphorylated at serine 15 and stabilized even in the presence of cycloheximide. However, neither stabilization nor phosphorylation at serine 15 is observed in AT fibroblasts under the same conditions. These results indicate the significance of serine 15 phosphorylation for p53 stabilization after DNA double-strand breaks and an absolute requirement for ATM in this phosphorylation process.
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PMID:Requirement of ATM in phosphorylation of the human p53 protein at serine 15 following DNA double-strand breaks. 1008 48


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