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)

Xeroderma pigmentosum (XP), Cockayne syndrome (CS) and trichothiodystrophy (TTD) are genetic disorders with very different clinical features, but all associated with defects in nucleotide excision repair. Defects in the XPA or XPC genes confer sensitivity to UV carcinogenesis in both humans and mice, but only XPA(-/-) mice have increased acute responses to UV exposure, whereas XPC(-/-) mice are normal in this respect. Both XPE and XPF proteins have functions separate from their role in NER, but the exact nature of these functions has not yet been established. The CSA and CSB genes responsible for CS are both components of complexes associated with RNA polymerase II and their role is thought to be in assisting polII in dealing with transcription blocks. XPB and XPD proteins are components of transcription factor TFIIH, which is involved in both basal and activated transcription. XPB is part of the core of TFIIH and has a central role in transcription, whereas XPD connects the core to the CAK subcomplex, and can tolerate many different mutations. Subtle differences in the effects of these different mutations on the many activities of TFIIH and on its stability determine the clinical outcomes, which can be XP, TTD, XP with CS, XP with TTD or COFS. Features of single and double mutant mice indicate that the neurological and ageing features associated with these disorders result from the defects in NER in association with the transcriptional deficiencies. Skin tumours in XP patients have mutations characteristic of UV-induction in the ras, p53 and ptch genes, showing that sunlight-induced mutations in these genes are important in carcinogenesis in XP patients.
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PMID:DNA repair-deficient diseases, xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy. 1472 16

The pattern of somatic mutations in TP53 is distinct for particular cancers and carcinogenic exposures, providing clues to disease etiology, e.g. G:C-->T:A mutations in TP53 are more frequently observed in smoking-associated lung cancers. In order to investigate possible causes and mechanisms of lung cancer susceptibility differences, the TP53 gene was sequenced in a case-only study of lung cancers (206 men and 103 women). Our primary hypothesis was that the TP53 mutation spectrum is influenced by polymorphisms in genes involved in DNA repair and apoptosis. We observed a TP53 mutation frequency in exons 5-8 of 25%. Functional polymorphisms in XPD (Asp312Asn, rs1799793 and Lys751Gln, rs1052559), a protein required for nucleotide excision repair and with roles in p53-mediated apoptosis, were modestly associated with G:C-->T:A mutations in TP53 in lung tumors [Asp/Asn312 + Asn/Asn312 and/or Lys/Gln751 + Gln/Gln751 versus Asp/Asp312 + Lys/Lys751; odds ratio (OR) 2.73, 95% confidence interval (CI) 0.98-7.61], consistent with the role of this protein in repair of bulky carcinogen-DNA adducts. In addition, a TP53 polymorphism (Arg72Pro, rs1042522) with a known role in the efficiency of apoptosis was also associated with the presence of a TP53 mutation (Pro/Arg72 or Pro/Pro72 versus Arg/Arg72; OR 2.25, 95% CI 1.21-4.17) or a G:C-->T:A mutation in TP53 (Pro/Arg72 or Pro/Pro72 versus Arg/Arg72; OR 2.42, 95% CI 0.97-6.04). An interaction between the XPD variant alleles (Asn312 and Gln751) and the TP53 Pro72 allele was observed for TP53 mutations (any TP53 mutation P(int) = 0.027, G:C-->T:A TP53 mutation P(int) = 0.041). The statistical interaction observed in our study is consistent with the observed biological interaction for XPD and p53 in nucleotide excision repair and apoptosis. In conclusion, differences in TP53 mutation spectra in lung tumors are associated with several genetic factors and may reflect differences in lung cancer susceptibility and carcinogenesis.
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PMID:Polymorphisms in XPD and TP53 and mutation in human lung cancer. 1556 88

Progress in the treatment of colon cancer depends on the development of target-based molecules built on an improved understanding of the molecular biology of the disease. Defining end points for chemotherapy resistance is needed as drug resistance develops quickly and patients demonstrate variation in response to chemotherapy. Many techniques that measure a marker's preponderance have been developed including biochemical, immunohistochemical, genomics, proteomics or a combination thereof. However, standardization of these techniques that measure either genes or their protein products is urgently needed. This article reviews several markers (TS,TP, DPD, FT, EGFR, VEGF, CD44v6, TRAIL, microsatellite instability, allelic deletions, oncogenes and suppressor genes [c-myc, Ki-Ras, p53, p21, Topo I, Topo IIalpha, Fos, hMLH1, Bcl-2/Bax and MDR1], MDR-related proteins [Pgp, MRP and LRP], genomic polymorphisms [XPD, ERCC1, GSTP1 and TS 3 -UTR] and COX-;2) that influence DNA metabolism, DNA damage, programmed cell death, the immune or vascular system, or lead to mutations. When combined together and tested by newly developed genomic and proteomic approaches, many of these markers provide a more sensitive indicative predictor of response than when evaluated separately or by older biochemical, immunohistologic or morphologic methods. A global approach involving the simultaneous testing of several predictive multimarkers will provide critical information for improving chemotherapy to alleviate suffering from this disease.
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PMID:Molecular markers that predict response to colon cancer therapy. 1593 13

Although smoking is the primary risk factor for most lung cancers, genetic predisposition may play an important role. Familial aggregation studies suggest a greater genetic component in the risk for younger individuals developing lung cancer, for lifetime nonsmokers, and possibly for women. Low-penetrance, high-prevalence polymorphic genes may explain part of this genetic predisposition. Functional polymorphisms of xenobiotic metabolism may alter the total exposure of tobacco carcinogens in the host. Subtle alterations in the DNA repair, inflammatory, and cell cycle pathways may also alter lung cancer susceptibility. The role of individual polymorphisms has been evaluated for several genes including the CYP and glutathione s-transferase superfamilies, and the NAT genes; DNA repair genes such as XPD (nucleotide excision pathway), XRCC1 (base excision pathway), and MGMT; and tumor suppressor or cell cycle genes such as p53. Molecular epidemiological studies are now focused on building larger databases from existing smaller studies and developing strategies to simultaneously evaluate multiple polymorphisms and genes within the same pathway.
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PMID:Molecular epidemiology of non-small cell lung cancer. 1605 27

The severe xeroderma pigmentosum/Cockayne syndrome (XP/CS) syndrome is caused by mutations in the XPB, XPD and XPG genes that encode the helicase subunits of TFIIH and the 3' endonuclease of nucleotide excision repair (NER). Because XPB and XPD have been implicated in p53-mediated apoptosis, we examined the possible involvement of XPG in this process. After ultraviolet light (UV) irradiation, primary fibroblasts of XP complementation group G (XP-G) individuals with CS enter apoptosis more readily than other NER-deficient cells, but this is unlinked to unrepaired damage. These XP-G/CS cells accumulate p53 post-UV but they fail to accumulate the 90/92 kDa isoforms of Mdm2 and their cellular distribution of Mdm2 is impaired. Apoptosis levels revert to wild type, Mdm2 90/92 kDa isoforms accumulate, and Mdm2 regains its normal post-UV nuclear location in transduced XP-G/CS cells expressing wild-type XPG, but not an XPG catalytic site mutant. These results suggest that XPG suppresses UV-induced apoptosis and that this suppression, most simply, requires its endonuclease function.
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PMID:Suppression of UV-induced apoptosis by the human DNA repair protein XPG. 1616 68

The aim of our study was to identify occupational risk of irradiation exposure in the Czech nuclear power plant workers. We analyzed levels of chromosomal aberrations, a well-known biomarker of early biological effects and a predictor of cancer risk. We applied the conventional method of cytogenetic analysis and fluorescence in situ hybridization (FISH, whole chromosome painting for chromosomes 1 and 4, combined with a pancentromeric probe) to three groups: 123 subjects in the Temelin nuclear power plant (2 years in use), 114 subjects in the Dukovany nuclear power plant (20 years in use), and 53 matched controls from Ceske Budejovice. Nuclear power plant workers were divided into two groups: subjects with admittance into the monitored zone, and others. Following factors were also analyzed: GSTM1, GSTT1, GSTP1, XPD, XRCC1, hOGG1, p53, MTHFR, and MS gene polymorphisms, levels of vitamins A, C, E, and folate in plasma, and level of cotinine in urine. Long-term exposure to ionizing radiation in the monitored zone was 0.47+/-1.50 mSv (miliSievert) in the Temelin nuclear power plant and 5.74+/-9.57 mSv in the Dukovany nuclear power plant. Using the conventional cytogenetic analysis, we observed 1.90+/-0.95 and 1.82+/-1.19% AB.C. (percent of aberrant cells) in the Temelin nuclear power plant, and 2.39+/-1.01 and 2.33+/-1.04% AB.C. in the Dukovany nuclear power plant, for monitored zone workers and others, respectively. In the control group, we found 2.25+/-0.82% AB.C. Genomic frequency of translocations F(G)/100 measured by FISH was 1.89+/-1.40 and 2.01+/-1.68 in the Temelin nuclear power plant, and 2.48+/-1.93 and 2.14+/-1.62 in the Dukovany nuclear power plant for monitored zone workers and others, respectively. In the control group, F(G)/100 was 1.83+/-1.19. Following factors were identified as potential confounders by the conventional cytogenetic analysis: XPD-6, by the FISH: age, GSTP1 and p53Bst genotypes, long-term use of medication, alcohol consumption, and smoking. No association between the dose of irradiation and the level of chromosomal aberrations in any nuclear power plant was detected either by the conventional cytogenetic analysis or by FISH.
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PMID:Possible genetic damage in the Czech nuclear power plant workers. 1619 33

A subset of DNA helicases, the RecQ family, has been found to be associated with the p53-mediated apoptotic pathway and is involved in maintaining genomic integrity. This family contains the BLM and WRN helicases, in which germline mutations are responsible for Bloom and Werner syndromes, respectively. TFIIH DNA helicases, XPB and XPD, are also components in this apoptotic pathway. We hypothesized that there may be some redundancy between helicases in their ability to complement the attenuated p53-mediated apoptotic levels seen in cells from individuals with diseases associated with these defective helicase genes. The attenuated apoptotic phenotype in Bloom syndrome cells was rescued not only by ectopic expression of BLM, but also by WRN or XPB, both 3' --> 5' helicases, but not expression of the 5' --> 3' helicase XPD. Overexpression of Sgs1, a WRN/BLM yeast homolog, corrected the reduction in BS cells only, which is consistent with Sgs1 being evolutionarily most homologous to BLM. A restoration of apoptotic levels in cells from WS, XPB or XPD patients was attained only by overexpression of the specific helicase. Our data suggest a limited redundancy in the pathways of these RecQ helicases in p53-induced apoptosis.
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PMID:Redundancy of DNA helicases in p53-mediated apoptosis. 1628 11

We studied the effects of polymorphisms in nine genes involved in DNA repair and detoxification on occurrence and type of p53 mutation in 327 bladder cancer patients. The included polymorphisms are XPC(Lys939Gln), XPD(Lys751Gln), XPG(Asp1104His), XRCC1(Arg3999Gln), XRCC3(Thr241Met), NBS1(Glu185Gln), cyclin D1(Pro241Pro), MTHFR(Ala222Val and Glu429Ala) and NQO1(Arg139Trp and Pro187Ser). We found increased risk for p53 mutation among cyclin D1 variant allele homozygotes (OR 2.4 CI 0.8-6.7). Among non-smokers, 75% (3/4) with p53 mutation but only 12.5% (3/24) without p53 mutations were XRCC3 241Met homozygotes (P=0.03). Among smokers, all p53 transversions (3/3), but only 41.7% (5/12) of p53 transitions were found among carriers of the XPC 939Gln allele. Individuals carrying the NQO1 187Ser allele showed increased risk for p53 transversions (OR 4.7, CI 0.9-26.1). All (2/2) NQO1 139Trp allele carriers but only 17.5% (7/40) of the Arg139 homozygotes had p53 transversions. Our findings suggest that altered repair and detoxification due to genetic polymorphism may influence the occurrence of p53 mutations in bladder cancer.
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PMID:Influence of polymorphism in DNA repair and defence genes on p53 mutations in bladder tumours. 1634 42

The two BRCT domains (BRCT1 and BRCT2) of XRCC1 mediate a network of protein-protein interactions with several key factors of the DNA single-strand breaks (SSBs) and base damage repair pathways. BRCT1 is required for the immediate poly(ADP-ribose)-dependent recruitment of XRCC1 to DNA breaks and is essential for survival after DNA damage. To better understand the biological role of XRCC1 in the processing of DNA ends, a search for the BRCT1 domain-associated proteins was performed by mass spectrometry of GST-BRCT1 pulled-down proteins from HeLa cell extracts. Here, we report that the double-strand break (DSB) repair heterotrimeric complex DNA-PK interacts with the BRCT1 domain of XRCC1 and phosphorylates this domain at serine 371 after ionizing irradiation. This caused XRCC1 dimer dissociation. The XRCC1 R399Q variant allele did not affect this phosphorylation. We also show that XRCC1 strongly stimulates the phosphorylation of p53-Ser15 by DNA-PK. The pseudo phosphorylated S371D mutant was a much weaker stimulator of DNA-PK activity whereas the non-phosphorylable mutant S371L endowed with a DNA-PK stimulating capacity failed to fully rescue the DSB repair defect of XRCC1-deficient EM9 rodent cells. The functional association between XRCC1 and DNA-PK in response to IR provides the first evidence for their involvement in a common DSB repair pathway.
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PMID:XRCC1 is phosphorylated by DNA-dependent protein kinase in response to DNA damage. 1639 95

Polymorphisms exist in several genes involved in nucleotide excision repair (NER), the principal pathway for removal of smoking-induced DNA damage. An epidemiologic study was conducted to determine whether these polymorphisms modify the association between smoking and breast cancer. DNA samples and exposure histories were analyzed as part of a large population-based case-control study of breast cancer in North Carolina. The study population included 2311 cases (894 African Americans, 1417 whites) and 2022 controls (788 African Americans, 1234 whites). Odds ratios (ORs) were calculated for breast cancer and smoking, and for breast cancer and nine non-synonymous coding polymorphisms in six NER genes (XPD codons 312 and 751, RAD23B codon 249, XPG codon 1104, XPC codon 939, XPF codons 415 and 662, and ERCC6 codons 1213 and 1230). Modification of ORs for smoking by single and combined NER genotypes was investigated. In this study population, smoking was more strongly associated with breast cancer in African American women compared with white women. Among African American women, the association of breast cancer and smoking was strongest among women with specific combinations of NER genotypes. Evidence for multiplicative interaction was found between combined NER genotypes and smoking dose (likelihood ratio test P = 0.06), duration (P = 0.09), time since cessation (P = 0.02), age at initiation (P = 0.04) and former smoking (P = 0.03). No interactions were observed in white women. Therefore, polymorphisms in NER genes may modify the relationship between breast cancer and smoking. These results are consistent with previous evidence of exposure-specific p53 mutations in breast tumors from current and former smokers, suggesting that smoking may play a role in breast cancer etiology.
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PMID:Polymorphisms in nucleotide excision repair genes, smoking and breast cancer in African Americans and whites: a population-based case-control study. 1639 71


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