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 development of ischemic tolerance in the brain, whereby a brief period of sublethal 'preconditioning' ischemia attenuates injury from subsequent severe ischemia, may involve the activation of multiple intracellular signaling events that promote neuronal survival. In this study, the potential role of inducible DNA base-excision repair (BER), an endogenous adaptive response that prevents the detrimental effect of oxidative DNA damage, has been studied in the rat model of ischemic tolerance produced by three episodes of ischemic preconditioning (IP). This paradigm of IP, when applied 2 and 5 days before 2-h middle cerebral artery occlusion (MCAO), significantly decreased infarct volume in the frontal-parietal cortex 72 h later. Correlated with this protective effect, IP markedly attenuated the nuclear accumulations of several oxidative DNA lesions, including 8-oxodG, AP sites, and DNA strand breaks, after 2-h MCAO. Consequently, harmful DNA damage-responsive events, including NAD depletion and p53 activation, were reduced during postischemic reperfusion in preconditioned brains. The mechanism underlying the decreased DNA damage in preconditioned brain was then investigated by measuring BER activities in nuclear extracts. Beta-polymerase-mediated BER activity was markedly increased after IP, and this activation occurred before (24 h) and during the course of ischemic tolerance (48 to 72 h). In similar patterns, the activities for AP site and 8-oxodG incisions were also upregulated after IP. The upregulation of BER activities after IP was likely because of increased expression of repair enzymes beta-polymerase, AP endonuclease, and OGG1. These results suggest that the activation of the BER pathway may contribute to IP-induced neuroprotection by enhancing the repair of endogenous oxidative DNA damage after ischemic injury.
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PMID:Ischemic preconditioning in the rat brain enhances the repair of endogenous oxidative DNA damage by activating the base-excision repair pathway. 1600 Oct 17

Polymorphisms in DNA repair genes have been suggested to increase the risk of cancer and other diseases, but the epidemiological studies are often not consistent, and the results confusing. We have examined the effect of polymorphisms in base and nucleotide excision-repair genes, as well as regulatory and signalling genes, on cytotoxic sensitivity of tumour cell lines used for screening anticancer drugs by the National Cancer Institute. It was found that for the TP53 P72R and ERCC2 D312N polymorphisms, the heterozygous genotype was most sensitive, while for the OGG1 S326C and NOS3 g.-786T>C polymorphisms the homozygous-variant genotype was most sensitive. The biggest increase in sensitization was found with the XRCC1 R399Q homozygous dominant genotype. The sensitization was found across a broad range of drugs, indicating the importance of DNA repair responses. It was also found that while the other gene polymorphisms were in Hardy-Weinberg equilibrium, the TP53 P72R heterozygous genotype was relatively depleted. For the OGG1 polymorphism, the repair of 8-oxo-guainine from DNA was measured in three panel cell lines that differed in their OGG1 genotype. The cell line with the homozygous-variant genotype had a much poorer repair than the other genotypes, as predicted. The correlation of polymorphisms with cytotoxicity may be an approach to understanding their effects which may be difficult to reveal in epidemiological studies.
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PMID:DNA repair gene polymorphisms affect cytotoxicity in the National Cancer Institute Human Tumour Cell Line Screening Panel. 1607 32

A Ser326Cys amino acid variant encoded by OGG1 that removes the highly mutagenic 8-oxo-7,8-dihydroguanine adducts resulting from the oxidative damage produced by reactive oxygen species, has been suggested to reduce activity of the enzyme and result in an increase in G:C --> T:A transversions. Carriers homozygous for the Cys326 variant have been associated with increased risk in some cancers. In this study, we tested the association of this polymorphism with epithelial ovarian cancer (EOC) (n=91 cases) in comparison with women unaffected by the disease (n=57). Although the genotype encoding the homozygous Cys326 variant was found more often in cases (11%) than controls (9%), this was not statistically significant (p=0.297). As OGG1 at chromosome band 3p25.3 overlaps a region exhibiting allelic imbalance (AI) in EOC, we also examined the frequency of AI of the OGG1 locus and its association with somatic mutations in the TP53 tumor suppressor gene, which is frequently mutated in EOC. The frequency of AI and TP53 mutations in EOC was 32 and 37%, respectively. Although the proportion of EOC cases harboring the genotype homozygous for Cys326 was greater in TP53 mutation-positive cases (5 of 34, 15%) than mutation-negative cases (5 of 57, 9%), the distribution of genotypes was not significantly different (p=0.289). Four of the six heterozygous Ser326/Cys326 samples exhibiting AI, displayed loss of the Ser326 variant. About 16% of samples exhibited both AI of the OGG1 locus and a TP53 mutation. Proportionately more EOC samples harbored a mutation in the group of samples exhibiting AI (15 of 29, 52%) in comparison to the group of samples with no AI (19 of 62, 31%) (p=0.036). Although the OGG1 Cys326 variant appears to play a minor role in conferring increased risk of ovarian cancer, the observed AI of the OGG1 locus in association with TP53 somatic mutations warrants further investigation in this disease.
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PMID:OGG1 Cys326 variant, allelic imbalance of chromosome band 3p25.3 and TP53 mutations in ovarian cancer. 1621 Dec 27

Methionine deprivation stress (MDS) eliminates mitotic activity in melanoma cells regardless of stage, grade, or TP53 status, whereas it has a negligible effect on normal skin fibroblasts. In most cases, apoptosis accounts for the elimination of up to 90% of tumor cells from the culture within 72 hours after MDS, leaving a scattered population of multinucleated resistant cells. Loss of mitosis in tumor cells is associated with marked reduction of cyclin-dependent kinase (CDK) 1 transcription and/or loss of its active form (CDK1-P-Thr(161)), which is coincident with up-regulation of CDKN1A, CDKN1B, and CDKN1C (p21, p27, and p57). Expression of the proapoptotic LITAF, IFNGR, EREG, TNFSF/TNFRSF10 and TNFRSF12, FAS, and RNASEL is primarily up-regulated/induced in cells destined to undergo apoptosis. Loss of Aurora kinase B and BIRC5, which are required for histone H3 phosphorylation, is associated with the accumulation of surviving multinucleated cells. Nevertheless, noncycling survivors of MDS are sensitized to temozolomide, carmustin, and cisplatin to a much greater extent than normal skin fibroblasts possibly because of the suppression of MGMT/TOP1/POLB, MGMT/RAD52/RAD54, and cMET/RADD52, respectively. Sensitivity to these and additional genotoxic agents and radiation may also be acquired due to loss of cMET/OGG1, reduced glutathione reductase levels, and a G(2)-phase block that is a crucial step in the damage response associated with enhancement of drug toxicity. Although the genes controlling mitotic arrest and/or apoptosis in response to low extracellular methionine levels are unknown, it is likely that such control is exerted via the induction/up-regulation of tumor suppressors/growth inhibitor genes, such as TGFB, PTEN, GAS1, EGR3, BTG3, MDA7, and the proteoglycans (LUM, BGN, and DCN), as well as the down-regulation/loss of function of prosurvival genes, such as NFkappaB, MYC, and ERBB2. Although MDS targets several common genes in tumors, mutational variability among melanomas may decide which metabolic and signal transduction pathways will be activated or shutdown.
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PMID:Mitotic arrest, apoptosis, and sensitization to chemotherapy of melanomas by methionine deprivation stress. 1690 95

This study was done to characterize base excision repair (BER) genes and adenomatous polyposis coli (APC) alterations in the tumorigenesis of multiple colorectal adenomas in Korean patients. In total, 217 adenomas (mean number = 10) and 117 cancers were available from 143 patients. The heterozygous genotype of OGG1 c.1-18G>T was closely associated with multiple adenoma families (P < 0.001), while MYH A359V mutation exhibited a tendency (P = 0.053). MYH R170G mutation was exclusively identified in one patient. The G:C>T:A transversion or attenuated familial adenomatous polyposis (AFAP) mutations of APC was identified in the specific genotypes of BER variants. Tubular adenomas or adenomas with none-to-mild dysplasia were significantly associated with polymorphic genotypes of OGG1 IVS4-15 and S326C. In addition, large and pedunculated adenomas were more frequent in patients with G:C>T:A transversion and AFAP mutations of APC, respectively. However, BER variants were not associated with mismatch repair or altered p53 protein expression. Conclusively, two novel mutations of MYH and a novel OGG1 polymorphism seemed to be associated with multiple colorectal adenomas in Korean families, differing from those in other ethnic groups. Some BER variants involved in specific APC mutations are associated with characteristics of histogenesis other than altered mismatch repair or p53 pathway.
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PMID:MYH, OGG1, MTH1, and APC alterations involved in the colorectal tumorigenesis of Korean patients with multiple adenomas. 1725 31

We introduce a method to follow DNA repair that is suitable for both clinical and laboratory samples. An episomal construct with a unique 8-oxoguanine (8-oxoG) base at a defined position was prepared in vitro using single-stranded phage harboring a 678-bp tract from exons 5 to 9 of the human P53 gene. Mixing curve experiments showed that the real-time PCR method has a linear response to damage, suggesting that it is useful for DNA repair studies. The episomal construct with a unique 8-oxoG base was introduced into AD293 cells or human peripheral blood mononuclear cells, and plasmids were recovered as a function of time. The quantitative real-time PCR assay demonstrated that repair of the 8-oxoG was 80% complete in less than 48 h in AD293 cells. Transfection of small interfering RNAs down-regulated OGG1 expression in AD293 cells and reduced the repair of 8-oxoG to 30%. Transfection of the episome into unstimulated white blood cells showed that 8-oxoG repair had a half-life of 2 to 5h. This method is a rapid, reproducible, and robust way to monitor repair of specific adducts in virtually any cell type.
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PMID:Monitoring repair of DNA damage in cell lines and human peripheral blood mononuclear cells. 1744 3

Anthocyanins are a class of flavonoids, widely spread throughout the plant kingdom, exhibiting important antioxidant and anti-inflammatory actions as well as chemotherapeutic effects; nonetheless, little is known about the molecular mechanisms by which these activities are exerted. The present study is aimed at investigating molecular mechanisms involved in the chemotherapeutic effects induced by both cyanidin-3-O-beta glucopyranoside (CY3G) and its aglycon form, cyanidin chloride (CY), in human colon cancer cells (CaCo2). The effect on cell growth, reactive oxygen species (ROS) formation and cell cycle/stress proteins modification, including ataxia teleangectasia mutated protein (ATM), p53, p21, 8-oxoguanine DNA glycosylase (OGG1), 70 kDa heat shock protein (HSP70) and topoisomerase IIbeta, as well as on DNA fragmentation, was determined. CY and CY3G treatment affect cell growth and cell proliferation, this latter in a moderately dose-dependent way. Interestingly, ROS level is decreased by any concentration of CY and, only at the lowest concentration, by CY3G. Moreover, the two molecules exert their activities increasing ATM, topoisomerase II, HSP70 and p53 expression. The analysis of DNA fragmentation by Comet assay evidences: (1) a dose-dependent increase in DNA damage only after treatment with CY3G; (2) a more evident trend in the DNA fragmentation when the treatment is performed on agarose embedded cells (cellular atypical Comet); (3) a highly dose-dependent DNA fragmentation induced by CY when the treatment is carried out on agarose embedded naked DNA (acellular atypical Comet). The present findings substantiate a possible chemotherapeutic role of anthocyanins and suggest that CY and CY3G act on CaCo2 by different mechanisms, respectively, ROS-dependent and ROS-independent.
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PMID:Response of cell cycle/stress-related protein expression and DNA damage upon treatment of CaCo2 cells with anthocyanins. 1805 7

To determine ancestral allele in possible cancer-associated polymorphisms, DNA samples from 10 chimpanzees (Pan troglodytes) were sequenced for alleles corresponding to 17 polymorphisms: 8 short tandem repeats [IL1RN (alias IL-1RA) variable number tandem repeat (VNTR); TYMS (previously TS) VNTR; AR CAG repeat; dinucleotide repeats of UGT1A1, IGF1, IFNG (alias IFN-gamma), ESR1 (alias ER-alpha), and EGFR] and 9 single nucleotide polymorphisms (MMP1-1607 1G/2G, MMP3-1171 5A/6A, OGG1 Ser326Cys, ALDH2 Gly487Lys, TP53 Arg72Pro, ABCG2 Gln141Lys, MGMT Leu84Phe, SOD2 Ala-9Val, and MTHFR Ala222Val). No chimpanzee polymorphism corresponded to human IL1RN VNTR; the ancestral allele was a repeat lost in humans. Dinucleotide repeat polymorphisms of IGF1, IFNG, ESR1, and EGFR were shared by chimpanzees, but the length of repeats tended to be longer in humans than in chimpanzees. This tendency was particularly evident for IGF1. All of the SNPs tested are human-specific nucleotide changes. The ancestral allele 7A was shown to be lost in MMP3-1171 5A/6A. Thus, all of the possible cancer-associated polymorphisms tested have human-specific alleles, and the ancestral allele is lost in three polymorphisms (IL1RN VNTR, UGT1A1 CA repeat, and MMP3-1171 5A/6A), suggesting a possible involvement of human-specific alleles in cancer susceptibility.
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PMID:Determination of ancestral allele for possible human cancer-associated polymorphisms. 1806 29

The growing number of human cancers is the main reason for the search for new effective treatment strategies. The molecular basis for cancer transformation has to be elucidated in order to improve cancer treatment. It is stated that HNSCCs make up at least 5% of all registered malignant tumors in Poland. Exogenous factors influence HNSCC etiology. The prevalence of HNSCC is increased by several carcinogens, including tobacco smoke, life style, and others, such as oncogenous viral infections. It is more often emphasized that endogenous agents can also increase the risk of HNSCC development, especially genetic factors. The most recently characterized genetic factors for head and neck cancer are mutations in xenobiotic metabolism enzyme genes (GSTM1, GSTT1, GSTP1), suppressors mutations (TP53, RB1, BRCA1, ATM), polymorphisms of DNA repair genes (OGG1, XRCC1, XPD, RAD51), and mutations in mitochondrial DNA. It has been observed that single-gene polymorphisms could affect treatment, whereas the coincidence of other gene mutations may increase the risk of human head and neck cancer development.
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PMID:[Genetic predeterminations of head and neck cancer]. 1883 34

Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) is the redox regulator of multiple stress-inducible transcription factors, such as NF-kappaB, and the major 5'-endonuclease in base excision repair (BER). We utilized mice containing a heterozygous gene-targeted deletion of APE1/Ref-1 (Apex(+/-)) to determine the impact of APE1/Ref-1 haploinsufficiency on the processing of oxidative DNA damage induced by 2-nitropropane (2-NP) in the liver tissue of mice. APE1/Ref-1 haploinsufficiency results in a significant decline in NF-kappaB DNA-binding activity in response to oxidative stress in liver. In addition, loss of APE1/Ref-1 increases the apoptotic response to oxidative stress, in which significant increases in GADD45g expression, p53 protein stability, and caspase activity are observed. Oxidative stress displays a differential impact on monofunctional (UNG) and bifunctional (OGG1) DNA glycosylase-initiated BER in the liver of Apex(+/-) mice. APE1/Ref-1 haploinsufficiency results in a significant decline in the repair of oxidized bases (e.g., 8-OHdG), whereas removal of uracil is increased in liver nuclear extracts of mice using an in vitro BER assay. Apex(+/-) mice exposed to 2-NP displayed a significant decline in 3'-OH-containing single-strand breaks and an increase in aldehydic lesions in their liver DNA, suggesting an accumulation of repair intermediates of failed bifunctional DNA glycosylase-initiated BER.
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PMID:Oxidative stress alters base excision repair pathway and increases apoptotic response in apurinic/apyrimidinic endonuclease 1/redox factor-1 haploinsufficient mice. 1926 24


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