UNIPROT:P04637 - FACTA Search

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Query: UNIPROT:P04637 (p53)
77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Esophageal cancer, which is prevalent in China and some other parts of the world, is a complex disease likely resulting from polymorphisms of multiple interacting genes and gene-environment interactions. Recent efforts have been made to analyze the associations between risk of this cancer and hereditary sequence variations in genes involved in metabolism, DNA repair and cell cycle control. We summarized here the results of published case-control studies that have examined the effects of common alleles of 15 genes, MTHFR, CYP1A1, CYP2A6, CYP2E1, GSTM1, GSTT1, GSTP1, NAT2, XRCC1, XPD, hOGG1, MGMT, p53, CNDD1 and L-Myc, on risk of esophageal squamous cell carcinoma among Chinese. Statistically significant differences in genotype frequencies found in case-control comparisons were MTHFR C677T and A1298C polymorphisms, the XRCC1 Arg194Trp polymorphisms, the hOGG1 Ser326Cys polymorphism, and the p53 Arg72Pro polymorphism. The overall effects of these genetic polymorphisms were moderate in terms of relative risk, with ORs ranging from 2-10. There was also some evidence that genetic polymorphisms in certain carcinogen-metabolizing enzymes such as CYP2E1, CYP1A1, CYP2A6, GSTM1, and GSTP1 modulate risk of the cancer, although the results require confirmation with larger sample size studies. For polymorphisms in GSTT1, XPD, CCND1, and L-Myc, the risk estimate from the studies was sufficiently precise to exclude an OR >/=1.5.
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PMID:Genetic polymorphisms and susceptibility to esophageal cancer among Chinese population (review). 1288 49

Adenocarcinoma of the pancreas is refractory to chemotherapeutic agents, including BCNU and streptozotocin. We have previously shown that drugs, which adduct the O(6)- position of guanine, are ineffective against pancreatic tumor cell lines because of high expression of O(6)-methylguanine-DNA methyltransferase (MGMT). The effect of MGMT inactivation on the resistance of pancreatic tumors to carmustine (BCNU) and to temozolomide (TMZ) was examined in five human pancreatic tumor xenografts in athymic mice. Tumor-bearing mice were treated: (a) with a single i.p. injection of BCNU or TMZ at the maximum-tolerated doses of 75 and 340 mg/m(2), respectively; and (b) with O(6)-benzylguanine (BG) or O(6)-benzyl-2'-deoxyguanosine (dBG) in combination with BCNU or TMZ. Pretreatment with the MGMT inactivators BG or dBG reduced the maximum-tolerated doses of BCNU and TMZ to 35 and 170 mg/m(2), respectively. MIA PaCa-2, CFPAC-1, PANC-1, CAPAN-2, and BxPC-3 having MGMT levels of 890, 1680, 680, 900, and 330 fmol/mg protein, respectively, were unresponsive to BCNU. MIA PaCa-2 and CFPAC-1 were also unresponsive to TMZ, whereas CAPAN-2 responded with a tumor delay of 32 days. BG or dBG sensitized all tumors to both BCNU and TMZ. BG plus BCNU treatment of MIA PaCa-2, CFPAC-1, PANC-1, CAPAN-2, and BxPC-3 induced tumor delays of 18, 16, 12, 14, and 16 days, respectively. In comparison, dBG plus BCNU at doses that were equitoxic to BCNU plus BG yielded tumor delays of 30, 19, 16, 21, and 22 days, respectively. The pancreatic tumors tested displayed functional mismatch repair that, however, may not be always sufficiently restrictive to prevent mutations under alkylation stress. Treatments with either BCNU or TMZ resulted in some degree of mutation in recurring tumors with the exception of CAPAN-2, the only wt-p53 xenograft. dBG, a weak MGMT inactivator in vitro as compared with BG, was markedly more effective than the latter in enhancing the efficacy of BCNU against pancreatic tumor xenografts. Both BG and dBG also enhanced the efficacy of TMZ against pancreatic tumors, possibly because of the repression of MGMT, which cannot be achieved with TMZ treatments alone. These results suggest that pancreatic tumors, which are resistant to DNA alkylating agents, may be sensitized to such agents when pretreated with MGMT inactivators.
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PMID:Sensitization of pancreatic tumor xenografts to carmustine and temozolomide by inactivation of their O6-Methylguanine-DNA methyltransferase with O6-benzylguanine or O6-benzyl-2'-deoxyguanosine. 1450 74

The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) removes mutagenic adducts from the O6 position of guanine, thereby protecting the genome against guanine : cytosine to adenine : thymine transition and, meanwhile, conferring tumor resistance to many anti-cancer alkylating agents commonly used in the treatment of malignant gliomas. Studies on the involvement of p53 protein in expression of the MGMT gene have provided conflicting results regarding the relation between p53 protein and MGMT gene expression. To examine the potential immunostaining pattern of MGMT expression and to evaluate the possible relationship between p53 and MGMT regulation, we assessed MGMT and p53 accumulation on 35 cases of diffusely infiltrating astrocytomas. With a few cases showing cytoplasmic staining, MGMT accumulation was mainly nuclear. The percentage of labeled tumor cells was lower in high-grade astrocytomas than in low-grade astrocytomas (P < 0.05). Additionally, p53-immunopositive tumor cells were usually immunonegative to MGMT. Thus, it is suggested that MGMT expression is reduced during malignant transformation of diffusely infiltrating astrocytomas, and that mutant p53 protein might be associated with down regulation of the MGMT expression.
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PMID:A comparative immunohistochemistry of O6-methylguanine-DNA methyltransferase and p53 in diffusely infiltrating astrocytomas. 1457 Feb 88

We present an oligonucleotide microarray ("MetaboChip") based on the arrayed primer extension (APEX) technique, allowing genotyping of single nucleotide polymorphisms (SNPs) in genes of interest for cancer susceptibility and pharmacogenetics. APEX consists of a sequencing reaction primed by an oligonucleotide anchored with its 5' end to a glass slide and terminating one nucleotide before the polymorphic site. The extension with one fluorescently labeled dideoxynucleotide complementary to the template reveals the polymorphism. Ninety-three SNPs in 42 genes were selected among those resequenced in the context of the SNP500 project, using a set of 102 reference DNA samples from the Coriell Biorepository. Selected SNPs belong to the following genes: ADH1B, ALDH2, APEX, CDKN2A, COMT, CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2C19, CYP2C9, CYP2E1, CYP3A4, DRD2, DRD4, EPHX1, ERCC1, ERCC2, ERCC4, ERCC5, GRPR, GSTA4, GSTM3, GSTP1, GSTT2, LIG3, MDM2, MGMT, MPO, NAT1, NAT2, NQO1, OGG1, PCNA, POLB, SLC6A3, SOD2, TP53, XRCC1, XRCC2, XRCC3, and XRCC9. We assessed the performance of APEX by comparing the results obtained with MetaboChip against those reported by the SNP500. Among 88 SNPs that yielded signals, 6 showed less than 99% of concordance, whereas 82 performed accurately, showing that APEX is a reliable and sensitive genotyping method.
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PMID:Evaluation of a microarray for genotyping polymorphisms related to xenobiotic metabolism and DNA repair. 1457 48

Various tumor-therapeutic drugs and environmental carcinogens alkylate DNA inducing O(6)-methylguanine (O(6)MeG) that provokes cell death by apoptosis. In rodent fibroblasts, apoptosis triggered by O(6)MeG is executed via the mitochondrial damage pathway. Conversion of O(6)MeG into critical downstream lesions requires mismatch repair (MMR). This is thought to signal apoptosis upon binding to O(6)MeG lesions mispaired with thymine. Alternatively, O(6)MeG lesions might be processed by MMR giving rise to DNA double-strand breaks (DSBs) during replication that finally provoke apoptosis. To test this, we examined apoptosis triggered by O(6)MeG in human peripheral lymphocytes in which O(6)-methylguanine-DNA methyltransferase (MGMT) had been inactivated by O(6)-benzylguanine (O(6)BG) and which were not proliferating or proliferating upon CD3/CD28 stimulation. Treatment with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) or the anticancer drug temozolomide induced apoptosis only in proliferating, but not resting cells. With exceptional high alkylation doses (>/=15 microM of MNNG), apoptosis was also observed in resting lymphocytes, albeit at a lower level than in proliferating cells. This response was not affected by O(6)BG, suggesting that replication-independent apoptosis at high dose levels is caused by lesions other than O(6)MeG. O(6)MeG-triggered apoptosis in proliferating lymphocytes was preceded by a wave of DSBs, which coincided with p53 and Fas receptor upregulation, while Fas ligand, Bax and Bcl-2 expression was not altered. Treatment with anti-Fas neutralizing antibody attenuated MNNG-induced apoptosis in MGMT-depleted proliferating lymphocytes. The data suggest that O(6)MeG is converted by MMR and DNA replication into DSBs that trigger apoptosis by p53 stabilization and Fas/CD95/Apo-1 upregulation. This is supported by the finding that ionizing radiation, inducing DSBs on its own, provokes apoptosis in lymphocytes in a replication-independent way. The strict proliferation dependence of apoptosis triggered by O(6)MeG may explain the specific killing response of MGMT-deficient proliferating cells, including tumors, to O(6)MeG generating anticancer drugs and suggests that tumor proliferation rate, Fas responsiveness, MGMT and MMR status are important prognosis parameters.
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PMID:Apoptosis triggered by DNA damage O6-methylguanine in human lymphocytes requires DNA replication and is mediated by p53 and Fas/CD95/Apo-1. 1472 64

DNA damage, if the repair process, especially nucleotide excision repair (NER), is compromised or the lesion is repaired by some other error-prone mechanism, causes mutation and ultimately contributes to neoplastic transformation. Impairment of components of the DNA damage response pathway (e.g., p53) is also implicated in carcinogenesis. We currently have considerable knowledge of the role of DNA repair genes as tumor suppressors, both clinically and experimentally. The deleterious clinical consequences of inherited defects in DNA repair system are apparent from several human cancer predisposition syndromes (e.g., NER-compromised xeroderma pigmentosum [XP] and p53-deficient Li-Fraumeni syndrome). However, experimental studies to support the clinical evidence are hampered by the lack of powerful animal models. Here, we review in vivo experimental data suggesting the protective function of DNA repair machinery in chemical carcinogenesis. We specifically focus on the three DNA repair genes, O(6)-methylguanine-DNA methyltransferase gene (MGMT ), XP group A gene (XPA) and p53. First, mice overexpressing MGMT display substantial resistance to nitrosamine-induced hepatocarcinogenesis. In addition, a reduction of spontaneous liver tumors and longer survival times were evident. However, there are no known mutations in the human MGMT and therefore no associated cancer syndrome. Secondly, XPA mutant mice are indeed prone to spontaneous and carcinogen-induced tumorigenesis in internal organs (which are not exposed to sunlight). The concomitant loss of p53 resulted in accelerated onset of carcinogenesis. Finally, p53 null mice are predisposed to brain tumors upon transplacental exposure to a carcinogen. Accumulated evidence in these three mutant mouse models firmly supports the notion that the DNA repair system is vital for protection against cancer.
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PMID:DNA repair and cancer: lessons from mutant mouse models. 1496 59

O6-methylguanine-DNA methyltransferase (MGMT) plays a major role in repairing DNA damage from alkylating agents. By removing alkyl groups from the O6-position in guanine, MGMT can prevent G:C to A:T transition mutations, a type of variation frequently involving TP53 mutations in brain tumors. Promoter hypermethylation of CpG islands in tumor-related genes can lead to their transcriptional inactivation, and this epigenetic mechanism has been shown to participate in MGMT silencing in some cancers, including those affecting the nervous system. Accordingly, a link between both genetic and epigenetic anomalies may exist in these neoplasms. To determine the relevance of defective MGMT function due to aberrant methylation in relation to the presence of TP53 mutations, we studied 469 nervous system tumors (including all major histological subtypes) for MGMT promoter methylation and TP53 mutations at exons 5-8. Overall, aberrant methylation occurred in 38% of the samples (180/469), with values higher than 50% in the more malignant forms such as glioblastomas and anaplastic gliomas including those with astrocytic, oligodendroglial and ependymal differentiation. In contrast, the non-glial tumors displayed an overall aberrant MGMT promoter methylation of 26%, even though this group includes highly malignant tumors such as neuroblastomas, medulloblastomas and brain metastases. Overall, TP53 mutations were found in 25% of the methylated MGMT tumors (45/180), whereas only 10% of the unmethylated MGMT tumors (30/289) showed TP53 changes (P < 0.001). G:C to A:T changes occurred at CpG sites in 9% of methylated tumors, and in 0.7% of the unmethylated samples. This type of transition at non-CpG dinucleotides was also more frequent in the tumors with aberrant MGMT methylation (5%) than the unmethylated tumors (0.7%). These data suggest that MGMT silencing as a result of promoter hypermethylation may lead to G:C to A:T transition mutations in the TP53 gene of some histological nervous system tumor subtypes.
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PMID:Hypermethylation of the DNA repair gene MGMT: association with TP53 G:C to A:T transitions in a series of 469 nervous system tumors. 1545 Apr 1

Epigenetic silencing of O(6)-methylguanine-DNA methyltransferase (MGMT) by promoter methylation can confer cancer cells with an increased sensitivity to alkylating chemotherapeutic agents and a higher susceptibility to TP53 transition mutations. The aim of our study was to assess the correlation of promoter methylation of the MGMT gene with TP53 mutations and the clinical characteristics of malignant astrocytomas. We analyzed the MGMT promoter methylation and TP53 mutations in 45 malignant astrocytomas (16 anaplastic astrocytomas and 29 glioblastomas multiforme) treated prospectively with 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-2(2-chloroethyl)-3-nitrosourea, interferon-beta and radiation therapy, and evaluated their clinical usefulness. MGMT promoter methylation was found in 17 (38%) of the 45 newly diagnosed malignant astrocytomas. A clear trend existed between MGMT methylation and G:C to A:T transition mutations of TP53 (p = 0.0596). Patients with MGMT-methylated tumors displayed a greater chance of responding to adjuvant therapy as compared with those with MGMT-unmethylated tumors (p = 0.0393). TP53 mutation was not significantly associated with the clinical response (p = 0.1310). While neither MGMT methylation nor TP53 mutation had a significant effect on prognosis of the whole population, the presence of MGMT methylation emerged as a significant predictor of a longer survival when exclusively analyzing 29 patients with glioblastomas multiforme. These findings highlight the importance of MGMT methylation as a specific predictive factor for responsiveness to nitrosourea chemotherapy.
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PMID:O6-methylguanine-DNA methyltransferase methylation and TP53 mutation in malignant astrocytomas and their relationships with clinical course. 1545 76

Despite a prolongation of patient survival, the overall response of doxorubicin (DX) treatment on patients with hepatocellular carcinoma (HCC) remains modest. This is largely attributed to the development of tumor drug resistance either at the onset or during the course of treatment. To investigate the genetic changes associated with DX chemo-resistance, we examined the cytotoxic effect of DX on a panel of 9 HCC cell lines (HepG2, Hep3B, PLC/PRF/5, and six in-house established, HKCI-1, 2, 3 and 4, C1 and C2). The karyotypic abnormalities were examined by spectral karyotyping (SKY) and the chromosome loci defined were investigated for underlying deregulated genes by positional expression profiling. Quantitative RT-PCR was employed to verify the profiling findings, and also used to examine a number of drug resistance-related candidate genes (MDR1, MRP1, MGMT, PTEN, BCL2, BAX, TP53 and P21). Our results indicated that the cytotoxic effect of DX in cell lines exhibited IC50 values that ranged from sensitive to resistant (0.07 to 3.55 microM). While the overall chromosome aneuploidy did not correlate with DX resistance, aberrations on chromosome 10 demonstrated significant correlation with increasing IC50 (p=0.007). Positional profiling further suggested the consistent down-regulation of CGI-18 and ECHS1 on chromosome 10q. The array findings were substantiated by quantitative RT-PCR, which further pointed to a repressed ECHS1 expression in correlation with DX resistance (p=0.021). Among the candidate genes studied, an inverse relationship of P21 (p=0.034) and BAX (p=0.002) expression with DX resistance was also indicated. Our present study highlights the usefulness of multimodality approaches in identifying genetic markers, and further describes the novel finding of ECHS1 down-regulation in the DX chemo-resistance of HCC.
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PMID:Genetic alterations in doxorubicin-resistant hepatocellular carcinoma cells: a combined study of spectral karyotyping, positional expression profiling and candidate genes. 1549 26

Gliomas of astrocytic, oligodendroglial and ependymal origin account for more than 70% of all brain tumors. The most frequent (65%) and most malignant histological type is the glioblastoma. Since the introduction of computerized tomography and magnetic resonance imaging, the incidence rates of brain tumors have been rather stable, with a tendency of higher rates in highly developed, industrialized countries. Some reports indicate that Caucasians have higher incidence than black or Asian populations, but to some extent, this may reflect socio-economic differences and under-ascertainment in some regions, rather than a significant difference in genetic susceptibility. With the exception of pilocytic astrocytomas, the prognosis of glioma patients is still poor. Less than 3% of glioblastoma patients are still alive at 5 years after diagnosis, higher age being the most significant predictor of poor outcome. Brain tumors are a component of several inherited tumor syndromes, but the prevalence of these syndromes is very low. Several occupations, environmental carcinogens, and diet (N-nitroso compounds) have been reported to be associated with an elevated glioma risk, but the only environmental factor unequivocally associated with an increased risk of brain tumors, including gliomas, is therapeutic X-irradiation. In particular, children treated with X-irradiation for acute lymphoblastic leukemia show a significantly elevated risk of developing gliomas and primitive neuroectodermal tumor (PNET), often within 10 years after therapy. TP53 mutations are frequent in low-grade gliomas and secondary glioblastomas derived therefrom. Approximately 60% of mutations are located in the hot spot codons 248 and 273, and the majority of these are G:C-->A:T transitions at CpG sites. TP53 mutations are significantly more frequent in low-grade astrocytomas with promoter methylation of the O(6)-methylguanine-DNA methyltransferase repair gene, suggesting that, in addition to deamination of 5-methylcytosine, exogenous or endogenous alkylation in the O(6) position of guanine may contribute to the formation of these mutations.
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PMID:Epidemiology and etiology of gliomas. 1568 39

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