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)

Gallbladder carcinomas are rare but highly lethal neoplasms. We examined the expression of five cell-cycle-related molecules (p53, RB, cyclin D1, p27, Ki-67), and MSH2, in 46 carcinomas, 14 adenomas, 15 low-grade dysplasias, 9 intestinal metaplasias and 20 normal gallbladder epithelia. The expression of these molecules was altered in gallbladder carcinomas and adenomas. In gallbladder carcinomas we observed increased expression of p53, cyclin D1, Ki-67, and MSH2 together with decreased expression of RB and p27 protein. Aberrant expression of cyclin D1 and reduced expression of RB were noted in adenomas, and expression of cyclin D1 was elevated in low-grade dysplasias. However, there was no change in the levels of these cell-cycle molecules in metaplasia. Expression of p53, p27, Ki-67, and MSH2 was correlated with clinical stage (P<0.05) and there was also a correlation between the expression of Ki-67 and MSH-2 and patient age (P<0.05). These results suggest that altered expression of cell-cycle molecules p53, cyclin D1, RB, p27, and of MSH-2 is involved in the progression of gallbladder carcinomas.
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PMID:An immunohistochemical study of the expression of cell-cycle-regulated proteins p53, cyclin D1, RB, p27, Ki67 and MSH2 in gallbladder carcinoma and its precursor lesions. 1557 23

Hypoxia promotes genetic instability by undefined mechanisms. The transcription factor HIF-1alpha is crucial for the cellular response to hypoxia and is frequently overexpressed in human cancers, resulting in the activation of genes essential for cell survival. Here, we demonstrate that HIF-1alpha is responsible for genetic instability at the nucleotide level by inhibiting MSH2 and MSH6, thereby decreasing levels of the MSH2-MSH6 complex, MutSalpha, which recognizes base mismatches. HIF-1alpha displaces the transcriptional activator Myc from Sp1 binding to repress MutSalpha expression in a p53-dependent manner; Sp1 serves as a molecular switch by recruiting HIF-1alpha to the gene promoter under hypoxia. Furthermore, in human sporadic colon cancers, HIF-1alpha overexpression is statistically associated with the loss of MSH2 expression, especially when p53 is immunochemically undetectable. These findings indicate that the regulation of DNA repair is an integral part of the hypoxic response, providing molecular insights into the mechanisms underlying hypoxia-induced genetic instability.
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PMID:HIF-1alpha induces genetic instability by transcriptionally downregulating MutSalpha expression. 1578 Sep 36

Under low oxygen tension, the activated transcription factor HIF-1alpha upregulates an array of hypoxia-inducible genes via heterodimerization with ARNT and binding to the hypoxia-responsive element in the promoter. Alternatively, HIF-1alpha regulates hypoxia-responsive genes by functionally antagonizing the oncoprotein Myc via protein-protein interactions. This so-called HIF-1alpha-Myc mechanism apparently not only accounts for the gene upregulation, but also for the gene downregulation during hypoxia, depending upon the activating and repressive nature of Myc in gene expression. Indeed, our recent study demonstrated that both mismatch repair genes, MSH2 and MSH6, are inhibited by this mechanism in a p53-dependent manner. In particular, the constitutively bound transcription factor Sp1 serves as a molecular switch by recruiting HIF-1alpha in hypoxia to displace the transcription activator Myc from the promoter. Therefore, our findings shed light on the mechanisms underlying hypoxia-induced genetic instability, an "adverse"effect of the hypoxic response, and yet a germane process to tumor survival and progression.
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PMID:Genetic instability: the dark side of the hypoxic response. 1597 Jul 7

The polymorphic variants at codon 72 of the p53 gene were shown to be functionally distinct in vitro, whereby the arginine (arg) variant induces apoptosis more efficiently than the proline (pro) variant. From the evidence that the DNA mismatch repair system and p53 interact to maintain genomic integrity, we hypothesized that the codon 72 variation may influence the age of onset of disease in HNPCC patients. We tested 538 patients for p53 codon 72 variants, including 167 unrelated patients with pathogenic germline mutations in MSH2 or MLH1 and colorectal carcinoma as first tumour, 126 patients with sporadic microsatellite stable colorectal cancers, and 245 healthy controls. The median age of onset was 41, 36, and 32 years for MSH2 or MLH1 mutation carriers with arg/arg, arg/pro, and pro/pro genotypes, respectively. The log rank test revealed significant differences in the age of onset between arg/arg and pro/pro individuals (p = 0.0002) and in arg/pro versus arg/arg and pro/pro individuals (p = 0.0026 and p = 0.0217, respectively). A Cox regression model indicated an additive mode of inheritance. No significant differences in age of onset were observed among different genotype carriers with microsatellite stable tumours. Our results suggest that p53 codon 72 genotypes are associated with the age of onset of colorectal carcinoma in a mismatch repair deficient background in a dose dependent manner. These findings may be relevant for preventive strategies in HNPCC.
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PMID:The p53 codon 72 variation is associated with the age of onset of hereditary non-polyposis colorectal cancer (HNPCC). 1619 49

The p53 protein has been implicated in multiple cellular responses related to DNA damage. Alterations in any of these cellular responses could be related to increased genomic instability. Our previous study has shown that mutations in p53 lead to hypermutability to ionizing radiation. To investigate further how p53 is involved in regulating mutational processes, we used 8K cDNA microarrays to compare the patterns of gene expression among three closely related human cell lines with different p53 status including TK6 (wild-type p53), NH32 (p53-null), and WTK1 (mutant p53). Total RNA samples were collected at 1, 3, 6, 9, and 24 h after 10 Gy gamma-irradiation. Template-based clustering analysis of the gene expression over the time course showed that 464 genes are either up or downregulated by at least twofold following radiation treatment. In addition, cluster analyses of gene expression profiles among these three cell lines revealed distinct patterns. In TK6, 165 genes were upregulated, while 36 genes were downregulated. In contrast, in WTK1 75 genes were upregulated and 12 genes were downregulated. In NH32, only 54 genes were upregulated. Furthermore, we found several genes associated with DNA repair namely p53R2, DDB2, XPC, PCNA, BTG2, and MSH2 that were highly induced in TK6 compared to WTK1 and NH32. p53R2, which is regulated by the tumor suppressor p53, is a small subunit of ribonucleotide reductase. To determine whether it is involved in radiation-induced mutagenesis, p53R2 protein was inhibited by siRNA in TK6 cells and followed by 2 Gy radiation. The background mutation frequencies at the TK locus of siRNA-transfected TK6 cells were about three times higher than those seen in TK6 cells. The mutation frequencies of siRNA-transfected TK6 cells after 2 Gy radiation were significantly higher than the irradiated TK6 cells without p53R2 knock down. These results indicate that p53R2 was induced by p53 protein and is involved in protecting against radiation-induced mutagenesis.
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PMID:Transcriptional responses to ionizing radiation reveal that p53R2 protects against radiation-induced mutagenesis in human lymphoblastoid cells. 1624 78

In order to investigate the mechanism of acute lymphoblastic leukemic cell malignant proliferation, the expressions of hMSH2 mRNA and mutation P53 (mtP53) protein in bone marrow cells of de novo acute lymphoblastic leukemia (ALL) were determined by in situ hybridization and immunocytochemical methods. The results showed the that percentage of positive cell with hMSH2 mRNA expression was (32.88 +/- 11.46)% in the de novo ALL group and (64.22 +/- 8.51)% in the control group. The percentage of positive cell with mtP53 protein expression was (29.25 +/- 9.45)% in the de novo ALL group, and (12.63 +/- 6.66)% in the control group. There was a significant negative correlation between the positive percentages of hMSH2 mRNA expression and mtP53 protein expression (r = -0.45, P < 0.05). It is concluded that defective MSH2 mRNA expression plays an important role in the pathogenesis of acute lymphoblastic leukemia, mtP53 protein mutation plays an important role in the development of acute lymphoblastic leukemia, the hMSH2 mRNA defect can lead to accumulation of the mutant P53 protein in acute lymphoblastic leukemia, and both jointly promote the pathogenesis of ALL.
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PMID:[Abnormal expression of hMSH2 mRNA and mutation P53 protein in acute lymphoblastic leukemia]. 1640 56

Gene targeting provides a powerful means for analyzing gene function, as exemplified by knockout mouse studies and recent work with the highly recombinogenic chicken DT40 B-lymphocyte line. In human cultured cells, however, the low frequency of gene targeting is a serious barrier to efficiently generate knockout clones. Moreover, commonly used human cell lines are karyotypically abnormal or unstable. Here, we show using promoterless targeting constructs that Nalm-6, a human pre-B ALL cell line, is highly proficient for gene targeting by homologous recombination. Indeed, the efficiency of TP53 gene targeting in Nalm-6 appears nearly two orders of magnitude higher than that in HCT116, a colon cancer cell line popularly used for gene targeting. Expression analysis revealed a lack of MSH2 expression in this cell line. As Nalm-6 has a stable neardiploid karyotype with normal p53 status, our results underscore the usefulness of Nalm-6 for gene knockout studies in humans.
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PMID:The human pre-B cell line Nalm-6 is highly proficient in gene targeting by homologous recombination. 1640 97

Clear cell adenocarcinoma (CCA) of the endometrium has a poor prognosis, although the biologic features of this rare tumor are not clear. In this study, we analyzed the expression of biologic markers relating to carcinogenesis, tumor growth, and progression. Thirteen cases of CCA were compared with cases of endometrioid adenocarcinoma (EMA) of the endometrium. Immunohistochemical staining for p53; Ki-67; cyclins A, D1, and E; E-cadherin; progesterone receptor (PR)-A and PR-B; P-glycoprotein; MLH1; and MSH2 was performed. Labeling indices of p53, Ki-67, and cyclins A, D1, and E in CCA were 46.4 +/- 24.3%, 52.1 +/- 20.5%, 37.9 +/- 21.4%, 12.3 +/- 27.9%, and 8.2 +/- 22.9%, respectively. E-cadherin was expressed in only 1 case (7.7%) of CCA, as compared to 39 cases (61.0%) of EMA. No CCAs were positive for PR-A and PR-B. P-glycoprotein was detected in seven cases (53.8%). Loss of either MLH1 or MSH2 expression occurred in eight cases (61.5%). High-level expression of p53, cyclin A, and P-glycoprotein, and low-level or no expression of cyclin E, E-cadherin, PR-A, and PR-B was observed in CCA compared with EMA. The mechanism of cell-cycle regulation in endometrial CCA is different from that in EMA and may influence its malignant potential. Endometrial CCA is a distinct entity from EMA.
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PMID:Clear cell adenocarcinoma of the endometrium is a biologically distinct entity from endometrioid adenocarcinoma. 1644 64

Human tumor suppressor p53 is a sequence-specific master regulatory transcription factor that targets response elements (REs) in many genes. p53 missense mutations in the DNA-binding domain are often cancer associated. As shown with systems based on the yeast Saccharomyces cerevisiae, p53 mutants can alter the spectra and intensities of transactivation from individual REs. We address directly in human cells the relationship between changes in the p53 master regulatory network and biological outcomes. Expression of integrated, tightly regulated DNA-binding domain p53 mutants resulted in many patterns of apoptosis and survival following UV or ionizing radiation, or spontaneously. These patterns reflected changes in the spectra and activities of target genes, as demonstrated for P21, MDM2, BAX, and MSH2. Thus, as originally proposed for "master genes of diversity," p53 mutations in human cells can differentially influence target gene transactivation, resulting in a variety of biological consequences which, in turn, might be expected to influence tumor development and therapeutic efficacy.
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PMID:The biological impact of the human master regulator p53 can be altered by mutations that change the spectrum and expression of its target genes. 1650 5

Pancreatic cancer is fundamentally a disease of inherited and acquired mutations in cancer-related genes. The genes targeted in pancreatic cancer include tumor-suppressor genes (p16/CDKN2A, TP53 and SMAD4), oncogenes (KRAS, BRAF, AKT2, MYB, and AIB1), and genome-maintenance genes (MLH1, MSH2, BRAC2 and other Fanconi anemia genes). An understanding of the cancer-related genes that are altered in pancreatic cancer has a number of clinical applications including genetic counseling for individuals with a family history of cancer, early detection of pancreatic neoplasia, and mechanism-based therapies for patients with advanced disease. This chapter will provide an overview of the molecular pathogenesis of pancreatic cancer with emphasis on clinical applications.
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PMID:Molecular pathogenesis of pancreatic cancer. 1654 25


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