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)

We assessed the possible association between CagA+ Helicobacter pylori infection and gastric carcinogenesis in gastric cancer patients. Gastric biopsy specimens were obtained from 64 patients with gastric cancer and were histologically classified into intestinal and diffuse types. H. pylori infection was determined by cultivation, flaA-PCR and serum antibody against CagA. p53, BAX and transforming growth factor-beta-RII (TGFbeta-RII) gene mutations were analyzed by PCR-SSCP and direct sequencing. Intestinal and diffuse types of cancer were detected in 45 and 19 patients, respectively. H. pylori infection was found in 55 (85.9%) of 64 patients. There was no significant difference in H. pylori positivity between intestinal and diffuse types. However, the CagA antibody was positive in 15 (78.9%) of 19 patients with the diffuse type and in 22 (48.9%) of 45 patients with the intestinal type (p = 0.030). Among the 55 H. pylori-positive cases, 11 (29.7%) of the 37 patients in the CagA+ group were found to have p53 alterations, compared with 2 (11.1%) in the 18 CagA- group (p = 0.182). Moreover, among the 64 gastric cancer patients, p53 alterations were more frequently found in the CagA+ group (29.7%) than in the H. pylori-positive CagA- and H. pylori-negative groups (7.4%; p = 0.033). BAX gene mutations were found in 19 (29.7%) of 64 patients and there was no relationship among CagA seropositivity, cancer stages and histopathological phenotypes. In contrast, the TGFbeta-RII gene mutation was only detected in one CagA- patient. The results suggest that CagA+ H. pylori infection may have an important role in the development of gastric cancer patients with p53 mutations
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PMID:Association between CagA+ Helicobacter pylori infection and p53, bax and transforming growth factor-beta-RII gene mutations in gastric cancer patients. 1125 69

An important regulator of the proapoptotic BAX is the tumor suppressor protein p53. Unlike the p21 gene, in which p53-dependent transcriptional activation is mediated by a response element containing two consensus p53 half-sites, it previously was reported that activation of the BAX element by p53 requires additional sequences. Here, it is demonstrated that the minimal BAX response element capable of mediating p53-dependent transcriptional activation consists of two p53 half-sites plus an adjacent 6 base pairs (5'-GGGCGT-3'). This GC-rich region constitutes a "GC box" capable both of binding members of the Sp family of transcription factors, including Sp1 in vitro, and of conferring Sp1-dependent transcriptional activation on a minimal promoter in cells. Mutations within this GC box abrogated the ability of p53 to activate transcription without affecting the affinity of p53 for its binding site, demonstrating that these 6 bases are required for p53-dependent activation. In addition, a positive correlation was observed between the ability of p53 to activate transcription in cells and the ability of Sp1 to bind this response element in vitro. Mutations that inhibited Sp1 binding also blocked the ability of p53 to activate transcription through this element. Together, these results suggest a model in which p53 requires the cooperation of Sp1 or a Sp1-like factor to mediate transcriptional activation of the human BAX promoter.
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PMID:The tumor suppressor protein p53 requires a cofactor to activate transcriptionally the human BAX promoter. 1127 53

The tumor suppressor protein p53 is essential for neuronal death in several experimental settings and may participate in human neurodegenerative disorders. Based upon recent studies characterizing chemical inhibitors of p53 in preclinical studies in the cancer therapy field, we synthesized the compound pifithrin-alpha and evaluated its potential neuroprotective properties in experimental models relevant to the pathogenesis of stroke and neurodegenerative disorders. Pifithrin-alpha protected neurons against apoptosis induced by DNA-damaging agents, amyloid beta-peptide and glutamate. Protection by pifithrin-alpha was correlated with decreased p53 DNA-binding activity, decreased expression of the p53 target gene BAX and suppression of mitochondrial dysfunction and caspase activation. Mice given pifithrin-alpha exhibited increased resistance of cortical and striatal neurons to focal ischemic injury and of hippocampal neurons to excitotoxic damage. These preclinical studies demonstrate the efficacy of a p53 inhibitor in models of stroke and neurodegenerative disorders, and suggest that drugs that inhibit p53 may reduce the extent of brain damage in related human neurodegenerative conditions.
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PMID:A synthetic inhibitor of p53 protects neurons against death induced by ischemic and excitotoxic insults, and amyloid beta-peptide. 1127 78

Human malignant gliomas are highly lethal neoplasms. Involved-field radiotherapy is the most important therapeutic measure. Most relapses originate from the close vicinity of the irradiated target field. Here, we report that sublethal doses of irradiation enhance the migration and invasiveness of human malignant glioma cells. This hitherto unknown biological effect of irradiation is p53 independent, involves enhanced alphavbeta3 integrin expression, an altered profile of matrix metalloproteinase-2 and matrix metalloproteinase-9 (MMP-2 and MMP-9) expression and activity, altered membrane type 1 MMP and tissue inhibitor of metalloproteinases-2 expression, and an altered BCL-2/BAX rheostat favoring resistance to apoptosis. BCL-2 gene transfer and irradiation cooperate to enhance migration and invasiveness in a synergistic manner. Sublethal irradiation of rat 9L glioma cells results in the formation of a greater number of tumor satellites in the rat brain in vivo concomitant with enhanced MMP-2 and reduced tissue inhibitor of metalloproteinases-2 expression. Collectively, these data suggest that the current concepts of involved-field radiotherapy for malignant glioma need to be reconsidered and that the pharmacological inhibition of migration and invasion during radiotherapy may represent a new therapeutic approach to improve the therapeutic efficacy of radiotherapy for malignant glioma.
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PMID:Sublethal irradiation promotes migration and invasiveness of glioma cells: implications for radiotherapy of human glioblastoma. 1128 57

Some studies have shown an inverse relationship between microsatellite instability in colon cancer and mutations in p53 and K-ras, whereas others have not. We therefore evaluated these features in a population-based sample of 496 individuals with colon cancer. Microsatellite instability was determined by a panel of 10 tetranucleotide repeats, the Bethesda consensus panel of mono- and dinucleotide repeats, and coding mononucleotide repeats in transforming growth factor-beta receptor type II, hMSH3, BAX, hMSH6, and insulin-like growth factor receptor type II. Mutations in codons 12 and 13 in K-ras were evaluated by sequencing. p53 overexpression (as detected by immunohistochemistry) was used as an indicator of p53 mutation; this was evaluated in 275 of the tumors. K-ras mutations were present in 33.2% of tumors, p53 overexpression in 51.5%, and microsatellite instability (as determined by the Bethesda consensus panel) in 12.5%. K-ras mutations were significantly less common in unstable tumors than stable tumors (11.8% versus 36.9%, P: < 0.001). p53 overexpression was significantly less common in unstable tumors than stable tumors (20.0% versus 55.7%, P: < 0.001). These inverse relationships between microsatellite instability and ras gene mutations and p53 overexpression were shown to be independent of tumor site in logistic regression analyses. All other measures of instability also showed statistically significant inverse relationships independent of tumor site with alterations in ras and p53, and instability results determined by the panel of 10 tetranucleotide repeats were highly significantly related to those determined by the Bethesda consensus panel. Coding mononucleotide repeat mutations were significantly more common in unstable tumors than stable tumors (85.7% versus 1.0%, P: < 0.001). We conclude that there is an inverse relationship between microsatellite instability and mutations in p53 and K-ras, and that the molecular profile of colon cancers with microsatellite instability is characterized by relatively infrequent mutations in K-ras and p53 and relatively frequent mutations in coding mononucleotide repeats.
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PMID:Inverse relationship between microsatellite instability and K-ras and p53 gene alterations in colon cancer. 1129 May 69

Glioma cell lines show variable responses to radiation in a manner influenced by their p53 status. Irradiation of glioma cell lines does not generally induce apoptosis. When wild-type p53 is present, these cells undergo a G1 arrest that is closely associated with increased radiosensitivity as measured by clonogenic survival. Previously, others have shown that dysregulated overexpression of E2F1 induces apoptosis in cell lines with either functional or inactivated p53. We found that regardless of p53 status, apoptosis induced by overexpression of E2F1 in glioma cell lines was further enhanced by treatment with ionizing radiation. BAX induction did not follow E2F1 overexpression or irradiation in the glioma cell lines tested. Thus, the apoptotic response of glioma-derived cells to irradiation can be enhanced by E2F1 by a mechanism that does not involve the induction of BAX.
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PMID:Overexpression of E2F1 in glioma-derived cell lines induces a p53-independent apoptosis that is further enhanced by ionizing radiation. 1130 49

The incidences of microsatellite instability (MSI) and underlying DNA mismatch repair (MMR) defects in pancreatic carcinogenesis have not been well established. We analyzed 100 sporadic and 3 hereditary pancreatic ductal adenocarcinomas for MSI, and high-frequency MSI (MSI-H) and low-frequency MSI (MSI-L) tumors were further analyzed for frameshift mutations of possible target genes and for promoter methylation and mutation of DNA MMR genes, including hMLH1, hMSH2, hMSH3, and hMSH6 genes. Among the 100 sporadic tumors, 13 (13%) were MSI-H, 13 (13%) were MSI-L, and 74 (74%) were microsatellite stable (MSS) tumors. All of the three hereditary tumors from hereditary nonpolyposis colorectal cancer (HNPCC) patients were MSI-H. MSI-H tumors were significantly associated with poor differentiation and the presence of wild-type K-RAS and p53 genes. Patients with MSI-H tumors had a significantly longer overall survival time than did those with MSI-L or MSS tumors (P = 0.0057). Frameshift mutations of hMSH3, hMLH3, BRCA-2, TGF-beta type II receptor, and BAX genes were detected in MSI-H tumors. Hypermethylation of the hMLH1 promoter was observed in 6 (46%) of the 13 sporadic MSI-H tumors but not in any of the 3 hereditary MSI-H tumors or 13 MSI-L tumors. All of the 3 HNPCC cases had germ-line hMLH1 mutation accompanied by loss of heterogeneity or other mutation in the tumor. Our results suggest that pancreatic carcinomas with MSI-H represent a distinctive oncogenic pathway because they exhibit peculiar clinical, pathological, and molecular characteristics. Our results also suggest the principal involvement of epigenetic or genetic inactivation of the hMLH1 gene in the pathogenesis of pancreatic carcinoma with MSI-H.
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PMID:Genetic and clinical features of human pancreatic ductal adenocarcinomas with widespread microsatellite instability. 1130 99

Therapeutic approaches which are effective in tumour cells resistant to conventional chemotherapy would be of value. An E1B 55 kDa-deleted adenovirus (ONYX-015) induces lysis in cells with mutant p53, although the specificity of these observations for different cell types is unclear. We have used a matched set of drug-resistant human ovarian tumour cell lines to examine the potential of ONYX-015 for preferential replication and lysis of drug-resistant ovarian tumour cells with documented alterations in p53 function. Marked preferential replication of ONYX-015 is observed after infection of mutant p53 transfectant and cisplatin-resistant derivatives, compared to the wild-type p53 expressing parental A2780 line. Infection causes increased cytopathic effects in vitro and inhibition of tumour growth in vivo of the drug-resistant derivatives, but not the parental line. In apparent contrast, increased apoptosis and reduced clonogenic survival is induced by ONYX-015 infection of the chemosensitive parental cell line. ONYX-015 induces increased pro-apoptotic BAX and reduced anti-apoptotic BCLX(L) in parental cells, but not in the resistant derivative A2780/cp70. We propose that induction of apoptosis is one factor which prevents ONYX-015 spread and cytolysis after infection of chemosensitive cells, while it is the failure to engage apoptosis in drug-resistant cells that allows preferential viral replication, spread and cytolysis.
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PMID:Replication and cytolysis of an E1B-attenuated adenovirus in drug-resistant ovarian tumour cells is associated with reduced apoptosis. 1131 13

We examined the effects of cathepsin inhibitor 1 (CATI-1), a selective inhibitor of cysteine cathepsins, on human leukemia and lymphoma cells. CATI-1 induced apoptosis in all 12 cell lines tested. Apoptosis of CATI-1-treated leukemia/lymphoma cells was caspase-independent, p53-independent, BAX-independent as well as MAP kinase-independent. Our findings provide unprecedented experimental evidence that cathepsins play a pivotal role for the survival of human leukemia/lymphoma cells. Therefore, cathepsin inhibitors may provide the basis for new treatment programs against leukemia and lymphoma.
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PMID:Cathepsin inhibition induces apoptotic death in human leukemia and lymphoma cells. 1134 15

The purpose of our study was to determine the expression of the pro-apoptotic BAX protein in relation to the mutational status of BAX and p53 (as transcriptional activator of the BAX gene) in benign and malignant thyroid tissue. In 47 patients with thyroid tumours (14 follicular and 3 papillary carcinomas, 14 adenomas and 16 goitres), the DNA was screened for mutations of BAX (exon 1-6) and p53 (exon 5-8) by single-strand conformation polymorphism polymerase chain reaction (SSCP-PCR). Furthermore, the protein expression of BAX, p53 and p21 (which is also increased transcriptionally by p53) was investigated by immunohistochemistry. Surprisingly, we observed elevated BAX levels in patients with thyroid carcinomas compared with patients with adenomas (unpaired t-test: p<0.05) or with goitres (p<0.02). This is in clear contrast to other carcinomas where BAX is frequently inactivated which correlates to a poor prognosis (Sturm et al. J. Clin. Oncol. 1999;17:1364-74.). There were no significant differences of the BAX levels between goitres or the adenomas. In the SSCP-PCR analysis, no BAX mutations were detectable. P53 mutation analysis by SSCP-PCR did not reveal any functional p53 mutations in the patients with carcinomas, adenomas or goitres. Nevertheless, patients with carcinomas showed an overexpression (preferentially cytoplasmic) of p53 protein compared with patients with benign tumours (p<0.05). The absence of p53 mutations suggests that the overexpressed p53 is wild type. This is in line with the expression profile of BAX and p21, which showed a higher protein expression in these p53 positive tumours (p<0.05 in the carcinomas compared with the non-malignant lesions). Consequently, the overexpressed p53 might be a correlate for dysregulation without loss of function. This, in turn, might be a reason for the good outcome of some patients with thyroid cancer.
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PMID:Bax expression in benign and malignant thyroid tumours: dysregulation of wild-type P53 is associated with a high Bax and P21 expression in thyroid carcinoma. 1135 Dec 99


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