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)

Cytogenetic alterations that characterize different histologic subtypes of soft tissue sarcomas have been identified. In a few situations, more precise chromosomal mapping has allowed identification of certain genes that may be involved in the development or tumor progression of sarcomas. Careful family histories must be elicited in sarcoma patients. While "cancer families" are rarely identified when screening close relatives of sarcoma patients, the discovery of the currently known tumor suppressor gene syndromes associated with germ line retinoblastoma gene and p53 gene defects were made possible by their association with sarcomas. Optimal management of primary sarcomas includes function-sparing complete resection and radiotherapy. Innovative radiotherapy, utilizing radiation sensitizers or brachytherapy, may increase local control in patients with unresectable tumors. New drugs are needed. Epirubicin and other anthracycline analogues do have significant activity; however, no other novel drugs have documented efficacy. Dose intensity is being explored with sarcoma trials providing the "vehicle" to evaluate new cytokines. Several mechanisms of doxorubicin resistance have been identified in cell lines and fresh tumors, including alterations in glutathione peroxidase activity and MDR-1 gene expression. These observations need to be taken to the clinic.
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PMID:Advances in the diagnosis and management of sarcomas. 151 Oct 24

Expression of mdr1 and p53 was assessed on 119 cases of bronchial carcinomas, and compared with clinical chemoresistance. mdr1 expression was evaluated by immunohistochemistry (IHC), using the monoclonal antibody JSB1. The study of p53 expression was performed by both IHC, using six different antibodies, and Northern blotting. We observed a correlation between the expression of mdr1 and the presence of a mutation of p53 in neuro endocrine (NE) carcinomas (P = 0.02). Correlation was not observed when non NE carcinomas were evaluated, nor was found any correlation between mdr1 expression and clinical chemoresistance in patients with small cell lung carcinoma (SCLC). The frequency of complete response however was significantly higher in patients whose tumor did no express mdr1 (P = 0.02). Chemoresistance correlated well with the phenotype of p53 mutant in SCC (P = 0.015). We conclude that p53 mutation is a better predictive factor of clinical chemoresistance in SCLC than mdr1 IHC detection.
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PMID:[Respective roles of the products of the mdr1 and p53 genes in drug resistance of bronchial cancers]. 772 71

P glycoprotein, the product of multidrug resistance (mdr1) gene, is frequently expressed in advanced myelodysplastic syndromes (MDS) with an excess of bone marrow blasts and could explain their frequent resistance to chemotherapy. P53 gene mutations are also found in 10 to 15% of advanced MDS. Because it has recently been suggested that normal p53 suppressed, but that mutated p53 activated, the mdr1 gene promoter, we tried to correlate p53 mutations and P glycoprotein expression in 34 patients with MDS and an excess of bone marrow blasts (> 5%). P glycoprotein expression was assessed by immunocytochemistry using JSB1 monoclonal antibody and was found positive in 13 out of the 34 patients. p53 mutations were detected both by immunocytochemistry using three different monoclonal antibodies and by single stranded conformation polymorphism (SSCP) analysis of exons 5 to 8 of the P53 gene. Both methods detected a point mutation in 5 out of the 34 patients. Only one out of the 5 patients with a p53 mutation expressed P glycoprotein, as compared to 12 out of the 29 patients without p53 mutations. This suggested the mutant and normal p53 are not major determinants of the regulation of mdr1 expression in vivo, at least in MDS.
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PMID:Relationship between p53 gene mutations and multidrug resistance (mdr1) gene expression in myelodysplastic syndromes. 790 57

The overexpression of P-glycoprotein is thought to be responsible for resistance to chemotherapy in some non-responsive cancers. The mechanism by which P-glycoprotein is overexpressed in human tumors is poorly understood. However, several lines of evidence suggest that the major regulatory mechanism of P-glycoprotein overexpression in human tumors is at the transcriptional level. During tumor progression one of the most commonly observed alterations is mutation of the p53 tumor-suppressor gene. It has been shown that the p53 protein plays a role in transcriptional regulation. To gain insight into the effect p53 protein may have on P-glycoprotein promoter activity, we transiently co-transfected plasmids containing the hamster pgp1 or human mdr1 promoter linked to the chloramphenicol acetyltransferase (CAT) reporter gene with plasmids encoding either wild-type or mutant p53 protein into Chinese hamster ovary (CHO) cells. In this report, we show that wild-type p53 protein represses P-glycoprotein promoter activity, while mutant forms of p53 protein enhance P-glycoprotein promoter activity. Furthermore, we present data which indicate that the transcriptional regulatory effects of p53 are mediated through interactions with pgp1/mdr1 core promoter sequences. These findings have implications for our understanding of the molecular mechanism(s) by which p53 protein functions as a transcriptional regulator of gene expression. In addition, our results suggest a mechanism by which P-glycoprotein may be overexpressed in human cancers that also express mutant forms of p53 protein.
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PMID:The core promoter region of the P-glycoprotein gene is sufficient to confer differential responsiveness to wild-type and mutant p53. 850 78

The ability of ras oncogenes and mutant p53 to activate reporter gene expression from human and rodent mdr1 gene promoters was described, although functional significance of this finding was unclear. We analyzed the influence of various forms of recombinant human ras and p53 on the mdr1 gene expression and P-glycoprotein (Pgp) function in rodent immortalized fibroblasts. The ras genes, in addition to activation of exogenous human mdr1 gene promoter, caused an increase in (i) expression of endogenous mdr1 mRNA, (ii) Pgp activity as determined by flow cytometry analysis of Rhodamine 123 exclusion, and (iii) resistance of cells to the cytotoxic action of colchicine and some other drugs. To elucidate whether the same signalling pathway is responsible for multidrug resistance induced by various oncogenes and protein kinase C (PKC), we tested the effects of v-mos and the PKC agonist 12-O-tetradecanoylphorbol-13-acetate. Similarly to cells transformed by ras, a Rat1 subline transformed by the v-mos oncogene was characterized by decreased drug sensitivity. On the contrary, Rat1 cells treated with the protein kinase C agonist 12-O-tetradecanoylphorbol-13-acetate showed neither increased mdr1 mRNA expression nor stimulation of Pgp function. Introduction by retrovirus-mediated gene transfer of wild-type p53 into Rat1 cells or into murine p53-deficient 10(1) and 10(3) cells did not change the Pgp function significantly, whereas in Rat1 cells transformed by activated N-ras or v-mos, expression of wild-type p53 caused partial reversion of oncogene-induced drug resistance.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Influence of exogenous ras and p53 on P-glycoprotein function in immortalized rodent fibroblasts. 852 64

We investigated whether the expression of protein kinase C (PKC) isoenzymes, topoisomerase II alpha, II beta, multidrug resistance associated protein (MRP), p53 or the activity of glutathione-S- transferase (GST) are additional factors contributing to the resistance mediated by multidrug resistance gene 1 (mdr 1). the cell lines employed for these studies were human lymphoblastoid CCRF cells selected for resistance with actinomycin D, vincristine and adriamycin, KB-3-1 and matched resistant KB-8-5 and KB-C1 cells (selected with colchicine), and a HeLa cell line, in which the resistance was obtained by transfection with the mdr1-gene. Analysis of PKC isozymes showed that there is no correlation of a specific isoenzyme with resistance, although minor differences in the expression were observed. In vincristine and adriamycin selected cells, topoisomerase II alpha- and II beta-MRNA levels were reduced, and in vincristine selected cells the MRP-mRNA was elevated compared with the sensitive line. In KB cells the levels of topoisomerase II alpha and II beta mRNA were increasing with the resistance. Expression of p53 did not correlate with Pgp levels. In summary, MRP and topoisomerase II may contribute to the mdr1 -mediated resistance in some cell lines, but PKC, p53 and GST seem to be of minor or no importance.
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PMID:Protein kinase C isoenzymes, p53, accumulation of rhodamine 123, glutathione-S-transferase, topoisomerase II and MRP in multidrug resistant cell lines. 861 23

A role for p53 in the regulation of multidrug-resistance (MDR) has been postulated as wild-type p53 suppresses and mutant p53 specifically activates the mdr1 promoter. Moreover, changes in p53 expression and/or functions could be implicated in drug resistance. As the parental lymphoblastic CCRF-CEM cell line has been described as expressing a mutated form of p53, we have examined p53 and mdm2 protein levels in the human multidrug-resistant CEM-VLB cell line variant. These drug-resistant CEM-VLB cells, which have increased expressions of mdr1 and P-glycoprotein, displayed p53 and mdm2 protein expressions similar to those observed in their sensitive CCRF-CEM counterparts. Treatment of these drug-resistant cells with non-toxic doses of the resistance-inducing drug vinblastin induced a strong increase in p53 protein and mRNA but was ineffective on mdm2 protein expression, or mdr1 mRNA expression. These data indicate that mutant p53 protein was not overexpressed in these MDR cells. This overexpression could be induced by microtubule-active drug treatment, but, as previously observed in other sensitive cell lines, mutant p53 from these MDR cells was unable to positively regulate mdm2 gene product expression.
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PMID:P53 protein expression in human multidrug-resistant CEM lymphoblasts. 911 32

Multidrug resistance of cancer (CA) is one of a major problems in CA chemotherapy that is frequently associated with the expression of P-glycoprotein (P-gp) encoded by mdr1 genes. However, the controversial results exist regarding to the significance of mdr1 gene expression on clinical drug resistance to chemotherapy of breast CA cells. Recent evidence reported a strong correlation between the increased P-gp levels and the prognosis in advanced breast CA. The current study investigated whether mdr1 gene expression has any impact on prognosis and response to chemotherapy in breast CA patients. We determined mdr1 expression in 127 primary and 8 locally relapsed breast CA using a sensitive, specific and quantitative technique based on a RT-PCR and Southern blot hybridization detection by non-radioactive labelled-probe. In patients with primary breast CA, mdr1 expression were negative (mdr1-ve), low (< 10 units), high (> or = 10 units) in 63.8, 8.7 and 27.5 per cent of the patients, respectively. No differences in age, menopause status, tumor size, stage, lymph node involvement, estrogen receptor level and p53 level were observed between mdr1-ve and mdr1+ve expression patients. However, mdr1 gene expression is often associated with number of positive lymph nodes and negative estrogen receptors (p = 0.008 and 0.0007, respectively). In locally relapsed cases, mdr1-ve was 62.5 per cent whereas 37.5 per cent were mdr1+ve with high level of mdr1 RNA. No differences in other prognostic factors: lymph nodal involvement, estrogen receptor level and p53 level, were detected in both groups. Response to chemotherapy in primary and recurrent breast CA was not different in mdr1-ve and mdr1+ve patients. Finally, our results show that mdr1 gene expression is frequently present in breast CA both before and after chemotherapy. Association of mdr1 gene overexpression with other two prognostic factors suggests that they may confer a more aggressive nature of the tumor, drug resistance and poor prognosis. Evaluation of these factors may improve the ability to identify and select breast CA patients at high risk for poor prognosis for aggressive treatment. However, in this series response to CMF chemotherapy of primary and locally recurrent breast CA were not affected by the presence or absence of mdr1 gene product.
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PMID:Association of mdr1 gene expression with other prognostic factors and clinical outcome in human breast cancer. 934 65

Loss of functional p53 paradoxically results in either increased or decreased resistance to chemotherapeutic drugs. The inconsistent relationship between p53 status and drug sensitivity may reflect p53's selective regulation of genes important to cytotoxic response of chemotherapeutic agents. We reasoned that the discrepant effects of p53 on chemotherapeutic cytotoxicity is due to p53-dependent regulation of the multidrug resistance gene (MDR1) expression in tumors that normally express MDR1. To test the hypothesis that wild-type p53 regulates the endogenous mdr1 gene we stably introduced a trans-dominant negative (TDN) p53 into rodent H35 hepatoma cells that express P-glycoprotein (Pgp) and have wild-type p53. Levels of Pgp and mdr1a mRNA were markedly elevated in cells expressing TDN p53 and were linked to impaired p53 function (both transactivation and transrepression) in these cells. Enhanced mdr1a gene expression in the TDN p53 cells was not secondary to mdr1 gene amplification and Pgp was functional as demonstrated by the decreased uptake of vinblastine. Cytotoxicity assays revealed that the TDN p53 cell lines were selectively insensitive to Pgp substrates. Sensitivity was restored by the Pgp inhibitor reserpine, demonstrating that only drug retention was the basis for loss of drug sensitivity. Similar findings were evident in human LS180 colon carcinoma cells engineered to overexpress TDN p53. Therefore, the p53 inactivation seen in cancers likely leads to selective resistance to chemotherapeutic agents because of up-regulation of MDR1 expression.
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PMID:p53-dependent regulation of MDR1 gene expression causes selective resistance to chemotherapeutic agents. 938 Jul 55

Several oncoproteins or tumor suppressor gene products have been indicated to be of value as predictors of the de novo resistance to cytotoxic agents. In this study, we have investigated the role of MDM2 (murine double minutes) overexpression in doxorubicin resistance of breast cancer. Immunocytochemical analysis demonstrated that MDM2-positive tumors, even with p53-negative phenotype, were significantly more resistant to doxorubicin treatment compared to MDM2-negative tumors. An in vitro experimental model using stable mdm2-transfected MCF-7 cells carrying wild-type p53 confirmed that the cells become approximately 3-fold more resistant to doxorubicin as a result of MDM2 overexpression, and the wild-type p53 function, such as the induction of p21Waf1 following DNA damage, was significantly suppressed. MDM2 overexpression is suggested to be a novel marker for predicting lack of response to doxorubicin treatment in breast cancer patients.
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PMID:Role of MDM2 overexpression in doxorubicin resistance of breast carcinoma. 954 51


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