Document Detail


Mutant p53 gain of function: differential effects of different p53 mutants on resistance of cultured cells to chemotherapy.
MedLine Citation:
PMID:  9927204     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Many tumors overexpress mutant forms of p53. A growing number of studies suggest that the nature of a p53 mutation in a cell can impact upon cellular properties, clinical responses to therapy and prognosis of a tumor. To explore the cellular basis of these observations, experiments were designed to compare the properties of cells with and without p53 mutations within the same cell population. To that end, various tumor-derived human p53 mutants were introduced into p53-null H1299 lung adenocarcinoma cells. Clonogenic survival assays revealed that cells overexpressing the p53His175 mutant, but not the p53His273 mutant, recover preferentially from etoposide treatment. Moreover, p53His175 as well as p53His179 reduced substantially the rate of etoposide-induced apoptosis, whereas p53His273 and p53Trp248 had a much milder protective effect. In contrast, p53His175 and p53His273 exerted very similar effects on the cellular response to cisplatin; both conferred increased resistance to low concentrations of the drug (2.5 microg/ml), but did not protect at all against high concentrations (10 microg/ml). Hence particular p53 mutants may confer upon tumor cells a selective survival advantage during chemotherapy. These findings define a new type of mutant p53 selective gain of function, which may compromise the efficacy of cancer chemotherapy.
Authors:
G Blandino; A J Levine; M Oren
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Oncogene     Volume:  18     ISSN:  0950-9232     ISO Abbreviation:  Oncogene     Publication Date:  1999 Jan 
Date Detail:
Created Date:  1999-02-16     Completed Date:  1999-02-16     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  8711562     Medline TA:  Oncogene     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  477-85     Citation Subset:  IM    
Affiliation:
Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel.
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MeSH Terms
Descriptor/Qualifier:
Adenocarcinoma / genetics,  pathology
Antineoplastic Agents / pharmacology*
Blotting, Western
Cell Separation
Cell Survival / drug effects
Cisplatin / pharmacology
Drug Resistance, Neoplasm / genetics*
Etoposide / pharmacology
Flow Cytometry
Fluorescent Antibody Technique, Indirect
Genes, p53*
Humans
Lung Neoplasms / genetics,  pathology
Mutation*
Grant Support
ID/Acronym/Agency:
R01 CA 40099/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 15663-27-1/Cisplatin; 33419-42-0/Etoposide

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