p53 mutants without a functional tetramerisation domain are not oncogenic

p53 is altered in about 50 % of cancers. Most of the p53 mutants have lost the wild-type tumour suppressor activity but show oncogenic properties. The majority of the p53 alterations are missense mutations of residues located in its DNA binding domain (DBD). Only a few mutations concern residues in...

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Bibliographic Details
Published in:Journal of molecular biology 1999-03, Vol.286 (5), p.1269-1274
Main Authors: Chène, P, Bechter, E
Format: Article
Language:English
Subjects:
Amino Acid Substitution
ATP-Binding Cassette, Sub-Family B, Member 1 - genetics
Genes, Dominant - genetics
Genes, p53
Humans
Mutation
Neoplasms - etiology
Neoplasms - genetics
Oligodeoxyribonucleotides - genetics
Oligodeoxyribonucleotides - metabolism
Osteosarcoma
Phenotype
Precipitin Tests
Promoter Regions, Genetic - genetics
Protein Binding
Protein Biosynthesis
Recombinant Proteins - biosynthesis
Recombinant Proteins - genetics
Recombinant Proteins - metabolism
Response Elements - genetics
Transfection
Tumor Cells, Cultured
Tumor Suppressor Protein p53 - antagonists & inhibitors
Tumor Suppressor Protein p53 - chemistry
Tumor Suppressor Protein p53 - genetics
Tumor Suppressor Protein p53 - metabolism
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Summary:p53 is altered in about 50 % of cancers. Most of the p53 mutants have lost the wild-type tumour suppressor activity but show oncogenic properties. The majority of the p53 alterations are missense mutations of residues located in its DNA binding domain (DBD). Only a few mutations concern residues in its tetramerisation domain (TD). However, the study of mutant proteins identified in tumors that do not form tetramers has shown that they have lost the wild-type activity like most of the p53 DBD mutants. Here, we show that two of such mutant proteins, Arg342Pro and Leu344Pro are not dominant negative and do not stimulate the expression of a reporter gene under the control of the multi-drug resistance gene-1 (MDR-1). This suggests that to be oncogenic, p53 mutants need to form tetramers. Accordingly, the dominant negative effect and the ability of a tetrameric mutant protein, Asp281Gly, to stimulate the MDR-1 promoter are abolished when its TD is rendered non-functional by the mutation of leucine 344 to a proline residue. These results suggest that mutations in the TD, are less selected in tumors than mutations in the DBD because they do not lead to oncogenic proteins.
ISSN:0022-2836
DOI:10.1006/jmbi.1999.2563