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Increased apoptosis induction by 121F mutant p53
Author(s) -
Saller Elisabeth,
Tom Edward,
Brunori Michele,
Otter Michèle,
Estreicher Anne,
Mack David H.,
Iggo Richard
Publication year - 1999
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/18.16.4424
Subject(s) - biology , mutant , mdm2 , apoptosis , gene , microbiology and biotechnology , phenotype , wild type , transcription factor , genetics
p53 mutants in tumours have a reduced affinity for DNA and a reduced ability to induce apoptosis. We describe a mutant with the opposite phenotype, an increased affinity for some p53‐binding sites and an increased ability to induce apoptosis. The apoptotic function requires transcription activation by p53. The mutant has an altered sequence specificity and selectively fails to activate MDM2 transcription. Loss of MDM2 feedback results in overexpression of the mutant, but the mutant kills better than wild‐type p53 even in MDM2‐null cells. Thus the apoptotic phenotype is due to a combination of decreased MDM2 feedback control and increased or unbalanced expression of other apoptosis‐inducing p53 target genes. To identify these genes, DNA chips were screened using RNA from cells expressing the apoptosis‐inducing mutant, 121F, and a sequence‐specificity mutant with the reciprocal phenotype, 277R. Two potential new mediators of p53‐dependent apoptosis were identified, Rad and PIR121, which are induced better by 121F than wild‐type p53 and not induced by 277R. The 121F mutant kills untransformed MDM2‐null but not wild‐type mouse embryo fibroblasts and kills tumour cells irrespective of p53 status. It may thus expand the range of tumours which can be treated by p53 gene therapy.

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