A global suppressor motif for p53 cancer mutants.

Abstract:

:The transcription factor and tumor suppressor protein p53 is frequently inactivated in human cancers. In many cases, p53 gene mutations result in high levels of inactive, full-length p53 protein with one amino acid change in the core domain that recognizes p53 DNA-binding sites. The ability to endow function to mutated p53 proteins would dramatically improve cancer therapy, because it would reactivate a central apoptotic pathway. By using genetic strategies and p53 assays in yeast and mammalian cells, we identified a global suppressor motif involving codons 235, 239, and 240. These intragenic suppressor mutations, either alone or in combination, restored function to 16 of 30 of the most common p53 cancer mutants tested. The 235-239-240 suppressor motif establishes that manipulation of a small region of the core domain is sufficient to activate a large number of p53 cancer mutants. Understanding the structural basis of the rescue mechanism will allow the pursuit of small compounds able to achieve a similar stabilization of p53 cancer mutants.

authors

Baroni TE,Wang T,Qian H,Dearth LR,Truong LN,Zeng J,Denes AE,Chen SW,Brachmann RK

doi

10.1073/pnas.0401162101

keywords:

subject

Has Abstract

pub_date

2004-04-06 00:00:00

pages

4930-5

issue

14

eissn

0027-8424

issn

1091-6490

pii

0401162101

journal_volume

101

pub_type

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