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.
journal_name
Proc Natl Acad Sci U S Aauthors
Baroni TE,Wang T,Qian H,Dearth LR,Truong LN,Zeng J,Denes AE,Chen SW,Brachmann RKdoi
10.1073/pnas.0401162101keywords:
subject
Has Abstractpub_date
2004-04-06 00:00:00pages
4930-5issue
14eissn
0027-8424issn
1091-6490pii
0401162101journal_volume
101pub_type
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