A global suppressor motif for p53 cancer mutants.
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.
Baroni
Timothy E
TE
Department of Medicine, Division of Oncology, Washington University School of Medicine, 660 South Euclid Avenue, P.O. Box 8069, St. Louis, MO 63110, USA.
Wang
Ting
T
Qian
Hua
H
Dearth
Lawrence R
LR
Truong
Lan N
LN
Zeng
Jue
J
Denes
Alec E
AE
Chen
Stephanie W
SW
Brachmann
Rainer K
RK
D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D016153:Genes, Suppressor; D016158:Genes, p53; D006801:Humans; D016296:Mutagenesis; D009369:Neoplasms / Q000235:genetics*; D016133:Polymerase Chain Reaction