TY - JOUR
T1 - A global suppressor motif for p53 cancer mutants
AU - Baroni, Timothy E.
AU - Wang, Ting
AU - Qian, Hua
AU - Dearth, Lawrence R.
AU - Truong, Lan N.
AU - Zeng, Jue
AU - Denes, Alec E.
AU - Chen, Stephanie W.
AU - Brachmann, Rainer K.
PY - 2004/4/6
Y1 - 2004/4/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=1842737710&partnerID=8YFLogxK
U2 - 10.1073/pnas.0401162101
DO - 10.1073/pnas.0401162101
M3 - Article
C2 - 15037740
AN - SCOPUS:1842737710
SN - 0027-8424
VL - 101
SP - 4930
EP - 4935
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 14
ER -