A global suppressor motif for p53 cancer mutants

Timothy E. Baroni, Ting Wang, Hua Qian, Lawrence R. Dearth, Lan N. Truong, Jue Zeng, Alex Denes, Stephanie W. Chen, Rainer K. Brachmann

Research output: Contribution to journalArticle

64 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)4930-4935
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number14
DOIs
StatePublished - Apr 6 2004
Externally publishedYes

Fingerprint

Neoplasms
Genetic Suppression
Tumor Suppressor Protein p53
p53 Genes
Codon
Proteins
Transcription Factors
Yeasts
Binding Sites
Amino Acids
Mutation
DNA
Therapeutics

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Baroni, T. E., Wang, T., Qian, H., Dearth, L. R., Truong, L. N., Zeng, J., ... Brachmann, R. K. (2004). A global suppressor motif for p53 cancer mutants. Proceedings of the National Academy of Sciences of the United States of America, 101(14), 4930-4935. https://doi.org/10.1073/pnas.0401162101

A global suppressor motif for p53 cancer mutants. / Baroni, Timothy E.; Wang, Ting; Qian, Hua; Dearth, Lawrence R.; Truong, Lan N.; Zeng, Jue; Denes, Alex; Chen, Stephanie W.; Brachmann, Rainer K.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 101, No. 14, 06.04.2004, p. 4930-4935.

Research output: Contribution to journalArticle

Baroni, TE, Wang, T, Qian, H, Dearth, LR, Truong, LN, Zeng, J, Denes, A, Chen, SW & Brachmann, RK 2004, 'A global suppressor motif for p53 cancer mutants', Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 14, pp. 4930-4935. https://doi.org/10.1073/pnas.0401162101
Baroni, Timothy E. ; Wang, Ting ; Qian, Hua ; Dearth, Lawrence R. ; Truong, Lan N. ; Zeng, Jue ; Denes, Alex ; Chen, Stephanie W. ; Brachmann, Rainer K. / A global suppressor motif for p53 cancer mutants. In: Proceedings of the National Academy of Sciences of the United States of America. 2004 ; Vol. 101, No. 14. pp. 4930-4935.
@article{2b64d8e7e8ac40ebb621c1786752e709,
title = "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.",
author = "Baroni, {Timothy E.} and Ting Wang and Hua Qian and Dearth, {Lawrence R.} and Truong, {Lan N.} and Jue Zeng and Alex Denes and Chen, {Stephanie W.} and Brachmann, {Rainer K.}",
year = "2004",
month = "4",
day = "6",
doi = "10.1073/pnas.0401162101",
language = "English (US)",
volume = "101",
pages = "4930--4935",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "14",

}

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, Alex

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

UR - http://www.scopus.com/inward/citedby.url?scp=1842737710&partnerID=8YFLogxK

U2 - 10.1073/pnas.0401162101

DO - 10.1073/pnas.0401162101

M3 - Article

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

SN - 0027-8424

IS - 14

ER -