Genetic selection of intragenic suppressor mutations that reverse the effect of common p53 cancer mutations

Rainer K. Brachmann, Kexin Yu, Yolanda Eby, Nikola P. Pavletich, Jef D. Boeke

Research output: Contribution to journalArticle

Abstract

Several lines of evidence suggest that the presence of the wild-type tumor suppressor gene p53 in human cancers correlates well with successful anti-cancer therapy. Restoration of wild-type p53 function to cancer cells that have lost it might therefore improve treatment outcomes. Using a systematic yeast genetic approach, we selected second-site suppressor mutations that can overcome the deleterious effects of common p53 cancer mutations in human cells. We identified several suppressor mutations for the V143A, G245S and R249S cancer mutations. The beneficial effects of these suppressor mutations were demonstrated using mammalian reporter gene and apoptosis assays. Further experiments showed that these suppressor mutations could override additional p53 cancer mutations. The mechanisms of such suppressor mutations can be elucidated by structural studies, ultimately leading to a framework for the discovery of small molecules able to stabilize p53 mutants.

Original languageEnglish (US)
Pages (from-to)1847-1859
Number of pages13
JournalThe EMBO journal
Volume17
Issue number7
DOIs
StatePublished - Apr 1 1998

Fingerprint

Genetic Suppression
Genetic Selection
Genes
Cells
Mutation
Yeast
Restoration
Tumors
Assays
Neoplasms
Apoptosis
Molecules
Experiments
Tumor Suppressor Genes
Reporter Genes
Yeasts

Keywords

  • Human
  • Saccharomyces cerevisiae
  • Tumor suppressor
  • Yeast

ASJC Scopus subject areas

  • Genetics
  • Cell Biology

Cite this

Genetic selection of intragenic suppressor mutations that reverse the effect of common p53 cancer mutations. / Brachmann, Rainer K.; Yu, Kexin; Eby, Yolanda; Pavletich, Nikola P.; Boeke, Jef D.

In: The EMBO journal, Vol. 17, No. 7, 01.04.1998, p. 1847-1859.

Research output: Contribution to journalArticle

Brachmann, Rainer K. ; Yu, Kexin ; Eby, Yolanda ; Pavletich, Nikola P. ; Boeke, Jef D. / Genetic selection of intragenic suppressor mutations that reverse the effect of common p53 cancer mutations. In: The EMBO journal. 1998 ; Vol. 17, No. 7. pp. 1847-1859.
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