Genetic selection of intragenic suppressor mutations that reverse the effect of common p53 cancer mutations Journal Article
| Authors: | Brachmann, R. K.; Yu, K.; Eby, Y.; Pavletich, N. P.; Boeke, J. D. |
| Article Title: | Genetic selection of intragenic suppressor mutations that reverse the effect of common p53 cancer mutations |
| 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. |
| Keywords: | controlled study; gene mutation; mutation; nonhuman; polymerase chain reaction; protein conformation; animal cell; phenotype; mammalia; animals; dna repair; apoptosis; cell line; protein p53; assay; animalia; tumor suppressor gene; dna; saccharomyces cerevisiae; reporter gene; tumor suppressor protein p53; models, molecular; binding sites; genes, reporter; tumor suppressor; yeast; mutagenesis; genes, p53; genetic selection; cricetinae; trans-activation (genetics); suppression, genetic; humans; human; priority journal; article |
| Journal Title: | EMBO Journal |
| Volume: | 17 |
| Issue: | 7 |
| ISSN: | 0261-4189 |
| Publisher: | Wiley Blackwell |
| Date Published: | 1998-04-01 |
| Start Page: | 1847 |
| End Page: | 1859 |
| Language: | English |
| DOI: | 10.1093/emboj/17.7.1847 |
| PUBMED: | 9524109 |
| PROVIDER: | scopus |
| PMCID: | PMC1170532 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 12 December 2016 -- Source: Scopus |
