V600E B-Raf requires the Hsp90 chaperone for stability and is degraded in response to Hsp90 inhibitors Journal Article
| Authors: | Grbovic, O. M.; Basso, A. D.; Sawai, A.; Ye, Q.; Friedlander, P.; Solit, D.; Rosen, N. |
| Article Title: | V600E B-Raf requires the Hsp90 chaperone for stability and is degraded in response to Hsp90 inhibitors |
| Abstract: | The Raf family includes three members, of which B-Raf is frequently mutated in melanoma and other tumors. We show that Raf-1 and A-Raf require Hsp90 for stability, whereas B-Raf does not. In contrast, mutated, activated B-Raf binds to an Hsp90-cdc37 complex, which is required for its stability and function. Exposure of melanoma cells and tumors to the Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin results in the degradation of mutant B-Raf, inhibition of mitogen-activated protein kinase activation and cell proliferation, induction of apoptosis, and antitumor activity. These data suggest that activated mutated B-Raf proteins are incompetent for folding in the absence of Hsp90, thus suggesting that the chaperone is required for the clonal evolution of melanomas and other tumors that depend on this mutation. Hsp90 inhibition represents a therapeutic strategy for the treatment of melanoma. © 2005 by The National Academy of Sciences of the USA. |
| Keywords: | mitogen activated protein kinase; controlled study; protein expression; human cell; mutation, missense; raf protein; cell proliferation; animals; cell cycle proteins; mice; melanoma; apoptosis; protein degradation; protein stability; antineoplastic activity; cancer cell culture; enzyme activation; tumor xenograft; enzyme activity; cell line, tumor; mice, inbred balb c; cancer inhibition; gene expression regulation, neoplastic; heat shock protein 90 inhibitor; heat shock protein 90; cell cycle arrest; protein folding; b raf kinase; proto-oncogene proteins b-raf; benzoquinones; lactams, macrocyclic; electrophoresis, polyacrylamide gel; rifabutin; chaperone; proto-oncogene proteins c-raf; 17-allylamino-17-demethoxygeldanamycin; cell cycle protein 37; 17 allylamino 17 demethoxygeldanamycin; cdc37; a raf kinase; chaperonins; proto-oncogene proteins a-raf |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 103 |
| Issue: | 1 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2006-01-03 |
| Start Page: | 57 |
| End Page: | 62 |
| Language: | English |
| DOI: | 10.1073/pnas.0609973103 |
| PUBMED: | 16371460 |
| PROVIDER: | scopus |
| PMCID: | PMC1325013 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 117" - "Export Date: 4 June 2012" - "CODEN: PNASA" - "Source: Scopus" |
Altmetric
Citation Impact
BMJ Impact Analytics
MSK Authors
Related MSK Work