Activated B-RAF is an Hsp90 client protein that is targeted by the anticancer drug 17-allylamino-17-demethoxygeldanamycin.

Hsp90 is a ubiquitously expressed molecular chaperone that folds, stabilizes, and functionally regulates many cellular proteins. The benzoquinone ansamysin 17-allylamino-17-demethoxygeldanamycin (17-AAG) is an anticancer drug that disrupts Hsp90 binding to its clients, causing their degradation through the ubiquitin-dependent proteasomal pathway. The protein kinase B-RAF is mutated in approximately 7% of ...
human cancers. The most common mutation (approximately 90%) is (V600E)B-RAF, which has constitutively elevated kinase activity, stimulates cancer cell proliferation, and promotes survival. Here, we show that (V600E)B-RAF is an Hsp90 client protein that requires Hsp90 for its folding and stability. (V600E)BRAF is more sensitive to degradation by 17-AAG treatment than (WT)B-RAF and we show that the majority of the other mutant forms of B-RAF are also sensitive to 17-AAG-mediated proteasomal degradation. Our data show that B-RAF is an important target for 17-AAG in human cancer.
Mesh Terms:
Animals, Antineoplastic Agents, Benzoquinones, COS Cells, Cell Line, Tumor, Cercopithecus aethiops, HSP90 Heat-Shock Proteins, Humans, Lactams, Macrocyclic, Mutation, Proto-Oncogene Proteins B-raf, Rifabutin
Cancer Res.
Date: Dec. 01, 2005
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