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  • Title: Activated B-RAF is an Hsp90 client protein that is targeted by the anticancer drug 17-allylamino-17-demethoxygeldanamycin.
    Author: da Rocha Dias S, Friedlos F, Light Y, Springer C, Workman P, Marais R.
    Journal: Cancer Res; 2005 Dec 01; 65(23):10686-91. PubMed ID: 16322212.
    Abstract:
    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.
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