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[Cancer Research 65, 10686-10691, December 1, 2005]
© 2005 American Association for Cancer Research

Priority Reports

Activated B-RAF Is an Hsp90 Client Protein That Is Targeted by the Anticancer Drug 17-Allylamino-17-Demethoxygeldanamycin

Silvy da Rocha Dias1, Frank Friedlos2, Yvonne Light1, Caroline Springer2, Paul Workman3 and Richard Marais1

1 The Institute of Cancer Research, Signal Transduction Team, Cancer Research UK Centre for Cell and Molecular Biology, London, United Kingdom; 2 Gene and Oncogene Targeting Team and 3 Signal Transduction and Molecular Pharmacology Team, Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Sutton, United Kingdom

Requests for reprints: Richard Marais, Signal Transduction Team, Cancer Research UK Centre for Cell and Molecular Biology, The Institute of Cancer Research, 237 Fulham Road, London, United Kingdom. Phone: 44-20-7153-5171; Fax: 44-20-7153-5171; E-mail: richard.marais{at}icr.ac.uk.

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 ~7% of human cancers. The most common mutation (~90%) is V600EB-RAF, which has constitutively elevated kinase activity, stimulates cancer cell proliferation, and promotes survival. Here, we show that V600EB-RAF is an Hsp90 client protein that requires Hsp90 for its folding and stability. V600EBRAF is more sensitive to degradation by 17-AAG treatment than WTB-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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Copyright © 2005 by the American Association for Cancer Research.