PT  - JOURNAL ARTICLE
AU  - da Rocha Dias, Silvy
AU  - Friedlos, Frank
AU  - Light, Yvonne
AU  - Springer, Caroline
AU  - Workman, Paul
AU  - Marais, Richard
TI  - Activated B-RAF Is an Hsp90 Client Protein That Is Targeted by the Anticancer Drug 17-Allylamino-17-Demethoxygeldanamycin
AID  - 10.1158/0008-5472.CAN-05-2632
DP  - 2005 Dec 01
TA  - Cancer Research
PG  - 10686--10691
VI  - 65
IP  - 23
4099  - http://cancerres.aacrjournals.org/content/65/23/10686.short
4100  - http://cancerres.aacrjournals.org/content/65/23/10686.full
SO  - Cancer Res2005 Dec 01; 65
AB  - 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. ©2005 American Association for Cancer Research.