title: Activated B-RAF is an Hsp90 client protein that is targeted by the anticancer drug 17-allylamino-17-demethoxygeldanamycin.
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.
authors.affiliation: The Institute of Cancer Research, Signal Transduction Team, Cancer Research UK Centre for Cell and Molecular Biology, London, United Kingdom.
authors.forename: Silvy
authors.initials: S
authors.lastname: da Rocha Dias
authors.forename: Frank
authors.initials: F
authors.lastname: Friedlos
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Light
authors.forename: Caroline
authors.initials: C
authors.lastname: Springer
authors.forename: Paul
authors.initials: P
authors.lastname: Workman
authors.forename: Richard
authors.initials: R
authors.lastname: Marais
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016227:Benzoquinones; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D047029:Lactams, Macrocyclic; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism*; D017828:Rifabutin / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D017828:Rifabutin; C112765:tanespimycin; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf