Geldanamycin-induced PCNA degradation in isolated Hsp90 complex from cancer cells.
Hsp90 is a molecular chaperone involved in the folding and proteolytic turnover of many regulatory proteins associated with it. Some of the Hsp90 client proteins are known to be involved in tumorigenesis. An Hsp90-specific inhibitor, geldanamycin, is shown to bind to the ATP binding site of the chaperone to induce degradation of many client proteins, and results in antitumor activities. However, the mechanism of geldanamycin-induced client protein degradation is not fully understood. A large-scale immunoaffinity purification with anti-Hsp90 antibodies identified many Hsp90 client proteins from colon cancer cell line, HCT-116. One of the identified proteins, PCNA, was confirmed to be associated with Hsp90 in two additional cancer cell lines. After geldanamycin treatment, both PCNA and Hsp90 were shown to be degraded. More interestingly, this study demonstrated that in two different cancer cell lines, the degradation occurred in the isolated Hsp90 complex in vitro. This result indicated that the components responsible for the PCNA degradation are also associated with Hsp90. This finding provided a new mechanism for the Hsp90-mediated protein degradation induced by Hsp90-specific inhibitors.
Wang
Xing
X
Pfizer Global Research and Development, 700 Chesterfield Parkway West, St. Louis, MO 63017, USA. xing.wang@pfizer.com
Heuvelman
Deborah M
DM
Carroll
James A
JA
Dufield
Dawn R
DR
Masferrer
Jaime L
JL
D000255:Adenosine Triphosphate / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D016227:Benzoquinones / Q000494:pharmacology*; D001665:Binding Sites; D002846:Chromatography, Affinity; D003110:Colonic Neoplasms / Q000378:metabolism; D045325:HCT116 Cells; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019073:HT29 Cells; D006258:Head and Neck Neoplasms / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D046912:Multiprotein Complexes; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D040901:Proteomics / Q000379:methods; D015854:Up-Regulation
D000903:Antibiotics, Antineoplastic; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D046912:Multiprotein Complexes; D018809:Proliferating Cell Nuclear Antigen; D000255:Adenosine Triphosphate; C001277:geldanamycin