Hsp-90-associated oncoproteins: multiple targets of geldanamycin and its analogs.
Geldanamycin (GA), herbimycin A and radicicol bind heat-shock protein-90 (Hsp90) and destabilize its client proteins including v-Src, Bcr-Abl, Raf-1, ErbB2, some growth factor receptors and steroid receptors. Thus, Hsp90-active agents induce ubiquitination and proteasomal degradation of numerous oncoproteins. Depending on the cellular context, HSP90-active agents cause growth arrest, differentiation and apoptosis, or can prevent apoptosis. HSP-active agents are undergoing clinical trials. Like targets of most chemotherapeutics, Hsp90 is not a cancer-specific protein. By attacking a nonspecific target, HSP-90-active compounds still may preferentially kill certain tumor cells. How can this be achieved? How can therapeutic potentials be exploited? This article starts the discussion.
Blagosklonny
M V
MV
National Cancer Institute, NIH, Bethesda, MD 20892, USA.
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D016227:Benzoquinones; D002986:Clinical Trials as Topic; D006131:Growth Inhibitors / Q000494:pharmacology; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D047029:Lactams, Macrocyclic; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D015513:Oncogene Proteins / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism; D011809:Quinones / Q000494:pharmacology*; D017978:Receptors, Growth Factor / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D016227:Benzoquinones; D006131:Growth Inhibitors; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D015513:Oncogene Proteins; D011809:Quinones; D017978:Receptors, Growth Factor; D014157:Transcription Factors; D011494:Protein Kinases; C001277:geldanamycin