Heat shock protein 90 suppresses tumor necrosis factor alpha induced apoptosis by preventing the cleavage of Bid in NIH3T3 fibroblasts.
Two highly conserved mechanisms for maintaining cellular homeostasis are apoptosis and the cellular stress response. Hsp90 is one of the most abundant, highly conserved, and inducible Hsps in eukaryotes. Recently, Hsp90 has been shown to play important antiapoptotic roles through binding with Apaf-1, RIP and kinase domain of IKKalpha/beta. Our present studies demonstrate that Hsp90 can suppress tumor necrosis factor alpha (TNFalpha)-induced apoptosis in stable Hsp90-overexpressing NIH3T3 cells by preventing the cleavage of Bid. The prevention of the cleavage of Bid can be partially explained by the direct interaction between Hsp90 and Bid. Furthermore, disrupting the function of Hsp90 by the addition of its specific inhibitor, geldanamycin, blocked Hsp90's protection of Bid cleavage. These results show that Hsp90 can function at different levels within apoptotic signal transduction pathways.
Zhao
Chen
C
Department of Microbiology and Immunology, Keio University School of Medicine, 35 Shinano-machi, Tokyo 160-8582, Shinjuku, Japan. zhaochen@sc.itc.keio.ac.jp
Wang
Enhua
E
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051023:BH3 Interacting Domain Death Agonist Protein; D016227:Benzoquinones; D002352:Carrier Proteins / Q000378:metabolism*; D053148:Caspase 3; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism; D002455:Cell Division; D002478:Cells, Cultured; D003124:Colorimetry; D003513:Cycloheximide / Q000494:pharmacology; D045304:Cytochromes c / Q000502:physiology; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D047029:Lactams, Macrocyclic; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D041681:NIH 3T3 Cells; D011809:Quinones / Q000494:pharmacology; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D016227:Benzoquinones; C494815:Bid protein, mouse; D002352:Carrier Proteins; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D011809:Quinones; D014409:Tumor Necrosis Factor-alpha; D045304:Cytochromes c; D003513:Cycloheximide; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C505409:Casp3 protein, mouse; C505526:Casp8 protein, mouse; D053148:Caspase 3; D053181:Caspase 8; D020169:Caspases; C001277:geldanamycin