Inhibition of Hsp90 function delays and impairs recovery from heat shock.
The induction of the heat shock response as well as its termination is autoregulated by heat shock protein activities. In this study we have investigated whether Hsp90 functional protein levels influence the characteristics and duration of the heat shock response. Treatment of cells with several benzoquinone ansamycin inhibitors of Hsp90 (geldanamycin, herbimycin A) activated a heat shock response in the absence of heat shock, as reported previously. Pretreatment of cells with the Hsp90 inhibitors significantly delayed the rate of restoration of normal protein synthesis following a brief heat shock. Concurrently, the rate of Hsp synthesis and accumulation was substantially increased and prolonged. The cessation of heat shock protein synthesis did not occur until the levels of Hsp70 were substantially elevated relative to its standard threshold for autoregulation. The elevated levels of HSPS 22-28 (the small HSPS) and Hsp70 are not able to promote thermotolerance when Hsp90 activity is repressed by ansamycins; rather a suppression of thermotolerance is observed. These results suggest that a multicomponent protein chaperone complex involving both Hsp90 and Hsp70 signals the cessation of heat shock protein synthesis, the restoration of normal translation, and likely the establishment of thermotolerance. Impaired function of either component is sufficient to alter the heat shock response.
Duncan
Roger F
RF
Department of Molecular Pharmacology and Toxicology, University of Southern California School of Pharmacy, Los Angeles, CA, USA. rduncan@usc.edu
D000818:Animals; D016227:Benzoquinones; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D004330:Drosophila / Q000166:cytology; D029721:Drosophila Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins / Q000378:metabolism; D018869:Heat-Shock Response / Q000187:drug effects / Q000502:physiology*; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011809:Quinones / Q000494:pharmacology; D017828:Rifabutin / Q000031:analogs & derivatives; D014157:Transcription Factors / Q000378:metabolism
D016227:Benzoquinones; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins; C053134:Hsf protein, Drosophila; C490752:Hsp22 protein, Drosophila; C105998:Hsp23 protein, Drosophila; D047029:Lactams, Macrocyclic; D011809:Quinones; D014157:Transcription Factors; D017828:Rifabutin; C020754:herbimycin; C001277:geldanamycin