Repression of Heat Shock Transcription Factor HSF1 Activation by HSP90 (HSP90 Complex) that Forms a Stress-Sensitive Complex with HSF1

Abstract

Heat shock and other proteotoxic stresses cause accumulation of nonnative proteins that trigger activation of heat shock protein (Hsp) genes. A chaperone/Hsp functioning as repressor of heat shock transcription factor (HSF) could make activation of hsp genes dependent on protein unfolding. In a novel in vitro system, in which human HSF1 can be activated by nonnative protein, heat, and geldanamycin, addition of Hsp90 inhibits activation. Reduction of the level of Hsp90 but not of Hsp/c70, Hop, Hip, p23, CyP40, or Hsp40 dramatically activates HSF1. In vivo, geldanamycin activates HSF1 under conditions in which it is an Hsp90-specific reagent. Hsp90-containing HSF1 complex is present in the unstressed cell and dissociates during stress. We conclude that Hsp90, by itself and/or associated with multichaperone complexes, is a major repressor of HSF1.

Akt shows variable sensitivity to an Hsp90 inhibitor depending on cell context

“…1A and B). Besides stimulating client kinase degradation, GA also stimulates induction of Hsp70 and other chaperones whose expression is regulated by heat shock factor [20]. In the parent Ba/F3 cell line, Hsp70 is induced at levels of GA that are comparable with those that stimulate client kinase degradation.…”

Hsp90 inhibitors deplete key anti‐apoptotic proteins in pediatric solid tumor cells and demonstrate synergistic anticancer activity with cisplatin

“…40 -42 It is possible that cisplatin binding directly alters the redox-sensitive interactions of Hsp90 and its co-chaperones with HSF1, the major transcriptional regulator of the vertebrate heat shock response. 43 It is also possible that direct damage to heat shock response elements by cisplatin may impair their ability to be transcriptionally activated by HSF1 despite its activation by GA.…”

Firefly luciferase mutants as sensors of proteome stress

“…Adapted from (Neef et al, 2011). 3. Under normal physiological conditions, monomeric HSF1 is diffusely distributed in cytoplasm and nucleus and is kept in an inactive complex with Hsp70, Hsp40 and Hsp90 (Ali et al, 1998;Mosser et al, 1993;Nadeau et al, 1993;Zou et al, 1998). During proteotoxic stress, the structure and function of proteins is compromised, leading to the depletion of the chaperone reservoir.…”