Overexpression of unliganded steroid receptors activates endogenous heat shock factor.

The synthesis of a number of heat shock proteins is induced in response to various environmental stresses. The resultant induction of heat shock protein gene transcription is brought about by the activation of specific transcription factors termed heat shock factors (HSFs) that exist in a latent form in nonstressed cells. Multiple mechanisms are likely to contribute to negative regulation of HSF activity. One model, which remains controversial, proposes the existence of a negative feedback loop by which one of the products of HSF activation, the 70-kDa heat shock protein (hsp70), acts as one of its negative regulators. Accordingly, HSF activation would proceed upon sequestration of hsp70 by substrates (i.e. unfolded proteins) that may accumulate to relatively high levels in stressed cells. To examine whether putative native substrates of hsp70 (e.g. steroid receptors) could impact the regulation of HSF activity, we have examined whether steroid receptors could activate endogenous HSF. We have found that overexpression of androgen (AR), glucocorticoid (GR), mineralocorticoid, and progesterone receptors in transiently transfected COS-1 cells induced HSF activity. With the exception of AR, which was competent to activate HSF when either liganded or unliganded, all other steroid receptors tested only activated HSF when unliganded. This activity was mapped to the ligand-binding domain of rat GR, making it unlikely that HSF activation results from the induction of a novel gene product by unliganded receptors. As overexpression of hsp70 can eliminate HSF activation by AR, GR, and progesterone receptors, we favor the view that HSF activation can result from the sequestration, by steroid receptor ligand-binding domains, of a negative regulator of HSF, such as hsp70 or an hsp70-associated protein.