HEAT-SHOCK RESPONSE AND PROTEIN-DEGRADATION - REGULATION OF HSF2 BY THE UBIQUITIN-PROTEASOME PATHWAY

Mammalian cells coexpress a family of heat shock factors (HSFs) whose activities are regulated by diverse stress conditions to coordinate th e inducible expression of heat shock genes. Distinct from HSF1, which is expressed ubiquitously and activated by heat shock and other stress es that result in the appearance of nonnative proteins, the stress sig nal for HSF2 has not been identified. HSF2 activity has been associate d with development and differentiation, and the activation properties of HSF2 have been characterized in hemin-treated human K562 erythroleu kemia cells. Here, we demonstrate that a stress signal for HSF2 activa tion occurs when the ubiquitin-proteasome pathway is inhibited. HSF2 D NA-binding activity is induced upon exposure of mammalian cells to the proteasome inhibitors hemin, MG132, and lactacystin, and in the mouse ts85 cell line, which carries a temperature sensitivity mutation in t he ubiquitin-activating enzyme (El) upon shift to the nonpermissive te mperature. HSF2 is labile, and its activation requires both continued protein synthesis and reduced degradation. The downstream effect of HS F2 activation by proteasome inhibitors is the induction of the same se t of heat shock genes that are induced during heat shock by HSF1, thus revealing that HSF2 affords the cell with a novel heat shock gene-reg ulatory mechanism to respond to changes in the protein-degradative mac hinery.