MG132 and lactacystin, two 26S proteasome-specific protease inhibitors, can upregulate heat-shock gene transcription without heat shock. In this study, we showed that both of these inhibitors induce hyperphosphorylation and DNA-binding activity of HSF1 in the absence of heat shock (at 37 degreesC). Since trimerization of HSF1 is known to precede the acquisition of HSF1-DNA binding activity, it seems that MG132- and lactacystin-induced hyperphosphorylation of HSF1 causes conformational changes of HSF1 molecules at 37 degreesC and subsequently triggers its trimerization. Inhibition of protein synthesis by cycloheximide abolished the MG132- or lactacystin-induced hyperphosphorylation and DNA-binding activity of HSF1. These data suggest that the activity of a putative kinase(s) targeting HSF1 is upregulated in the presence of MG132 or lactacystin. The upregulation of the kinase activity requires de novo protein synthesis and is likely due to the inhibition of protein degradation of a short-lived, kinase(s) targeting HSF1 and/or the cofactor(s) for the kinases, through the ubiquitin-proteasome pathway.
Copyright 1999 Academic Press.