Disruption of heat shock factor 1 reveals an essential role in the ubiquitin proteolytic pathway

Inhibition of proteasome-mediated protein degradation machinery is a potent stress stimulus that causes accumulation of ubiquitinated proteins and inc reased expression of heat shock proteins (Hsps). Hsps play pivotal roles in homeostasis and protection in a cell, through their well-recognized proper ties as molecular chaperones. The inducible Hsp expression is regulated by the heat shock transcription factors (HSFs). Among mammalian HSFs, HSF1 has been shown to be important for regulation of the heat-induced stress gene expression, whereas the function of HSF2 in stress response is unclear. Rec ent reports have suggested that both HSF1 and HSF2 are affected during down -regulation of ubiquitin-proteasome pathway (Y. Kawazoe et al., Eur. J. Bio chem. 255:356-362, 1998; A. Mathew et al., Mol. Cell. Biol, 18:5091-5098, 1 998; D. Kim et al., Biochem, Biophys, Res. Commun, 254:264-268, 1999). To d ate, however, no unambiguous evidence has been presented as to whether a si ngle specific HSF or multiple members of the NSF family are required for tr anscriptional induction of heat shock genes when proteasome activity is dow n-regulated. Therefore, by using loss-of-function and gain-of-function stra tegies, we investigated the specific roles of mammalian HSFs in regulation of the ubiquitin-proteasome-mediated stress response. Here we demonstrate t hat HSF1, but not HSF2, is essential and sufficient for up-regulation of Hs p70 expression during down-regulation of the ubiquitin proteolytic pathway. We propose that specificity of HSF1 could be an important therapeutic targ et during disease pathogenesis associated with abnormal ubiquitin-dependent proteasome function.