Activation of Fas inhibits heat-induced activation of HSF1 and up-regulation of hsp70

Activation of heat shock factor (HSF) 1-DNA binding and inducible heat shoc k protein (hsp) 70 (also called hsp72) expression enables cells to resist v arious forms of stress and survive. Fas, a membrane-bound protein, is a cen tral proapoptotic factor; its activation leads to a cascade of events, resu lting in programmed cell death. These two mechanisms with contradictory fun ctions, promoting either cell survival or death, were examined for their po tential to inhibit each other's activation. Induction of FAS-mediated signa ling was followed by a rapid decrease in HSF1-DNA binding and inducible hsp 70 expression. Inhibition of HSF1-DNA binding was demonstrated to be based on absent hyperphosphorylation of HSF1 during FAS signaling. These effects of FAS activation on the HSF1/hsp70 stress response were blocked by ICE (ca spase 1) inhibitors, suggesting an ICE-mediated process. Furthermore, inhib ition of HSF1/hsp70 was accompanied by an increase in apoptosis rates from 20% to 50% in response to heat stress. When analyzing the effects of HSF1/h sp70 activation on Fas-mediated apoptosis, protection from apoptosis was se en in cells with induced hsp70 protein levels, but not in cells that were j ust induced for HSF1-DNA binding. Thus, we conclude that inhibition of HSF1 /hsp70 stress response during Fas-mediated apoptosis and vice versa may fac ilitate a cell. to pass a previously chosen pathway, stress resistance or a poptosis, without the influence of inhibitory signals.