Geldanamycin restores a defective heat shock response in vivo

Induced expression of heat shock proteins (Hsps) plays a central role in pr omoting cellular survival after environmental and physiological stress. We have previously shown that scrapie-infected mouse neuroblastoma (ScN2a) cel ls fail to induce the expression of Hsp72 and Hsp28 after various stress co nditions. Here we present evidence that this impaired stress response is du e to an altered regulation of HSF1 activity. Upon stress in ScN2a cells, HS F1 was converted into hyperphosphorylated trimers but failed to acquire tra nsactivation competence. A kinetic analysis of HSF1 activation revealed tha t in ScN2a cells trimer formation after stress was efficient, but disassemb ly of trimers proceeded much faster than in the uninfected cell line. Gelda namycin, a Hsp90-binding drug, significantly delayed disassembly of HSF1 tr imers after a heat shock and restored stress-induced expression of Hsp72 in ScN2a cells. Heat-induced Hsp72 expression required geldanamycin to be pre sent; following removal of the drug ScN2a cells again lost their ability to mount a stress response. Thus, our studies show that a defective stress re sponse can be pharmacologically restored and suggest that the HSF1 deactiva tion pathway may play an important role in the regulation of Hsp expression .