THE PHORBOL ESTER 12-O-TETRADECANOYLPHORBOL 13-ACETATE ENHANCES THE HEAT-INDUCED STRESS-RESPONSE

Induction of heat shock: gene expression is mediated by specific heat shock transcription factors (HSFs), but the signaling pathways leading to activation of HSFs are poorly understood. To elucidate whether pro tein kinase C-responsive signaling pathways could be involved in the r egulation of heat shock gene expression, we have examined the effects of the protein kinase C activator 12-O-tetradecanoylphorbol 13-acetate (TPA) on the heat-induced stress response in K562 cells. We demonstra te that TPA treatment markedly enhances heat shock gene expression dur ing heat stress, although TPA alone does not induce the heat shock res ponse. This TPA-mediated enhancement can initially be detected as an a ccelerated acquisition of DNA binding and transcriptional activity of HSF1 resulting in elevated Hsp70 protein concentrations. In the presen ce of TPA, the attenuation of HSF1 DNA binding activity during continu ous exposure to heat shock occurs more rapidly and in concert with the appearance of newly synthesized Hsp70, which supports earlier studies on the autoregulatory role of Hsp70 in deactivation of HSF1. During h eat stress, a correlation between the hyperphosphorylation of HSF1 and its transcriptional activity was observed, in both the presence and t he absence of TPA. Our results show that the heat-induced stress respo nse can be significantly modulated by activation of protein kinase C-r esponsive signaling pathways.