The Phorbol Ester 12-O-Tetradecanoylphorbol 13-Acetate Enhances the Heat-induced Stress Response

doi:10.1074/jbc.272.10.6792

The Phorbol Ester 12-O-Tetradecanoylphorbol 13-Acetate Enhances the Heat-induced Stress Response*

From the ^‡ Turku Centre for Biotechnology, University of Turku, Åbo Akademi University, and the
^§ Department of Biochemistry and Pharmacy, Åbo Akademi University, FIN-20521 Turku, Finland

^∥ To whom correspondence should be addressed:
Turku Centre for Biotechnology, P.O. Box 123, FIN-20521 Turku, Finland.
Tel.: 358-2-333-8028; Fax: 358-2-333-8000; E-mail: lea.sistonen{at}btk.utu.fi

Abstract

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 protein kinase C-responsive signaling pathways could be involved in the regulation 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 demonstrate that TPA treatment markedly enhances heat shock gene expression during heat stress, although TPA alone does not induce the heat shock response. This TPA-mediated enhancement can initially be detected as an accelerated acquisition of DNA binding and transcriptional activity of HSF1 resulting in elevated Hsp70 protein concentrations. In the presence of TPA, the attenuation of HSF1 DNA binding activity during continuous 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 heat stress, a correlation between the hyperphosphorylation of HSF1 and its transcriptional activity was observed, in both the presence and the absence of TPA. Our results show that the heat-induced stress response can be significantly modulated by activation of protein kinase C-responsive signaling pathways.

Footnotes

↵^¶ Financed by the Graduate School of Biomedical Sciences at the Turku University. The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵* This work was supported by funds from the Academy of Finland (to J. E. E., S. L., and L. S.), the Emil Aaltonen Foundation (to S. L.), and the Sigrid Jusélius Foundation (to L. S.). The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
↵¹ The abbreviations used are:

Hsp

heat shock protein

HSF

heat shock transcription factor

HSE

heat shock element

PKC

protein kinase C

TPA

12-O-tetradecanoylphorbol 13-acetate

4α-TPA

4α-12-O-tetradecanoylphorbol 13-acetate

PAGE

polyacrylamide gel electrophoresis

GAPDH

glyceraldehyde 3-phosphate dehydrogenase

MAPK

mitogen-activated protein kinase.
↵²C. I. Holmberg, I. Elo, J. E. Eriksson, and L. Sistonen, unpublished observation.
- Received July 8, 1996.
- Revision received November 22, 1996.