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Mitogen-activated Protein Kinase Acts as a Negative Regulator of the Heat Shock Response in NIH3T3 Cells¹

Department of Radiation Oncology, Cancer Biology Research Laboratory, Stanford University School of Medicine, Stanford, California 94305

Exposure of NIH3T3 cells to elevated temperatures induces the phosphorylation and activation of mitogen-activated protein (MAP) kinases [or extracellular signal-regulated kinases (ERKs)]. To investigate the significance of MAP kinase activation by heat shock, we examined the effect of inhibiting the activity of MAP kinase on heat shock protein 70 (hsp 70) expression. Overexpression of a dominant inhibitory mutant of ERK1, but not ERK2, in heat-shocked cells increased hsp70 reporter gene activity, suggesting that ERK1 acts as a repressor of hsp70 gene expression. Increases in ERK1 activity through treatment of cells with sodium vanadate (SV), an inhibitor of the dual-specificity MAP kinase phosphatase 1 (PAC1), resulted in increased phosphorylation of the heat shock transcription factor-1 (HSF-1) in unheated cells, delayed the activation of HSF-1 by heat shock, and inhibited the induction of hsp 70 by heat shock. Furthermore, the induction of thermotolerance was reduced significantly in cells that increased ERK1 activity by SV pretreatment. Immune complex kinase assays of heat shocked or SV-pretreated cells indicated that HSF-1 is a potential in vivo substrate for ERK1 phosphorylation. Taken together, these results suggest that agents that modulate MAP kinase act as negative regulators of the heat shock response in mammalian cells by modulating HSF-1 activity and hsp 70 expression.

¹ This work was supported by NIH Grants CA 59053 (to N. F. M.) and CA 58838 (to A. J. G.).

² To whom requests for reprints should be addressed, at Institute of Molecular Medicine and Genetics, MCG CB2803, 1120 15th Street, August, GA 30912.

Received 8/17/95. Accepted 10/18/95.

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