This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mivechi, N. F. Articles by Giaccia, A. J. Search for Related Content PubMed PubMed Citation Articles by Mivechi, N. F. Articles by Giaccia, A. J.

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.

This article has been cited by other articles:

				H. R. Seo, D.-Y. Chung, Y.-J. Lee, D.-H. Lee, J.-I. Kim, S. Bae, H.-Y. Chung, S.-J. Lee, D. Jeoung, and Y.-S. Lee Heat Shock Protein 25 or Inducible Heat Shock Protein 70 Activates Heat Shock Factor 1: DEPHOSPHORYLATION ON SERINE 307 THROUGH INHIBITION OF ERK1/2 PHOSPHORYLATION J. Biol. Chem., June 23, 2006; 281(25): 17220 - 17227. [Abstract] [Full Text] [PDF]

				X. Wang, N. Grammatikakis, A. Siganou, M. A. Stevenson, and S. K. Calderwood Interactions between Extracellular Signal-regulated Protein Kinase 1, 14-3-3{epsilon}, and Heat Shock Factor 1 during Stress J. Biol. Chem., November 19, 2004; 279(47): 49460 - 49469. [Abstract] [Full Text] [PDF]

				X. Wang, N. Grammatikakis, A. Siganou, and S. K. Calderwood Regulation of Molecular Chaperone Gene Transcription Involves the Serine Phosphorylation, 14-3-3{varepsilon} Binding, and Cytoplasmic Sequestration of Heat Shock Factor 1 Mol. Cell. Biol., September 1, 2003; 23(17): 6013 - 6026. [Abstract] [Full Text] [PDF]

				Y. Guo, T. Guettouche, M. Fenna, F. Boellmann, W. B. Pratt, D. O. Toft, D. F. Smith, and R. Voellmy Evidence for a Mechanism of Repression of Heat Shock Factor 1 Transcriptional Activity by a Multichaperone Complex J. Biol. Chem., November 30, 2001; 276(49): 45791 - 45799. [Abstract] [Full Text] [PDF]

				S. A. Wadekar, D. Li, S. Periyasamy, and E. R. Sanchez Inhibition of Heat Shock Transcription Factor by GR Mol. Endocrinol., August 1, 2001; 15(8): 1396 - 1410. [Abstract] [Full Text] [PDF]

				F. Hochholdinger, G. Baier, A. Nogalo, B. Bauer, H. H. Grunicke, and F. Uberall Novel Membrane-Targeted ERK1 and ERK2 Chimeras Which Act as Dominant Negative, Isotype-Specific Mitogen-Activated Protein Kinase Inhibitors of Ras-Raf-Mediated Transcriptional Activation of c-fos in NIH 3T3 Cells Mol. Cell. Biol., December 1, 1999; 19(12): 8052 - 8065. [Abstract] [Full Text] [PDF]

				Y. Zhang, S. Koushik, R. Dai, and N. F. Mivechi Structural Organization and Promoter Analysis of Murine Heat Shock Transcription Factor-1 Gene J. Biol. Chem., December 4, 1998; 273(49): 32514 - 32521. [Abstract] [Full Text] [PDF]

				B. He, Y.-H. Meng, and N. F. Mivechi Glycogen Synthase Kinase 3beta and Extracellular Signal-Regulated Kinase Inactivate Heat Shock Transcription Factor 1 by Facilitating the Disappearance of Transcriptionally Active Granules after Heat Shock Mol. Cell. Biol., November 1, 1998; 18(11): 6624 - 6633. [Abstract] [Full Text]

				B. Chu, R. Zhong, F. Soncin, M. A. Stevenson, and S. K. Calderwood Transcriptional Activity of Heat Shock Factor 1 at 37 oC Is Repressed through Phosphorylation on Two Distinct Serine Residues by Glycogen Synthase Kinase 3alpha and Protein Kinases Calpha and Czeta J. Biol. Chem., July 17, 1998; 273(29): 18640 - 18646. [Abstract] [Full Text] [PDF]

				W. Xia, Y. Guo, N. Vilaboa, J. Zuo, and R. Voellmy Transcriptional Activation of Heat Shock Factor HSF1 Probed by Phosphopeptide Analysis of Factor 32P-labeled in Vivo J. Biol. Chem., April 10, 1998; 273(15): 8749 - 8755. [Abstract] [Full Text] [PDF]

				C. Holmberg, P. Roos, J. Lord, J. Eriksson, and L Sistonen Conventional and novel PKC isoenzymes modify the heat-induced stress response but are not activated by heat shock J. Cell Sci., January 11, 1998; 111(22): 3357 - 3365. [Abstract] [PDF]

				J. Huang, A. Nueda, S. Yoo, and W. S. Dynan Heat Shock Transcription Factor 1 Binds Selectively in Vitro to Ku Protein and the Catalytic Subunit of the DNA-dependent Protein Kinase J. Biol. Chem., October 10, 1997; 272(41): 26009 - 26016. [Abstract] [Full Text] [PDF]

				D Hopwood, S Moitra, B Vojtesek, D A Johnston, J F Dillon, and T R Hupp Biochemical analysis of the stress protein response in human oesophageal epithelium Gut, August 1, 1997; 41(2): 156 - 163. [Abstract] [Full Text] [PDF]

				B. Chu, F. Soncin, B. D. Price, M. A. Stevenson, and S. K. Calderwood Sequential Phosphorylation by Mitogen-activated Protein Kinase and Glycogen Synthase Kinase 3Represses Transcriptional Activation by Heat Shock Factor-1 J. Biol. Chem., November 29, 1996; 271(48): 30847 - 30857. [Abstract] [Full Text] [PDF]

				U Knauf, E M Newton, J Kyriakis, and R E Kingston Repression of human heat shock factor 1 activity at control temperature by phosphorylation. Genes & Dev., November 1, 1996; 10(21): 2782 - 2793. [Abstract] [PDF]

				R. Dai, W. Frejtag, B. He, Y. Zhang, and N. F. Mivechi c-Jun NH2-terminal Kinase Targeting and Phosphorylation of Heat Shock Factor-1 Suppress Its Transcriptional Activity J. Biol. Chem., June 9, 2000; 275(24): 18210 - 18218. [Abstract] [Full Text] [PDF]

				I. J. Xavier, P. A. Mercier, C. M. McLoughlin, A. Ali, J. R. Woodgett, and N. Ovsenek Glycogen Synthase Kinase 3beta Negatively Regulates Both DNA-binding and Transcriptional Activities of Heat Shock Factor 1 J. Biol. Chem., September 8, 2000; 275(37): 29147 - 29152. [Abstract] [Full Text] [PDF]

				D.-P. Li, S. Periyasamy, T. J. Jones, and E. R. Sanchez Heat and Chemical Shock Potentiation of Glucocorticoid Receptor Transactivation Requires Heat Shock Factor (HSF) Activity. MODULATION OF HSF BY VANADATE AND WORTMANNIN J. Biol. Chem., August 18, 2000; 275(34): 26058 - 26065. [Abstract] [Full Text] [PDF]

				M. Ozaki, S. S. Deshpande, P. Angkeow, S. Suzuki, and K. Irani Rac1 Regulates Stress-induced, Redox-dependent Heat Shock Factor Activation J. Biol. Chem., November 3, 2000; 275(45): 35377 - 35383. [Abstract] [Full Text] [PDF]