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J. Biol. Chem., Vol. 279, Issue 47, 49460-49469, November 19, 2004

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Interactions between Extracellular Signal-regulated Protein Kinase 1, 14-3-3, and Heat Shock Factor 1 during Stress^*

XiaoZhe Wang, Nicholas Grammatikakis¶, Aliki Siganou¶, Mary Ann Stevenson¶, and Stuart K. Calderwood¶||**

From the Dana-Farber Cancer Institute and ^¶Division of Molecular and Cellular Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, and ^||Department of Medicine, Boston University School of Medicine, Boston, Massachusetts 02118

Cytoprotection during the heat shock response is a complex phenomenon involving multiple inducible mechanisms. We have examined the interaction of two key molecular components in the response, heat shock transcription factor 1 (HSF1) and extracellular signal regulated protein kinase (ERK). Whereas both HSF1 and ERK are required to protect cells against apoptosis, ERK activation is paradoxically antagonistic to trans-activation of hsp promoters by HSF1 and HSP accumulation during heat shock. We have found that the two pathways interact directly and that heat shock causes the physical association of ERK1 with HSF1, an interaction that promotes the kinase activity of ERK in heat-shocked cells. ERK activation results in the recruitment of the phosphoserine binding protein 14-3-3 in a manner dependent on previous HSF1 phosphorylation by ERK. The effects of 14-3-3 binding on HSF1 were complex, however, depending on extracellular conditions, in that HSF1-14-3-3 binding at 37 °C led to the cytoplasmic sequestration and repression of HSF1, whereas heat shock overrode these effects and caused quantitative nuclear localization of HSF1. Although the effects of 14-3-3 binding to HSF1 were overridden acutely by stress, during recovery from heat shock, 14-3-3 association again led to enhanced cytoplasmic localization of HSF1, implicating a role for ERK/14-3-3 in HSF1 deactivation in recovering cells. Association of HSF1 with ERK and 14-3-3 during heat shock may thus modulate the amplitude of the response and lead to efficient termination of HSP expression on resumption of growth conditions.

Received for publication, June 1, 2004 , and in revised form, August 2, 2004.

^* This work was supported in part by National Institutes of Health Grants CA47407, CA31303, and CA50642. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to this work.

^** To whom correspondence should be addressed: Beth Israel Deaconess Medical Center, 21–27 Burlington Avenue, Room 553B, Boston, MA 02215; Tel.: 617-632-0628; Fax: 617-632-0635; E-mail: scalderw{at}bidmc.harvard.edu.

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