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J. Biol. Chem., Vol. 281, Issue 25, 17220-17227, June 23, 2006

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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^*

Haeng Ran Seo¹, Da-Yeon Chung¹, Yoon-Jin Lee, Dae-Hoon Lee^¶, Jong-Il Kim, Sangwoo Bae, Hee-Yong Chung^||, Su-Jae Lee^**, Dooil Jeoung, and Yun-Sil Lee²

From the Laboratory of Radiation Effect and ^** Laboratory of Radiation Experimental Therapeutics, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, the Department of Food and Microbial Technology College of Natural Science, Seoul Women's University, Seoul 139-774, ^¶Seegene Inc., Seoul 138-050, the ^||Department of Microbiology, College of Medicine, Hanyang University, Seoul 133-791, and the Division of Life Sciences, Kangwon National University College of Natural Sciences, Chuncheon 200-701, Korea

The expression of heat shock proteins (HSPs) is known to be increased via activation of heat shock factor 1 (HSF1), and excess expression of HSPs exerts feedback inhibition of HSF1. However, the molecular mechanism to modulate such relationships between HSPs and HSF1 is not clear. In the present study, we show that stable transfection of either Hsp25 or inducible Hsp70 (Hsp70i) increased expression of endogenous HSPs such as HSP25 and HSP70i through HSF1 activation. However, these phenomena were abolished when the dominant negative Hsf1 mutant was transfected to HSP25 or HSP70i overexpressed cells. Moreover, the increased HSF1 activity by either HSP25 or HSP70i was found to result from dephosphorylation of HSF1 on serine 307 that increased the stability of HSF1. Either HSP25 or HSP70i inhibited ERK1/2 phosphorylation because of increased MKP1 phosphorylation by direct interaction of these HSPs with MKP1. Treatment of HOS and NCI-H358 cells, which showed high expressions of endogenous HSF1, with small interfering RNA (siRNA) of either HSP27 (siHSP27)or HSP70i (siHSP70i) inhibited both HSP27 and HSP70i proteins; this was because of increased ERK1/2 phosphorylation and serine phosphorylation of HSF1. The results, therefore, suggested that when the HSF1 protein level was high in cancer cells, excess expression of HSP27 or HSP70i strongly facilitates the expression of HSP proteins through HSF1 activation, resulting in severe radio- or chemoresistance.

Received for publication, January 4, 2006 , and in revised form, April 18, 2006.

^* This work was supported by Korea Institute of Science & Technology Evaluation and Planning and Ministry of Science & Technology (MOST) and the Korean government, through its National Nuclear Technology Program. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S3.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: 215-4 Gongneung-Dong, Nowon-Ku, Seoul 139-706, Korea. Tel.: 82-2-970-1325; Fax: 82-2-970-2402; E-mail: yslee{at}kcch.re.kr.

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