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J. Biol. Chem., Vol. 279, Issue 53, 56053-56060, December 31, 2004

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Celastrols as Inducers of the Heat Shock Response and Cytoprotection^*

Sandy D. Westerheide, Joshua D. Bosman, Bessie N. A. Mbadugha, Tiara L. A. Kawahara, Gen Matsumoto, Soojin Kim, Wenxin Gu, John P. Devlin¶, Richard B. Silverman, and Richard I. Morimoto||

From the Department of Biochemistry, Molecular Biology and Cell Biology, Rice Institute for Biomedical Research, Northwestern University, Evanston, Illinois 60208, the Department of Chemistry, Northwestern University, Evanston, Illinois 60208, and ^¶MicroSource Discovery Systems, Inc., Gaylordsville, Connecticut 06755

Alterations in protein folding and the regulation of conformational states have become increasingly important to the functionality of key molecules in signaling, cell growth, and cell death. Molecular chaperones, because of their properties in protein quality control, afford conformational flexibility to proteins and serve to integrate stress-signaling events that influence aging and a range of diseases including cancer, cystic fibrosis, amyloidoses, and neurodegenerative diseases. We describe here characteristics of celastrol, a quinone methide triterpene and an active component from Chinese herbal medicine identified in a screen of bioactive small molecules that activates the human heat shock response. From a structure/function examination, the celastrol structure is remarkably specific and activates heat shock transcription factor 1 (HSF1) with kinetics similar to those of heat stress, as determined by the induction of HSF1 DNA binding, hyperphosphorylation of HSF1, and expression of chaperone genes. Celastrol can activate heat shock gene transcription synergistically with other stresses and exhibits cytoprotection against subsequent exposures to other forms of lethal cell stress. These results suggest that celastrols exhibit promise as a new class of pharmacologically active regulators of the heat shock response.

Received for publication, August 12, 2004 , and in revised form, October 26, 2004.

^* This work was supported by American Cancer Society Postdoctoral Fellowship PF-00-023-01 and National Institutes of Health Training Grant in Signal Transduction and Cancer T32 CA70085 (to S. D. W.), National Institutes of Health Training Grant in Cellular and Molecular Basis of Disease T32 GM008061-21 (to J. D. B.), National Institutes of Health Drug Discovery Program Training Grant T32 AG00260 (to B. N. A. M.), a Human Frontiers Science Program long term fellowship (to G. M.), a National Institutes of Health Mechanisms of Aging and Dementia Training Grant (to S. K.), National Institute for General Medical Science Grant GM38109 and a grant from the Huntington Disease Society of America Coalition for the Cure (to R. I. M.), and National Institutes for Neurological Diseases and Stroke Grant NS047331 (to R. I. M. and R. B. S.). 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 figures and text.

^|| To whom correspondence should be addressed. Tel.: 847-491-3340; Fax: 847-491-4461; E-mail: r-morimoto{at}northwestern.edu.

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