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Vol. 19, Issue 3, 1104-1112, March 2008

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Activation of Heat Shock and Antioxidant Responses by the Natural Product Celastrol: Transcriptional Signatures of a Thiol-targeted Molecule

Amy Trott^*,, James D. West^,, Lada Klai, Sandy D. Westerheide, Richard B. Silverman, Richard I. Morimoto, and Kevin A. Morano^*

*Department of Microbiology and Molecular Genetics, University of Texas Medical School, Houston, TX 77030; Department of Biochemistry, Molecular Biology, and Cell Biology, Rice Institute for Biomedical Research, Northwestern University, Evanston, IL 60208; and Departments of Chemistry and Biochemistry, Molecular Biology, and Cell Biology, and Center for Drug Discovery and Chemical Biology, Northwestern University, Evanston, IL 60208

Submitted October 4, 2007; Revised December 26, 2007; Accepted January 4, 2008
Monitoring Editor: Peter Walter

Stress response pathways allow cells to sense and respond to environmental changes and adverse pathophysiological states. Pharmacological modulation of cellular stress pathways has implications in the treatment of human diseases, including neurodegenerative disorders, cardiovascular disease, and cancer. The quinone methide triterpene celastrol, derived from a traditional Chinese medicinal herb, has numerous pharmacological properties, and it is a potent activator of the mammalian heat shock transcription factor HSF1. However, its mode of action and spectrum of cellular targets are poorly understood. We show here that celastrol activates Hsf1 in Saccharomyces cerevisiae at a similar effective concentration seen in mammalian cells. Transcriptional profiling revealed that celastrol treatment induces a battery of oxidant defense genes in addition to heat shock genes. Celastrol activated the yeast Yap1 oxidant defense transcription factor via the carboxy-terminal redox center that responds to electrophilic compounds. Antioxidant response genes were likewise induced in mammalian cells, demonstrating that the activation of two major cell stress pathways by celastrol is conserved. We report that celastrol's biological effects, including inhibition of glucocorticoid receptor activity, can be blocked by the addition of excess free thiol, suggesting a chemical mechanism for biological activity based on modification of key reactive thiols by this natural product.

These authors contributed equally to this work.

Address correspondence to: Kevin A. Morano (kevin.a.morano{at}uth.tmc.edu)

Abbreviations used: AAD, aryl-alcohol dehydrogenase; ARE, antioxidant response element; Atf4, activating transcription factor 4; CRD, cysteine-rich domain; DOC, deoxycorticosterone; DMSO, dimethyl sulfoxide; DTT, dithiothreitol; GFP, green fluorescent protein; Gpx3, glutathione peroxidase 3; GR, glucocorticoid receptor; HSE, heat shock element; HSF1, heat shock transcription factor 1; HSP, heat shock protein; HSR, heat shock response; Nrf2, NF-E2-related factor-2; PGK, phosphoglycerate kinase; TAP, tandem affinity purification; Yap1, yeast AP-1.

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