Activation of heat shock and antioxidant responses by the natural product celastrol: transcriptional signatures of a thiol-targeted molecule. Export

@article{citeulike:3822030, abstract = {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.}, author = {Trott, A. and West, J. D. and Klai\'{c}, L. and Westerheide, S. D. and Silverman, R. B. and Morimoto, R. I. and Morano, K. A.}, citeulike-article-id = {3822030}, citeulike-linkout-0 = {http://dx.doi.org/10.1091/mbc.E07-10-1004}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/18199679}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=18199679}, doi = {10.1091/mbc.E07-10-1004}, issn = {1939-4586}, journal = {Molecular biology of the cell}, keywords = {antioxidants, celestrol, hsp70, hssp90, thiols}, month = {March}, number = {3}, pages = {1104--1112}, posted-at = {2008-12-23 13:31:15}, priority = {3}, title = {Activation of heat shock and antioxidant responses by the natural product celastrol: transcriptional signatures of a thiol-targeted molecule.}, url = {http://dx.doi.org/10.1091/mbc.E07-10-1004}, volume = {19}, year = {2008} }

TY - JOUR ID - citeulike:3822030 L3 - citeulike-article-id:3822030 N2 - 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. IS - 3 JF - Molecular biology of the cell SN - 1939-4586 EP - 1112 TI - Activation of heat shock and antioxidant responses by the natural product celastrol: transcriptional signatures of a thiol-targeted molecule. VL - 19 SP - 1104 KW - antioxidants KW - celestrol KW - hsp70 KW - hssp90 KW - thiols AU - Trott, A AU - West, JD AU - Klaić, L AU - Westerheide, SD AU - Silverman, RB AU - Morimoto, RI AU - Morano, KA PY - 2008/03// UR - http://dx.doi.org/10.1091/mbc.E07-10-1004 ER -