Celastrols as inducers of the heat shock response and cytoprotection

被引:324
作者
Westerheide, SD
Bosman, JD
Mbadugha, BNA
Kawahara, TLA
Matsumoto, G
Kim, SJ
Gu, WX
Devlin, JP
Silverman, RB
Morimoto, RI [1 ]
机构
[1] Northwestern Univ, Rice Inst Biomed Res, Dept Biochem Mol Biol & Cell Biol, Evanston, IL 60208 USA
[2] MicroSource Discovery Syst Inc, Gaylordsville, CT 06755 USA
[3] Northwestern Univ, Dept Chem, Evanston, IL 60208 USA
关键词
D O I
10.1074/jbc.M409267200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:56053 / 56060
页数:8
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