Celastrols as inducers of the heat shock response and cytoprotection.
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.
Westerheide
Sandy D
SD
Department of Biochemistry, Molecular Biology and Cell Biology, Rice Institute for Biomedical Research, Northwestern University, Evanston, IL 60208, USA.
Bosman
Joshua D
JD
Mbadugha
Bessie N A
BN
Kawahara
Tiara L A
TL
Matsumoto
Gen
G
Kim
Soojin
S
Gu
Wenxin
W
Devlin
John P
JP
Silverman
Richard B
RB
Morimoto
Richard I
RI
D015153:Blotting, Western; D002460:Cell Line; D049109:Cell Proliferation; D002843:Chromatin / Q000378:metabolism; D004247:DNA / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D006367:HeLa Cells; D000076249:Heat Shock Transcription Factors; D018869:Heat-Shock Response; D006801:Humans; D047468:Immunoprecipitation; D007700:Kinetics; D008156:Luciferases / Q000378:metabolism; D008956:Models, Chemical; D053978:Pentacyclic Triterpenes; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011487:Protein Conformation; D017510:Protein Folding; D011809:Quinones / Q000737:chemistry; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D013696:Temperature; D013997:Time Factors; D014157:Transcription Factors; D014162:Transfection; D014315:Triterpenes / Q000737:chemistry / Q000494:pharmacology*
D002843:Chromatin; D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; D053978:Pentacyclic Triterpenes; D011809:Quinones; D014157:Transcription Factors; D014315:Triterpenes; D004247:DNA; D008156:Luciferases; C050414:celastrol