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HSF1-dependent upregulation of Hsp70 by sulfhydryl-reactive inducers of the KEAP1/NRF2/ARE pathway. Chem Biol 2011 Nov 23;18(11):1355-61

Date

11/29/2011

Pubmed ID

22118669

Pubmed Central ID

PMC3302153

DOI

10.1016/j.chembiol.2011.09.008

Scopus ID

2-s2.0-82255181180   67 Citations

Abstract

The KEAP1/NRF2/ARE pathway and the heat shock response are inducible cytoprotective systems regulated by transcription factors NRF2 and HSF1, respectively. We report that structurally distinct small molecule NRF2 activators, all of which react with sulfhydryl groups but differ in potency by 15,000-fold, upregulate Hsp70, a prototypic HSF1-dependent gene. Hsp70 upregulation requires HSF1 but is NRF2 independent. We further demonstrate that a sulfoxythiocarbamate inducer conjugates to the negative regulator of HSF1, Hsp90. The differential concentration dependence of the two responses suggests that activation of NRF2 precedes that of HSF1: the KEAP1/NRF2/ARE pathway is at the forefront of cellular defense, protecting against instant danger; the heat shock response closely follows to resolve subsequent potentially devastating damage, saving the proteome. This uncovered duality undoubtedly contributes to the cytoprotective effects of such molecules in models of carcinogenesis, cardiovascular disease, and neurodegeneration.

Author List

Zhang Y, Ahn YH, Benjamin IJ, Honda T, Hicks RJ, Calabrese V, Cole PA, Dinkova-Kostova AT

Author

Ivor J. Benjamin MD Center Director, Professor in the Medicine department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Cell Line
DNA-Binding Proteins
HSP70 Heat-Shock Proteins
Heat Shock Transcription Factors
Humans
Intracellular Signaling Peptides and Proteins
Kelch-Like ECH-Associated Protein 1
Mice
NF-E2-Related Factor 2
Signal Transduction
Sulfhydryl Compounds
Transcription Factors
Triterpenes
Up-Regulation
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a