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
11/29/2011Pubmed ID
22118669Pubmed Central ID
PMC3302153DOI
10.1016/j.chembiol.2011.09.008Scopus ID
2-s2.0-82255181180 67 CitationsAbstract
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 ATAuthor
Ivor J. Benjamin MD Center Director, Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCell 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
