HSF1-dependent upregulation of Hsp70 by sulfhydryl-reactive inducers of the KEAP1/NRF2/ARE pathway

Chem Biol. 2011 Nov 23;18(11):1355-61. doi: 10.1016/j.chembiol.2011.09.008.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • DNA-Binding Proteins / antagonists & inhibitors
  • DNA-Binding Proteins / metabolism*
  • HSP70 Heat-Shock Proteins / metabolism*
  • Heat Shock Transcription Factors
  • Humans
  • Intracellular Signaling Peptides and Proteins / agonists
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Kelch-Like ECH-Associated Protein 1
  • Mice
  • NF-E2-Related Factor 2 / agonists
  • NF-E2-Related Factor 2 / metabolism
  • Signal Transduction*
  • Sulfhydryl Compounds / chemistry*
  • Sulfhydryl Compounds / pharmacology
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / metabolism*
  • Triterpenes / pharmacology
  • Up-Regulation / drug effects*

Substances

  • DNA-Binding Proteins
  • HSF1 protein, human
  • HSP70 Heat-Shock Proteins
  • Heat Shock Transcription Factors
  • Intracellular Signaling Peptides and Proteins
  • KEAP1 protein, human
  • Kelch-Like ECH-Associated Protein 1
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • Sulfhydryl Compounds
  • Transcription Factors
  • Triterpenes
  • tripterine