HSF1-Dependent Upregulation of Hsp70 by Sulfhydryl-Reactive Inducers of the KEAP1/NRF2/ARE Pathway

TY - JOUR

T1 - HSF1-Dependent Upregulation of Hsp70 by Sulfhydryl-Reactive Inducers of the KEAP1/NRF2/ARE Pathway

A1 - Zhang,Ying

A1 - Ahn,Young-Hoon

A1 - Benjamin,Ivor J.

A1 - Honda,Tadashi

A1 - Hicks,Ronald J.

A1 - Calabrese,Vittorio

A1 - Cole,Philip A.

A1 - Dinkova-Kostova,Albena T.

AU - Zhang,Ying

AU - Ahn,Young-Hoon

AU - Benjamin,Ivor J.

AU - Honda,Tadashi

AU - Hicks,Ronald J.

AU - Calabrese,Vittorio

AU - Cole,Philip A.

AU - Dinkova-Kostova,Albena T.

PY - 2011/11/23

Y1 - 2011/11/23

N2 - <p>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.</p>

AB - <p>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.</p>

KW - HEAT-SHOCK RESPONSE

KW - PHASE-2 ENZYMES

KW - INDUCTION

KW - STRESS

KW - CARCINOGENESIS

KW - PROTECTION

KW - SULFORAPHANE

KW - ACTIVATION

KW - OXIDANTS

KW - POTENCY

U2 - 10.1016/j.chembiol.2011.09.008

DO - 10.1016/j.chembiol.2011.09.008

M1 - Article

JO - Chemistry & Biology

JF - Chemistry & Biology

SN - 1074-5521

IS - 11

VL - 18

SP - 1355

EP - 1361

ER -