Document Detail


Identification and functional studies of a new Nrf2 partner IQGAP1: a critical role in the stability and transactivation of Nrf2.
MedLine Citation:
PMID:  22793650     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
AIMS: Nuclear factor-erythroid-related factor 2 (Nrf2) is a critical transcriptional factor that is used in regulating cellular defense against oxidative stress. This study is aimed at investigating new interacting protein partners of Nrf2 using One-strep tag pull-down coupled with LTQ Orbitrap LC/MS/MS, and at examining the impact on Nr2 signaling by the newly identified IQ motif containing GTPase activating protein 1 (IQGAP1).
RESULTS: Using the One-strep tag pull-down and LTQ Orbitrap LC/MS/MS, we identified IQGAP1 as a new Nrf2 interacting partner. Direct interactions between IQGAP1 and Nrf2 proteins were verified using in vitro glutathione S-transferase (GST) pull-down, transcription/translation assays, and in vivo utilizing Nrf2 overexpressing cells. Coexpression of Dsredmono-IQGAP1 and eGFP-Nrf2 increased the stability of eGFP-Nrf2 and enhanced the expression of Nrf2-target gene heme oxygenase-1 (HO-1). To confirm the functional role of IQGAP1 on Nrf2, knock-downed IQGAP1 using siIQGAP1 attenuated the expression of endogenous Nrf2, HO-1 proteins, and Nrf2-target genes GSTpi, GCLC, and
NAD(P)H: quinone oxidoreductase 1 (NQO-1). Furthermore, the stability of Nrf2 was dramatically decreased in IQGAP1-deficient mouse embryonic fibroblast (MEF) cells. Since IQGAP1 signaling could be mediated by calcium, treating the cells with calcium showed the translocation of IQGAP1/Nrf2 complex into the nucleus, suggesting that IQGAP1 may play a critical role in Nrf2 stability. Interestingly, consistent with calcium signaling for IQGAP1, treating the cells with calcium functionally enhanced Nrf2-mediated antioxidant responsive element-transcription activity and enhanced the expression of the endogenous Nrf2-target gene HO-1.
INNOVATION: In the aggregate, our current study identifies and functionally characterizes a new Nrf2 partner protein IQGAP1, which may contribute to Nrf2's regulation of antioxidant enzymes such as HO-1.
CONCLUSION: IQGAP1 may play a critical role in the stability and transactivation of Nrf2.
Authors:
Jung-Hwan Kim; Eugenia Y Xu; David B Sacks; Jonghun Lee; Limin Shu; Bing Xia; Ah-Ng Tony Kong
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, N.I.H., Intramural     Date:  2012-09-17
Journal Detail:
Title:  Antioxidants & redox signaling     Volume:  19     ISSN:  1557-7716     ISO Abbreviation:  Antioxid. Redox Signal.     Publication Date:  2013 Jul 
Date Detail:
Created Date:  2013-06-19     Completed Date:  2014-03-31     Revised Date:  2014-08-06    
Medline Journal Info:
Nlm Unique ID:  100888899     Medline TA:  Antioxid Redox Signal     Country:  United States    
Other Details:
Languages:  eng     Pagination:  89-101     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Antioxidants / metabolism
Calcium / metabolism
Cell Line
Cell Line, Tumor
Cell Nucleus / genetics,  metabolism
Fibroblasts / metabolism
Gene Silencing
HeLa Cells
Heme Oxygenase-1 / genetics,  metabolism
Humans
Mice
NF-E2-Related Factor 2 / genetics*,  metabolism*
Protein Interaction Domains and Motifs / genetics
Protein Stability
Protein Transport
Signal Transduction
Transcriptional Activation / genetics*
ras GTPase-Activating Proteins / genetics*,  metabolism*
Grant Support
ID/Acronym/Agency:
2R01CA118947/CA/NCI NIH HHS; P30 ES005022/ES/NIEHS NIH HHS; R01 CA94828/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antioxidants; 0/IQ motif containing GTPase activating protein 1; 0/NF-E2-Related Factor 2; 0/NFE2L2 protein, human; 0/ras GTPase-Activating Proteins; EC 1.14.99.3/HMOX1 protein, human; EC 1.14.99.3/Heme Oxygenase-1; SY7Q814VUP/Calcium
Comments/Corrections

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