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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:  Publisher    
Abstract/OtherAbstract:
Aims: Nuclear factor-erythroid-related factor 2 (Nrf2) is a critical transcriptional factor in regulating cellular defense against oxidative stress. This study is aimed to investigate new interacting protein partners of Nrf2 using one-strep tag pull-down coupled with LTQ Orbitrap LC/MS/MS, and to examine the impact on Nr2 signaling by the newly identified IQGAP1 (IQ motif containing GTPase activating protein 1). 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 GST pull-down, transcription/translation assays, and in vivo utilizing Nrf2 over-expressing cells. Co-expression of Dsredm-IQGAP1 and eGFP-Nrf2 increased the stability of eGFP-Nrf2 and enhanced the expression of Nrf2-target gene 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 NQO1. 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 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 ARE-transcription activity and enhanced the expression of 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.
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     Date:  2012-7-15
Journal Detail:
Title:  Antioxidants & redox signaling     Volume:  -     ISSN:  1557-7716     ISO Abbreviation:  -     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-7-16     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  100888899     Medline TA:  Antioxid Redox Signal     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Rutgers University, Pharmaceutics, Piscataway, New Jersey, United States; rla0132@gmail.com.
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