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Molecular and Cellular Biology, May 2009, p. 2658-2672, Vol. 29, No. 10
0270-7306/09/$08.00+0     doi:10.1128/MCB.01639-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Acetylation of Nrf2 by p300/CBP Augments Promoter-Specific DNA Binding of Nrf2 during the Antioxidant Response{triangledown} ,{dagger}

Zheng Sun,1 Y. Eugene Chin,2 and Donna D. Zhang1*

Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona 85721,1 Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University Medical School, Providence, Rhode Island 029032

Received 21 October 2008/ Returned for modification 15 November 2008/ Accepted 21 February 2009

To maintain intracellular redox homeostasis, genes encoding many antioxidants and detoxification enzymes are transcriptionally upregulated upon deleterious oxidative stress through the cis antioxidant responsive elements (AREs) in their promoter regions. Nrf2 is the critical transcription factor responsible for ARE-dependent transcription. We and others have previously demonstrated that Nrf2 is targeted for ubiquitin-mediated degradation by Keap1 in a redox-sensitive manner through modifications of distinct cysteine residues of Keap1. Here, we report that p300/CBP directly acetylates Nrf2 in response to arsenite-induced stress. We have identified multiple acetylated lysine residues within the Nrf2 Neh1 DNA-binding domain. Combined lysine-to-arginine mutations on the acetylation sites, with no effects on Nrf2 protein stability, compromised the DNA-binding activity of Nrf2 in a promoter-specific manner. These findings demonstrated that acetylation of Nrf2 by p300/CBP augments promoter-specific DNA binding of Nrf2 and established acetylation as a novel regulatory mechanism that functions in concert with Keap1-mediated ubiquitination in modulating the Nrf2-dependent antioxidant response.

* Corresponding author. Mailing address: Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ 85721. Phone: (520) 626-9918. Fax: (520) 626-2466. E-mail: dzhang{at}pharmacy.arizona.edu

{triangledown} Published ahead of print on 9 March 2009.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org.

Molecular and Cellular Biology, May 2009, p. 2658-2672, Vol. 29, No. 10
0270-7306/09/$08.00+0     doi:10.1128/MCB.01639-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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