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Role of G{alpha}12 and G{alpha}13 as Novel Switches for the Activity of Nrf2, a Key Antioxidative Transcription Factor

Cho, Min Kyung and Kim, Won Dong and Ki, Sung Hwan and Hwang, Jong-Ik and Choi, Sangdun and Lee, Chang Ho and Kim, Sang Geon (2007) Role of G{alpha}12 and G{alpha}13 as Novel Switches for the Activity of Nrf2, a Key Antioxidative Transcription Factor. Molecular and Cellular Biology, 27 (17). pp. 6195-6208. ISSN 0270-7306. doi:10.1128/MCB.02065-06.

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G{alpha}12 and G{alpha}13 function as molecular regulators responding to extracellular stimuli. NF-E2-related factor 2 (Nrf2) is involved in a protective adaptive response to oxidative stress. This study investigated the regulation of Nrf2 by G{alpha}12 and G{alpha}13. A deficiency of G{alpha}12, but not of G{alpha}13, enhanced Nrf2 activity and target gene transactivation in embryo fibroblasts. In mice, G{alpha}12 knockout activated Nrf2 and thereby facilitated heme catabolism to bilirubin and its glucuronosyl conjugations. An oligonucleotide microarray demonstrated the transactivation of Nrf2 target genes by G{alpha}12 gene knockout. G{alpha}12 deficiency reduced Jun N-terminal protein kinase (JNK)-dependent Nrf2 ubiquitination required for proteasomal degradation, and so did G{alpha}13 deficiency. The absence of G{alpha}12, but not of G{alpha}13, increased protein kinase C {delta} (PKC {delta}) activation and the PKC {delta}-mediated serine phosphorylation of Nrf2. G{alpha}13 gene knockout or knockdown abrogated the Nrf2 phosphorylation induced by G{alpha}12 deficiency, suggesting that relief from G{alpha}12 repression leads to the G{alpha}13-mediated activation of Nrf2. Constitutive activation of G{alpha}13 promoted Nrf2 activity and target gene induction via Rho-mediated PKC {delta} activation, corroborating positive regulation by G{alpha}13. In summary, G{alpha}12 and G{alpha}13 transmit a JNK-dependent signal for Nrf2 ubiquitination, whereas G{alpha}13 regulates Rho-PKC {delta}-mediated Nrf2 phosphorylation, which is negatively balanced by G{alpha}12.

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Additional Information:Copyright © 2007, American Society for Microbiology. Received 4 November 2006/ Returned for modification 2 January 2007/ Accepted 13 June 2007. Published ahead of print on 25 June 2007. This work was supported by Korea Research Foundation grant KRF-2004-015-E00096 (S.G.K.), in part by NIH grant R37GM024236 (M. I. Simon), and by an Ajou University internal research grant (2006; S.C.). We are grateful to S. Offermanns for helpful discussion regarding this paper. Supplemental material for this article may be found at M.K.C. and W.D.K. contributed equally to this work.
Issue or Number:17
Record Number:CaltechAUTHORS:CHOmcb07
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ID Code:8530
Deposited By: Archive Administrator
Deposited On:17 Aug 2007
Last Modified:08 Nov 2021 20:51

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