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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. https://resolver.caltech.edu/CaltechAUTHORS:CHOmcb07

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Abstract

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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1128/MCB.02065-06DOIUNSPECIFIED
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 http://mcb.asm.org/. M.K.C. and W.D.K. contributed equally to this work.
Issue or Number:17
Record Number:CaltechAUTHORS:CHOmcb07
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:CHOmcb07
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ID Code:8530
Collection:CaltechAUTHORS
Deposited By: Archive Administrator
Deposited On:17 Aug 2007
Last Modified:02 Oct 2019 23:51

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