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. 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.
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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 http://mcb.asm.org/. M.K.C. and W.D.K. contributed equally to this work. | ||||||
Issue or Number: | 17 | ||||||
DOI: | 10.1128/MCB.02065-06 | ||||||
Record Number: | CaltechAUTHORS:CHOmcb07 | ||||||
Persistent URL: | https://resolver.caltech.edu/CaltechAUTHORS:CHOmcb07 | ||||||
Usage Policy: | No commercial reproduction, distribution, display or performance rights in this work are provided. | ||||||
ID Code: | 8530 | ||||||
Collection: | CaltechAUTHORS | ||||||
Deposited By: | Archive Administrator | ||||||
Deposited On: | 17 Aug 2007 | ||||||
Last Modified: | 08 Nov 2021 20:51 |
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