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Mol. Cell. Biol. doi:10.1128/MCB.02065-06
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

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

Min Kyung Cho, Won Dong Kim, Sung Hwan Ki, Jong-Ik Hwang, Sangdun Choi, Chang Ho Lee, and Sang Geon Kim*

College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea; College of Oriental Medicine, Dongguk University, Kyungju, Korea; The Graduate School of Medicine, Korea University College of Medicine, Seoul, Korea; Division of Biology, California Institute of Technology, Pasadena, CA 91125, U.S.A; Department of Molecular Science and Technology, Ajou University, Suwon, Korea and Department of Pharmacology and Institute of Biomedical Science, College of Medicine, Hanyang University, Seoul, Korea

* To whom correspondence should be addressed. Email: sgk{at}snu.ac.kr.


  Abstract

G{alpha}12/G{alpha}13 function as molecular regulators responding to extracellular stimuli. Nrf2 is involved in a protective adaptive response to oxidative stress. This study investigated the regulation of Nrf2 by G{alpha}12/G{alpha}13. A deficiency of G{alpha}12, but not of G{alpha}13, enhanced Nrf2 activity and target gene transactivation in embryofibroblasts. In mice, G{alpha}12 knockout activated Nrf2 and thereby facilitated heme catabolism to bilirubin and its glucuronosyl conjugations. Oligonucleotide microarray demonstrated the transactivation of Nrf2 target genes by G{alpha}12 gene-knockout. G{alpha}12 deficiency reduced 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 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/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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