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Molecular and Cellular Biology, September 2007, p. 6195-6208, Vol. 27, No. 17
0270-7306/07/$08.00+0     doi:10.1128/MCB.02065-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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

Min Kyung Cho,1,2,{ddagger} Won Dong Kim,1,{ddagger} Sung Hwan Ki,1 Jong-Ik Hwang,3,4 Sangdun Choi,4,5 Chang Ho Lee,6 and Sang Geon Kim1*

College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea,1 College of Oriental Medicine, Dongguk University, Kyungju, South Korea,2 The Graduate School of Medicine, Korea University College of Medicine, Seoul, South Korea,3 Division of Biology, California Institute of Technology, Pasadena, California 91125,4 Department of Molecular Science and Technology, Ajou University, Suwon, South Korea,5 Department of Pharmacology and Institute of Biomedical Science, College of Medicine, Hanyang University, Seoul, South Korea6

Received 4 November 2006/ Returned for modification 2 January 2007/ Accepted 13 June 2007

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.

* Corresponding author. Mailing address: College of Pharmacy, Seoul National University, Sillim-dong, Gwanak-gu, Seoul, South Korea. Phone: 82 2 880 7840. Fax: 82 2 872 1795. E-mail: sgk{at}snu.ac.kr

{triangledown} Published ahead of print on 25 June 2007.

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

{ddagger} M.K.C. and W.D.K. contributed equally to this work.

Molecular and Cellular Biology, September 2007, p. 6195-6208, Vol. 27, No. 17
0270-7306/07/$08.00+0     doi:10.1128/MCB.02065-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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