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Role of G₁₂ and G₁₃ as Novel Switches for the Activity of Nrf2, a Key Antioxidative Transcription Factor ^,

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

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

G₁₂ and G₁₃ 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 G₁₂ and G₁₃. A deficiency of G₁₂, but not of G₁₃, enhanced Nrf2 activity and target gene transactivation in embryo fibroblasts. In mice, G₁₂ 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 G₁₂ gene knockout. G₁₂ deficiency reduced Jun N-terminal protein kinase (JNK)-dependent Nrf2 ubiquitination required for proteasomal degradation, and so did G₁₃ deficiency. The absence of G₁₂, but not of G₁₃, increased protein kinase C (PKC ) activation and the PKC -mediated serine phosphorylation of Nrf2. G₁₃ gene knockout or knockdown abrogated the Nrf2 phosphorylation induced by G₁₂ deficiency, suggesting that relief from G₁₂ repression leads to the G₁₃-mediated activation of Nrf2. Constitutive activation of G₁₃ promoted Nrf2 activity and target gene induction via Rho-mediated PKC activation, corroborating positive regulation by G₁₃. In summary, G₁₂ and G₁₃ transmit a JNK-dependent signal for Nrf2 ubiquitination, whereas G₁₃ regulates Rho-PKC -mediated Nrf2 phosphorylation, which is negatively balanced by G₁₂.

Published ahead of print on 25 June 2007.

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.