Role of Gα12 and Gα13 as novel switches for the activity of Nrf2, a key antioxidative transcription factor

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

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

12 and Gα13 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 Gα12 and Gα13. A deficiency of Gα12, but not of Gα13, enhanced Nrf2 activity and target gene transactivation in embryo fibroblasts. In mice, Gα12 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 Gα12 gene knockout. Gα12 deficiency reduced Jun N-terminal protein kinase (JNK)-dependent Nrf2 ubiquitination required for proteasomal degradation, and so did Gα13 deficiency. The absence of Gα12, but not of Gα13, increased protein kinase C δ (PKC δ) activation and the PKC δ-mediated serine phosphorylation of Nrf2. Gα13 gene knockout or knockdown abrogated the Nrf2 phosphorylation induced by Gα12 deficiency, suggesting that relief from Gα12 repression leads to the Gα13- mediated activation of Nrf2. Constitutive activation of Gα13 promoted Nrf2 activity and target gene induction via Rho-mediated PKC δ activation, corroborating positive regulation by Gα13. In summary, Gα12 and Gα13 transmit a JNK-dependent signal for Nrf2 ubiquitination, whereas Gα13 regulates Rho-PKC δ-mediated Nrf2 phosphorylation, which is negatively balanced by Gα12.

Original languageEnglish
Pages (from-to)6195-6208
Number of pages14
JournalMolecular and Cellular Biology
Volume27
Issue number17
DOIs
Publication statusPublished - 2007 Sep 1

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

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