Role of Gα 12 and Gα 13 as Novel Switches for the Activity of Nrf2, a Key Antioxidative Transcription Factor

Abstract

ABSTRACT Gα 12 and Gα 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 Gα 12 and Gα 13 . A deficiency of Gα 12 , but not of Gα 13 , enhanced Nrf2 activity and target gene transactivation in embryo fibroblasts. In mice, Gα 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 Gα 12 gene knockout. Gα 12 deficiency reduced Jun N-terminal protein kinase (JNK)-dependent Nrf2 ubiquitination required for proteasomal degradation, and so did Gα 13 deficiency. The absence of Gα 12 , but not of Gα 13 , increased protein kinase C δ (PKC δ) activation and the PKC δ-mediated serine phosphorylation of Nrf2. Gα 13 gene knockout or knockdown abrogated the Nrf2 phosphorylation induced by Gα 12 deficiency, suggesting that relief from Gα 12 repression leads to the Gα 13 -mediated activation of Nrf2. Constitutive activation of Gα 13 promoted Nrf2 activity and target gene induction via Rho-mediated PKC δ activation, corroborating positive regulation by Gα 13 . In summary, Gα 12 and Gα 13 transmit a JNK-dependent signal for Nrf2 ubiquitination, whereas Gα 13 regulates Rho-PKC δ-mediated Nrf2 phosphorylation, which is negatively balanced by Gα 12 .