Role of G alpha(12) and g alpha(13) as novel switches for the activity of Nrf2, a key antioxidative transcription factoropen access
- Authors
- Cho, Min Kyung; Kim, Won Dong; Ki, Sung Hwan; Hwang, Jong-IK; Choi, Sangdun; Lee, Chang Ho; Kim, Sang Geon
- Issue Date
- Sep-2007
- Publisher
- AMER SOC MICROBIOLOGY
- Citation
- MOLECULAR AND CELLULAR BIOLOGY, v.27, no.17, pp.6195 - 6208
- Indexed
- SCIE
SCOPUS
- Journal Title
- MOLECULAR AND CELLULAR BIOLOGY
- Volume
- 27
- Number
- 17
- Start Page
- 6195
- End Page
- 6208
- URI
- https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/179638
- DOI
- 10.1128/MCB.02065-06
- ISSN
- 0270-7306
- Abstract
- 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).
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