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J. Biol. Chem., Vol. 280, Issue 6, 4483-4490, February 11, 2005

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Nrf2 Transcriptionally Activates the mafG Gene through an Antioxidant Response Element^*

Fumiki Katsuoka¶, Hozumi Motohashi||, James Douglas Engel**, and Masayuki Yamamoto

From the Graduate School of Comprehensive Human Sciences, Center for Tsukuba Advanced Research Alliance, and ERATO Environmental Response Project, University of Tsukuba, Tsukuba 305-8577, Japan, and ^**Department of Cell and Developmental Biology and Center for Organogenesis, University of Michigan, Ann Arbor, Michigan 48109-0616

Nrf2 accumulates in nuclei upon exposure to oxidative stress, heterodimerizes with a small Maf protein, and activates the transcription of stress target genes through antioxidant response elements (AREs). We found that diethyl maleate (DEM), a well known activator of Nrf2, induces one of the small Maf genes, mafG. To elucidate roles MafG might play in the oxidative stress response, we examined transcriptional regulation of the mouse mafG gene. MafG utilizes three independent first exons that are each spliced to second and third coding exons. Among the small maf genes, mafG showed the strongest response to DEM, and of the three first exons, the highest -fold induction was seen with the proximal first exon (Ic). Importantly, one ARE (Ic-ARE) is conserved in the promoter flanking exon Ic of the human and mouse mafG genes. The Nrf2/MafG heterodimer bound the Ic-ARE and activated transcription, whereas DEM failed to activate mafG in nrf2-null mutant cells. Chromatin immunoprecipitation further revealed that both Nrf2 and small Maf proteins associate with the Ic-ARE in vivo. These results demonstrate that mafG is itself an ARE-dependent gene that is regulated by an Nrf2/small Maf heterodimer and suggest the presence of an autoregulatory feedback pathway for mafG transcriptional regulation.

Received for publication, October 7, 2004 , and in revised form, November 15, 2004.

^* This work was supported by National Institutes of Health Grants CA80088 and GM28896 (to F. K., H. M., and J. D. E.), ERATO-JST (to M. Y.), the Ministry of Education, Science, Sports, and Culture (to H. M. and M. Y.), the Ministry of Health, Labor, and Welfare (to H. M. and M. Y.), CREST (to H. M.), the Atherosclerosis Foundation (to M. Y.), the Naito Foundation (to M. Y.), and the Special Coordination Fund for Promoting Science and Technology (to H. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ A Japan Society for the Promotion of Science Research Fellow.

^|| To whom correspondence may be addressed. Tel.: 81-29-853-7320; Fax: 81-29-853-7318; E-mail: hozumim{at}tara.tsukuba.ac.jp. To whom correspondence may be addressed. Tel.: 81-29-853-7320; Fax: 81-29-853-7318; E-mail: masi{at}tara.tsukuba.ac.jp.

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