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Nuclear factor-erythroid 2p45 (NF-E2)-related factor 2 (Nrf2) is a key regulator of antioxidant response element (ARE)-mediated gene expression of phase II detoxifying enzymes and antioxidant enzymes and play critical role in carcinogenesis and chemoprevention. The regulation of the transcriptional activity of Nrf2 by chemopreventive compounds involves multiple signaling pathways, including mitogen-activated protein kinases (MAPKs) and other co-regulators such as small Maf proteins. In the present study a small Maf protein MafG, its function in the regulation of Nrf2-dependent ARE-driven gene expression has been somehow controversial, was found to repress the basal but potentiate Nrf2-activated ARE-driven luciferase expression in Nrf2 -/- MEFs. The effects of MafG depended on its dosage and the ratio to Nrf2. On the other hand, extracellular signal-regulated kinase 2 (ERK2), once activated by a constitutively activated MAPK/ERK kinase 1 (MEK1), significantly enhanced the expression of ARE-driven luciferase. Furthermore, ERK2 and MafG synergistically upregulated the Nrf2-activated ARE-driven luciferase expression. Additionally Nrf2 was identified as a direct substrate of ERK2 both in vivo as well as in vitro for the first time. The phosphorylation of Nrf2 by ERK2 increased its heterodimerization with small Maf proteins. This may be responsible for the synergistic action of ERK2 and MafG. Taken together, the results contribute to clarify the role of small Maf proteins in the regulation of Nrf2-dependent ARE-driven gene expression, and unraveled a new mechanism by which ERK2 and MafG regulate Nrf2 signaling. (Supported by NIH grant R01-CA094828).

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA