Genetic Evidence that Small Maf Proteins Are Essential for the Activation of Antioxidant Response Element-Dependent Genes

Abstract

While small Maf proteins have been suggested to be essential for the Nrf2-mediated activation of antioxidant response element (ARE)-dependent genes, the extent of their requirement remains to be fully documented. To address this issue, we generated mafG::mafF double-mutant mice possessing MafK as the single available small Maf. Induction of the NAD(P)H:quinone oxidoreductase 1 (NQO1) gene was significantly impaired in doublemutant mice treated with butylated hydroxyanisole, while other ARE-dependent genes were less affected. Similarly, in a keap1-null background, where many of the ARE-dependent genes are constitutively activated in an Nrf2-dependent manner, only a subset of ARE-dependent genes, including NQO1, were sensitive to a simultaneous deficiency in MafG and MafF. Examination of single and double small maf mutant cells revealed that MafK also contributes to the induction of ARE-dependent genes. To obtain decisive evidence, we established mafG::mafK::mafF triple-mutant fibroblasts that completely lack small Mafs and turned out to be highly susceptible to oxidative stress. We found that induction in response to diethyl maleate was abolished in a wider range of ARE-dependent genes in the triple-mutant cells. These data explicitly demonstrate that small Mafs play critical roles in the inducible expression of a significant portion of ARE-dependent genes.

Inflammation-induced repression of tumor suppressor miR-7 in gastric tumor cells

“…LPHN2 is a G protein-coupled receptor that binds a-latrotoxin (Ichtchenko et al, 1999), whereas BASP1 is implicated in neurite outgrowth (Korshunova et al, 2008). MAFG is one of the small Maf proteins that is important for antioxidant responses (Katsuoka et al, 2005). Although it remains to be investigated, it is of interest to examine whether these molecules have any role in the differentiation or tumorigenesis of gastric epithelial cells.…”

Modification in Oxidative Stress, Inflammation, and Lipoprotein Assembly in Response to Hepatocyte Nuclear Factor 4α Knockdown in Intestinal Epithelial Cells

“…Upon cytosolic activation of Nrf2, the transcription factor released from Keap1 translocates to the cell nucleus, binds to the promoters containing ARE, and accelerates transcription (52,53). Clusters transcribed include genes of GPX, SOD1, and CAT (54 -56) as well as those of several enzymes involved in cellular protection (51,53,(57)(58)(59)(60). According to our data, there was a down-regulation of Nrf2 in HNF4␣-depleted Caco-2 cells, which may explain the decline in the activity of CAT, GPx, and HO-1.…”

NF-E2 domination over Nrf2 promotes ROS accumulation and megakaryocytic maturation

“…The probes and primers for detecting Ho-1, Nqo1, Gsta4, Txnrd1, and Gpx1 have been previously described. 20,25 The probes and primers for detecting the expression of other genes are described in supplemental Table 1 (available on the Blood website; see the Supplemental Materials link at the top of the online article).…”

“…Through heterodimerization with small Maf proteins, Nrf2 confers cytoprotection against oxidative stress. [18][19][20] The transactivation domains of Nrf2 determine the heterodimer activity of Nrf2 and small Mafs. 21 Under basal conditions, Nrf2 is ubiquitinated by the Keap1-based ubiquitin E3 complex and is degraded by the proteasome.…”