Small Maf (MafG and MafK) Proteins Negatively Regulate Antioxidant Response Element-mediated Expression and Antioxidant Induction of the NAD(P)H:Quinone Oxidoreductase1 Gene

The antioxidant response element (ARE) is known to regulate expression and induction of NQO1, GST Ya, and other detoxifying enzyme genes in response to antioxidants and xenobiotics. The nuclear transcription factor Nrf2 and Nrf1 bind to the ARE and positively regulate expression and induction of the NQO1 and GST Ya genes. In this study, we demonstrate that overexpression of small Maf (MafG and MafK) proteins negatively regulate ARE-mediated expression and tert-butyl hydroquinone induction of the NQO1 and GST Ya genes in transfected Hep-G2 cells. In similar experiments, overexpression of small Maf proteins also repressed Nrf2-mediated up-regulation of ARE-mediated NQO1 and GST Ya genes expression in Hep-G2 cells co-transfected with Nrf2 and small Maf proteins. Band and supershift assays with the NQO1 gene ARE and nuclear proteins demonstrate that small MafG and MafK bind to the ARE as Maf-Maf homodimers and Maf-Nrf2 heterodimers. Therefore, Maf-Maf homodimers and possibly Maf-Nrf2 heterodimers play a role in negative regulation of ARE-mediated transcription and antioxidant induction of NQO1 and other detoxifying enzyme genes. In contrast to Maf-Nrf2, the Maf-Nrf1 heterodimers failed to bind with the NQO1 gene ARE and did not demonstrate the repressive effect in transfection assays. The antioxidant response element (ARE) is known to regulate expression and induction of NQO1, GST Ya, and other detoxifying enzyme genes in response to antioxidants and xenobiotics. The nuclear transcription factor Nrf2 and Nrf1 bind to the ARE and positively regulate expression and induction of the NQO1 and GST Ya genes. In this study, we demonstrate that overexpression of small Maf (MafG and MafK) proteins negatively regulate ARE-mediated expression and tert-butyl hydroquinone induction of the NQO1 and GST Ya genes in transfected Hep-G2 cells. In similar experiments, overexpression of small Maf proteins also repressed Nrf2-mediated up-regulation of ARE-mediated NQO1 and GST Ya genes expression in Hep-G2 cells co-transfected with Nrf2 and small Maf proteins. Band and supershift assays with the NQO1 gene ARE and nuclear proteins demonstrate that small MafG and MafK bind to the ARE as Maf-Maf homodimers and Maf-Nrf2 heterodimers. Therefore, Maf-Maf homodimers and possibly Maf-Nrf2 heterodimers play a role in negative regulation of ARE-mediated transcription and antioxidant induction of NQO1 and other detoxifying enzyme genes. In contrast to Maf-Nrf2, the Maf-Nrf1 heterodimers failed to bind with the NQO1 gene ARE and did not demonstrate the repressive effect in transfection assays. NAD(P)H:quinone oxidoreductase1 glutathioneS-transferase γ-glutamylcysteine synthetase antioxidant response element human NQO1 gene ARE tert-butyl hydroquinone reactive oxygen species polyacrylamide gel electrophoresis NAD(P)H:quinone oxidoreductase1 (NQO1)1 is a flavoprotein that catalyzes two-electron reductive metabolism and detoxification of quinones. This protects cells against quinone-induced oxidative stress and neoplasia (1Radjendirane V. Joseph P. Jaiswal A.K. Forman H.J. Cadenas E. Oxidative Stress and Signal Transduction. Chapman 82–83: 173-179Crossref PubMed Scopus (438) Google Scholar). Higher levels of NQO1 gene expression were observed in liver, lung, colon, and breast tumors, when compared with normal tissues of the same origin (3Cresteil T. Jaiswal A.K. Biochem. Pharmacol. 1991; 42: 1021-1027Crossref PubMed Scopus (168) Google Scholar, 4Schlager J.J. Powis G. Int. J. Cancer. 1990; 45: 403-409Crossref PubMed Scopus (247) Google Scholar). NQO1 gene transcription is coordinately activated with other detoxifying enzyme genes in response to xenobiotics (e.g. β-naphthoflavone) and antioxidants (e.g. tert-butylhydroquinone (t-BHQ)) (5Rushmore T.H. Pickett C.B. J. Biol. Chem. 1993; 268: 11475-11478Abstract Full Text PDF PubMed Google Scholar, 6Dhakshinamoorthy S. Long II D.J. Jaiswal A.K. Curr. Top. Cell. Regul. 2000; 36: 201-216Crossref PubMed Scopus (169) Google Scholar). The other detoxifying enzyme genes that are coordinately induced with NQO1 include glutathioneS-transferases (GSTs), which conjugate hydrophobic electrophiles and ROS with glutathione (7Pickett C.B. Lu A.Y.H. Annu. Rev. Biochem. 1989; 58: 743-764Crossref PubMed Scopus (544) Google Scholar, 8Tsuchida S. Sato K. Crit. Rev. Biochem. Mol. Biol. 1992; 27: 337-384Crossref PubMed Scopus (530) Google Scholar); UDP-glucuronosyl transferases, which catalyze the conjugation of glucuronic acid with xenobiotics and drugs for excretion (9Tephly T. Burchell B. Trends Pharmacol. 1990; 11: 276-279Abstract Full Text PDF PubMed Scopus (244) Google Scholar); epoxide hydrolase, which inactivates epoxides (10Oesch F. Gath I. Igarashi T. Glatt H.R. Thomas H. Arinc E. Schenkman J.B. Hodgson E. Molecular Aspects of Monooxygenases and Bioactivation of Toxic Compounds. Plenum Publishing Corp., New York1991: 447-461Crossref Google Scholar); γ-glutamylcysteine synthetase (γ-GCS), which plays a role in glutathione metabolism (11Mulcahy R.T. Wartman M.A. Bailey H.H. Gipp J.J. J. Biol. Chem. 1997; 272: 7445-7454Abstract Full Text Full Text PDF PubMed Scopus (418) Google Scholar); ferritin-L gene, which plays an important role in iron storage (12Wasserman W. Fahl W.E. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 5361-5366Crossref PubMed Scopus (630) Google Scholar); and heme oxygenase-1, which catalyzes the first and rate-limiting step in heme catabolism (13Choi A.M. Alam J. Am. J. Respir. Cell Mol. Biol. 1996; 15: 9-19Crossref PubMed Scopus (999) Google Scholar). The coordinated induction of these genes, including NQO1, protects cells against free radical damage, oxidative stress, and neoplasia. It is critical in achieving chemoprevention. Deletion mutagenesis studies of the human NQO1 gene promoter identified 24 base pairs of an antioxidant response element (ARE) between nucleotides −470 and −447. This region is required for basal expression and induction of NQO1 in response to β-naphthoflavone and t-BHQ (6Dhakshinamoorthy S. Long II D.J. Jaiswal A.K. Curr. Top. Cell. Regul. 2000; 36: 201-216Crossref PubMed Scopus (169) Google Scholar). ARE elements have also been found in the promoter region of the human NQO2 gene (14Jaiswal A.K. J. Biol. Chem. 1994; 269: 14502-14508Abstract Full Text PDF PubMed Google Scholar), the rat and mouse GST Ya subunit genes (15Rushmore T.H. King R.G. Paulson K.E. Pickett C.B. Proc. Natl. Acad. Sci. U. S. 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A. 1997; 94: 5361-5366Crossref PubMed Scopus (630) Google Scholar), and the human heme oxygenase-1 gene (21Alam J. Stewart D. Touchard C. Boinapally S. Choi M.K. Cook J.L. J. Biol. Chem. 1999; 274: 26071-26078Abstract Full Text Full Text PDF PubMed Scopus (1040) Google Scholar). Analysis of the AREs from various genes revealed that they contain AP1/AP1-like elements arranged as inverse or direct repeats. This is followed by a GC A.K. Biochem. Pharmacol. 1994; PubMed Scopus Google Scholar). and the have been to to the ARE-mediated expression and induction of detoxifying enzyme genes (12Wasserman W. Fahl W.E. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 5361-5366Crossref PubMed Scopus (630) Google Scholar, T. M. Y. Jaiswal A.K. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar, T. Holtzclaw W.D. Zhang Y. P. Proc. Natl. Acad. Sci. U. S. A. 1993; PubMed Scopus Google Scholar). The various AREs bind to a of nuclear proteins from cells of (15Rushmore T.H. King R.G. Paulson K.E. Pickett C.B. Proc. Natl. Acad. Sci. U. S. A. 1990; 87: 3826-3830Crossref PubMed Scopus (385) Google Scholar, 16Rushmore T.H. Pickett C.B. J. Biol. Chem. 1990; 265: 14648-14653Abstract Full Text PDF PubMed Google Scholar, 17Rushmore T.H. Morton M.R Pickett C.B. J. Biol. Chem. 1991; 266: 11632-11639Abstract Full Text PDF PubMed Google Scholar, 18Friling R.S. Bensimon A. Tichauer Y. Daniel V. Proc. Natl. Acad. Sci. U. S. A. 1990; 87: 6258-6262Crossref PubMed Scopus (422) Google Scholar, 19Friling R.S. Bergelson S. Daniel V. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 668-672Crossref PubMed Scopus (213) Google Scholar, A. Imagawa M. Maeda Y. Sakai M. Muramatsu M. EMBO J. 1990; 9: 1131-1135Crossref PubMed Scopus (87) Google Scholar, J. Stewart D. Touchard C. Boinapally S. Choi M.K. Cook J.L. J. Biol. Chem. 1999; 274: 26071-26078Abstract Full Text Full Text PDF PubMed Scopus (1040) Google Scholar, A.K. Biochem. Pharmacol. 1994; PubMed Scopus Google Scholar, T. M. Y. Jaiswal A.K. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar, Y. Jaiswal A.K. J. Biol. Chem. 1992; Full Text PDF PubMed Google Scholar). Analysis of have identified nuclear transcription including and the these transcription Nrf1 and Nrf2 have been to with and the ARE-mediated expression and induction of NQO1 in response to antioxidants and xenobiotics Jaiswal A.K. Proc. Natl. Acad. Sci. U. S. A. 1996; PubMed Scopus Google Scholar, Jaiswal A.K. PubMed Scopus Google Scholar). a of the of transcription and A. E. T. K. S. Igarashi K. M. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). The transcription factor Nrf2 and which regulate the ARE-mediated expression and induction of NQO1, were also to regulate the expression and induction of other detoxifying as GST Ya, γ-GCS and heme oxygenase-1 (21Alam J. Stewart D. Touchard C. Boinapally S. Choi M.K. Cook J.L. J. Biol. Chem. 1999; 274: 26071-26078Abstract Full Text Full Text PDF PubMed Scopus (1040) Google Scholar, Jaiswal A.K. Proc. Natl. Acad. Sci. U. S. A. 1996; PubMed Scopus Google Scholar, Jaiswal A.K. PubMed Scopus Google Scholar, A.K. I. S. H. S. T. J. Molecular of of and the Scholar, M. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar, H. R.T. Biochem. 1999; PubMed Scopus Google Scholar, H.R. R.T. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). to bind to the ARE of a gene a subunit of GST Ya K. T. S. T. Igarashi K. K. T. K. I. M. Y. Biochem. 1997; PubMed Scopus Google Scholar). It that heterodimers ARE-mediated expression and induction of the GST Ya a repressive role for MafK and MafG in expression of the γ-GCS gene H.R. R.T. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). Maf and proteins are proteins that are known to as as transcription of genes including gene K. M. M. Mol. Cell. Biol. 1994; PubMed Google Scholar, 1997; 89: PubMed Google Scholar, K. H. H. M. S. 1993; Google Scholar, K. M. S. J. 1993; PubMed Google Scholar). gene are to in the of the and The of these small Maf the of 1997; 89: PubMed Google Scholar, K. H. H. M. S. 1993; Google Scholar, K. M. S. J. 1993; PubMed Google Scholar). This is required for the of 1997; 89: PubMed Google Scholar, K. H. H. M. S. 1993; Google Scholar, K. M. S. J. 1993; PubMed Google Scholar). small Maf proteins were to and with Nrf1 and Nrf2 K. A. P. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar). Maf-Maf homodimers heterodimers activated transcription of the gene K. A. P. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar). the small Maf proteins are to play a role in regulation of NQO1 gene This role In the of MafG and MafK with Nrf2 and in the regulation of ARE-mediated expression and induction of NQO1 and other detoxifying enzyme genes, also In the we demonstrate that overexpression of MafG and or in with repressed ARE-mediated expression and induction of NQO1 and GST Ya genes. NQO1 gel with in MafG and and in with revealed that MafG and MafK proteins bind to the NQO1 as homodimers and heterodimers with that MafG and MafK homodimers and possibly and heterodimers negatively regulate NQO1 and other detoxifying enzyme gene expression and induction by In similar experiments, MafG and MafK failed to bind to the NQO1 gene ARE as heterodimers with The in this were from and were from from transfection from The Nrf2 were from t-BHQ and other were from The promoter gene, that the and the were from The and were from The NQO1 gene and GST Ya ARE were in the to and Ya The of the various AREs are in The and to the AREs were with and Ya The were and the in the promoter The GST Ya ARE the The various were by The mouse Nrf2 and Nrf1 were by Y. of The Nrf2 and Nrf1 were by and the expression to the expression and The MafG and MafK were by The MafG and MafK were the to the expression and The with an contain in the and with the contain in the The MafG and MafK were also with the of the expression the and proteins. The in the cells were in with Y. Jaiswal A.K. J. Biol. Chem. 1992; Full Text PDF PubMed Google Scholar). The transfection from to the by as in the of and GST Ya were and in with of the expression and MafK) and transfected Hep-G2 cells. The as the in The various were with and from the and for This followed by of to the This for The the Hep-G2 cells and with the the cells were with and in from the The from to the for as in the the for the of the of the Full Text PDF PubMed Google Scholar). The Hep-G2 cells were co-transfected with and in to Nrf2 and cells were with and t-BHQ for and nuclear by Y. Jaiswal A.K. J. Biol. Chem. 1992; Full Text PDF PubMed Google Scholar). of the and were the by as in the for in the the the proteins were for a and of the proteins were a with to and to In a similar the proteins were a and with Nrf2 and were to the Maf proteins. of the in proteins the The NQO1 gene ARE with and The ARE with nuclear or in proteins. Band and supershift assays were by Y. Jaiswal A.K. J. Biol. Chem. 1992; Full Text PDF PubMed Google Scholar, Jaiswal A.K. PubMed Scopus Google Scholar). of the nuclear or of in proteins were in the gel and supershift The supershift with nuclear of proteins. of and of Nrf2 or were in the supershift assays. The transfection of Hep-G2 cells with expression and to the overexpression of these proteins as by and not of the various proteins in between and of for Hep-G2 cells. In similar experiments, transfection of Hep-G2 cells with in did not in overexpression of the proteins. of Hep-G2 cells with the of MafG in Hep-G2 cells repressed in transfected cells This MafG The transfection of of repressed of in transfected Hep-G2 cells. transfection of Hep-G2 cells with MafG the The transfection of of in the to overexpression of Nrf2 in Hep-G2 cells to expression of the NQO1 gene ARE-mediated gene In a similar the Nrf2-mediated up-regulation of gene expression repressed of the overexpression of MafG This also MafG were also observed with Hep-G2 cells MafK or MafK with Nrf2 The overexpression of MafK repressed gene expression and by of the with in the of basal expression and of the gene by MafG and MafK In experiments, the overexpression of MafG and MafK also repressed GST Ya ARE-mediated gene expression and up-regulation by Nrf2 t-BHQ of Hep-G2 transfected with and GST Ya gene by t-BHQ induction of and GST Ya ARE-mediated gene expression also repressed in Hep-G2 cells that MafG and MafK The of t-BHQ induced expression or to the of basal In other overexpression of small Maf proteins the basal and t-BHQ induced of overexpression of MafG and MafK GST Ya gene ARE-mediated gene expression and up-regulation by The Hep-G2 cells were co-transfected with GST Ya and expression and or in as The of the various in the are also of as the in The cells were transfection and for The the of transfection of overexpression of MafG and MafK antioxidant induction of ARE-mediated gene Hep-G2 cells were co-transfected with or GST Ya and expression and in as of as the in The transfected cells were with or of t-BHQ The cells were the and for The the of transfection The and were in and with and MafG and MafK is in The in Nrf2 and Nrf1 proteins between the and Nrf1 The in and proteins the in The in proteins were by and with not The of in and Nrf1 to the NQO1 gene ARE by and supershift assays MafG and MafK to the as Maf-Maf homodimers and heterodimers The of and heterodimers of Maf and Nrf2 were with not The of MafG and MafK in Maf-Maf homodimers and heterodimers were by supershift assays with The against Nrf2 also heterodimers in with and The of assays with and nuclear from Hep-G2 cells with and t-BHQ are The as observed with in Nrf2 and Maf proteins The and to the heterodimers and Maf-Maf It that the and are not to and Maf-Maf are also to contain including Jaiswal A.K. PubMed Scopus Google Scholar). The of Nrf2 and Maf in the and by supershift assays with The Hep-G2 cells with t-BHQ in of nuclear proteins in and as compared with This is to of including Jaiswal A.K. PubMed Scopus Google Scholar). The Hep-G2 cells Nrf2 and MafG also as compared with the in of as compared with The of Hep-G2 cells with t-BHQ also in of and The overexpression of Nrf1 in Hep-G2 cells is known to the gene expression in transfected Hep-G2 cells Jaiswal A.K. Proc. Natl. Acad. Sci. U. S. A. 1996; PubMed Scopus Google Scholar). The of the of Nrf1 with a of MafG an in gene expression This Nrf1 in the similar the of Nrf1 with Nrf2 did not to in gene expression in transfected Hep-G2 cells The of the assays with NQO1 gene and in Nrf1 are in In experiments, in and with MafG or failed to bind to the NQO1 gene ARE as homodimers or heterodimers with MafG and MafK assays. of the with in Nrf1 and in with or or were as The and were for with The and polyacrylamide The gel and The the of Maf proteins and 1997; 89: PubMed Google Scholar, K. H. H. M. S. 1993; Google Scholar, K. M. S. J. 1993; PubMed Google Scholar, K. K. K. M. M. 1994; PubMed Scopus Google Scholar). studies the role of small Maf proteins were with expression of the gene K. K. K. M. M. 1994; PubMed Scopus Google Scholar). The small Maf proteins bind to the of the gene and the of factor K. K. K. M. M. 1994; PubMed Scopus Google Scholar). of the small Maf proteins as negative heterodimers of Maf and transcription in K. K. K. M. M. 1994; PubMed Scopus Google Scholar). small Maf proteins were also to and with the and regulate the gene expression K. A. P. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar). Maf-Maf homodimers repressed heterodimers activated transcription of the gene K. A. P. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar). The and Maf proteins are also known to bind with AREs from detoxifying enzyme genes K. T. S. T. Igarashi K. K. T. K. I. M. Y. Biochem. 1997; PubMed Scopus Google Scholar, H.R. R.T. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). Nrf2 and Nrf1 are known to the ARE-mediated expression and induction of NQO1, GST Ya, and heme oxygenase-1 genes (21Alam J. Stewart D. Touchard C. Boinapally S. Choi M.K. Cook J.L. J. Biol. Chem. 1999; 274: 26071-26078Abstract Full Text Full Text PDF PubMed Scopus (1040) Google Scholar, Jaiswal A.K. Proc. Natl. Acad. Sci. U. S. A. 1996; PubMed Scopus Google Scholar, Jaiswal A.K. PubMed Scopus Google Scholar, A.K. I. S. H. S. T. J. Molecular of of and the Scholar, H.R. R.T. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). the role of small Maf proteins in the ARE-mediated detoxifying enzyme genes expression of It that ARE is a element and A.K. Biochem. Pharmacol. 1994; PubMed Scopus Google Scholar, T. M. Y. Jaiswal A.K. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar, K. M. M. Mol. Cell. Biol. 1994; PubMed Google Scholar). Therefore, the role of Maf-Maf homodimers and heterodimers in ARE-mediated regulation of detoxifying enzyme genes expression In the we demonstrate that small Maf proteins to the regulation of ARE-mediated NQO1 and GST Ya gene The small Maf (MafG and MafK) proteins negatively regulate ARE-mediated expression and antioxidant induction of NQO1 and GST Ya gene This is the of MafG and MafK repressed ARE-mediated as as by The of t-BHQ induced expression or to the of basal Band and supershift assays that and homodimers bind with NQO1 gene ARE and in the of NQO1 gene Therefore, the studies demonstrate that small Maf homodimers negatively regulate NQO1 and other detoxifying enzyme gene to the negative role of small Maf proteins in ARE-mediated gene expression from the that the expression of of MafG and MafK the ARE-mediated NQO1 and GST Ya gene It that are small Maf proteins. include and Maf proteins are to Therefore, the of MafG not bind to MafG also to MafK and to of ARE-mediated gene the effect of are not of the small Maf proteins. of that small Maf-Nrf2 heterodimers also negatively regulate ARE-mediated NQO1 gene overexpression of MafG and MafK repressed Nrf2 up-regulation of ARE-mediated NQO1 and GST Ya gene the and heterodimers with the NQO1 gene and overexpression of of Nrf1 with of MafG to Nrf1 in ARE-mediated NQO1 gene In a similar an in Nrf2 with a of MafG failed to the ARE-mediated gene In the in Nrf2 with of MafG small in ARE-mediated gene This as negative of ARE-mediated gene Therefore, is that Maf heterodimers also to the negative regulation of ARE-mediated gene the role of Maf heterodimers in negative regulation of ARE-mediated gene expression to by the repressive role of Maf heterodimers is also by a the repressive role of in ARE-mediated gene expression T. Pickett C.B. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). This did not the Maf-Maf homodimers in assays as observed by in the The is that we gel that in the The Maf-Maf homodimers to an from and by the In we to demonstrate the of Maf-Maf homodimers in assays The supershift assays were not in the the role of MafK in ARE-mediated gene expression T. Pickett C.B. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). In similar to Nrf1 overexpression of with did not a role of in the negative regulation of NQO1 gene of of Nrf1 and Nrf2 with a of MafG The in Nrf1 and not Nrf2 in expression of ARE-mediated gene expression in transfected cells. In and heterodimers were not in the and supershift assays. to the that Maf heterodimers not bind to the ARE and have or effect the gene Nrf1 is known to heterodimers with which to and γ-GCS ARE K. A. P. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar, M. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). It is that Nrf1 heterodimers with MafG and MafK in and heterodimers failed to bind with NQO1 gene Nrf1 also been to bind with γ-GCS ARE as M. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). Nrf1 not bind with NQO1 gene ARE as Jaiswal A.K. PubMed Scopus Google and or as with small Maf proteins. The of this between NQO1 and γ-GCS ARE In the effect of Nrf2 and Nrf1 with Maf proteins NQO1 gene ARE also to demonstrate the negative role of small Maf (MafG and MafK) proteins in ARE-mediated expression and induction of NQO1 and other detoxifying enzyme genes is in The metabolism of antioxidants and xenobiotics electrophiles and ROS that the of a of genes including NQO1 and GST Ya (1Radjendirane V. Joseph P. Jaiswal A.K. Forman H.J. Cadenas E. Oxidative Stress and Signal Transduction. Chapman 274: Full Text Full Text PDF PubMed Scopus Google Scholar, H.R. R.T. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). also the role of in ARE-mediated gene expression in T. K. S. Sato H. T. Y. S. M. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). these the role of in regulation of ARE-mediated gene expression M. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar, H.R. R.T. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar, T. K. S. Sato H. T. Y. S. M. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). This in of these to the in transfection were in of a role of in regulation of ARE-mediated gene In the Nrf2 and Maf heterodimers have been to negatively regulate ARE-mediated GST Ya and genes expression and induction T. Pickett C.B. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). This the negative role of by in gel as as in transfection T. Pickett C.B. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). in the negative regulation by Maf-Maf homodimers and possibly by Maf-Nrf2 heterodimers. studies the negative or role of heterodimers in ARE-mediated gene The in the various genes ARE to heterodimers also to this and the small Maf proteins the identified negative and as of ARE-mediated gene expression Jaiswal A.K. Proc. Natl. Acad. Sci. U. S. A. 1996; PubMed Scopus Google Scholar, Jaiswal A.K. PubMed Scopus Google Scholar, V. Jaiswal A.K. Biochem. PubMed Scopus Google Scholar). an the of and negative in normal cells. is that small of and reactive species are required for the of detoxifying and proteins to a in the levels of free cells negative to the levels of from the to In small Maf homodimers and possibly Maf heterodimers negatively regulate ARE-mediated expression and antioxidant induction of NQO1 and other detoxifying enzyme genes. studies are required to the role of and negative in ARE-mediated expression and induction of detoxifying enzyme genes. are to Y. and W. from of for the Nrf2 and are also to for the of small Maf