MAFG explained

See also: Small Maf.

Transcription factor MafG is a bZip Maf transcription factor protein that in humans is encoded by the MAFG gene.^{[1] [2]}

MafG is one of the small Maf proteins, which are basic region and leucine zipper (bZIP)-type transcription factors. The HUGO Gene Nomenclature Committee-approved gene name of MAFG is “v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog G”.

Discovery

MafG was first cloned and identified in chicken in 1995 as a new member of the small Maf (sMaf) genes. MAFG has been identified in many vertebrates, including humans. There are three functionally redundant sMaf proteins in vertebrates, MafF, MafG, and MafK.^{[2] [3]}

Structure

MafG has a bZIP structure that consists of a basic region for DNA binding and a leucine zipper structure for dimer formation. Similar to other sMafs, MafG lacks any canonical transcriptional activation domains.

Expression

MAFG is broadly but differentially expressed in various tissues. MAFG expression was detected in all 16 tissues examined by the human BodyMap Project, but relatively abundant in lung, lymph node, skeletal muscle and thyroid tissues.^[4] MafG gene expression is induced by oxidative stresses, such as hydrogen peroxide and electrophilic compounds.^{[5] [6]} Mouse Mafg gene is induced by Nrf2-sMaf heterodimers through an antioxidant response element (ARE) at the promoter proximal region. In response to bile acids, mouse Mafg gene is induced by the nuclear receptor, FXR (Farnesoid X receptor).^[7]

Function

Because of sequence similarity, no functional differences have been observed among the sMafs in terms of their bZIP structures. sMafs form homodimers by themselves and heterodimers with other specific bZIP transcription factors, such as CNC (cap 'n' collar) proteins [p45 NF-E2 ([[NFE2]]), Nrf1 (NFE2L1), Nrf2 (NFE2L2), and Nrf3 (NFE2L3)]^{[8] [9] [10] [11]} and Bach proteins (BACH1 and BACH2).^[12]

sMaf homodimers bind to a palindromic DNA sequence called the Maf recognition element (MARE: TGCTGACTCAGCA) and its related sequences.^[13] Structural analyses have demonstrated that the basic region of a Maf factor recognizes the flanking GC sequences.^[14] By contrast, CNC-sMaf or Bach-sMaf heterodimers preferentially bind to DNA sequences (RTGA(C/G)NNNGC: R=A or G) that are slightly different from MARE.^[15] The latter DNA sequences have been recognized as antioxidant/electrophile response elements^{[16] [17]} or NF-E2-binding motifs^{[18] [19]} to which Nrf2-sMaf heterodimers and p45 NF-E2-sMaf heterodimer bind, respectively. It has been proposed that the latter sequences should be classified as CNC-sMaf-binding elements (CsMBEs).

It has also been reported that sMafs form heterodimers with other bZIP transcription factors, such as c-Jun and c-Fos.^[20]

Target genes

sMafs regulate different target genes depending on their partners. For instance, the p45-NF-E2-sMaf heterodimer regulate genes responsible for platelet production.^{[21] [22]} Nrf2-sMaf heterodimer regulates a battery of cytoprotective genes, such as antioxidant/xenobiotic metabolizing enzyme genes.^[23] The Bach1-sMaf heterodimer regulates the heme oxygenase-1 gene. In particular, it has been reported that Bach1-MafG heterodimers participate in the hypermethylation of genes with CpG island promoters in certain types of cancers.^[24] The contribution of individual sMafs to the transcriptional regulation of their target genes has not yet been well examined.

Disease linkage

Loss of sMafs results in disease-like phenotypes as summarized in table below. Mice lacking MafG exhibit mild neuronal phenotype and mild thrombocytopenia. However, mice lacking Mafg and one allele of Mafk (Mafg^−/−::Mafk^+/−) exhibit more severe neuronal phenotypes, severe thrombocytopenia and cataracts.^{[25] [26]} Mice lacking MafG and MafK (Mafg^−/−::Mafk^−/−) die in the perinatal stage.^[27] Finally, mice lacking MafF, MafG and MafK are embryonic lethal.^[28] Embryonic fibroblasts that are derived from Maff^−/−::Mafg^−/−::Mafk^−/− mice fail to activate Nrf2-dependent cytoprotective genes in response to stress.

Genotype			Mouse Phenotype
Maff	Mafg	Mafk
	−/−		Mild motor ataxia, mild thrombocytopenia
	−/−	+/−	Severe motor ataxia, progressive neuronal degeneration, severe thrombocytopenia, and cataract
	−/−	−/−	More severe neuronal phenotypes, and perinatal lethal
−/−	+/−	−/−	No severe abnormality (Fertile)
−/−	−/−	−/−	Growth retardation, fetal liver hypoplasia, and lethal around embryonic day, 13.5
+/− (heterozygote), −/− (homozygote), blank (wild-type)

In addition, accumulating evidence suggests that as partners of CNC and Bach proteins, sMafs are involved in the onset and progression of various human diseases, including neurodegeneration, arteriosclerosis and cancer.

Further reading

• Bonaldo MF, Lennon G, Soares MB . Normalization and subtraction: two approaches to facilitate gene discovery . Genome Research . 6 . 9 . 791–806 . Sep 1996 . 8889548 . 10.1101/gr.6.9.791 . free .
• Johnsen O, Skammelsrud N, Luna L, Nishizawa M, Prydz H, Kolstø AB . Small Maf proteins interact with the human transcription factor TCF11/Nrf1/LCR-F1 . Nucleic Acids Research . 24 . 21 . 4289–97 . Nov 1996 . 8932385 . 146217 . 10.1093/nar/24.21.4289 .
• Toki T, Itoh J, Kitazawa J, Arai K, Hatakeyama K, Akasaka J, Igarashi K, Nomura N, Yokoyama M, Yamamoto M, Ito E . Human small Maf proteins form heterodimers with CNC family transcription factors and recognize the NF-E2 motif . Oncogene . 14 . 16 . 1901–10 . Apr 1997 . 9150357 . 10.1038/sj.onc.1201024 . free .
• Blank V, Kim MJ, Andrews NC . Human MafG is a functional partner for p45 NF-E2 in activating globin gene expression . Blood . 89 . 11 . 3925–35 . Jun 1997 . 9166829 . 10.1182/blood.V89.11.3925. free .
• Marini MG, Chan K, Casula L, Kan YW, Cao A, Moi P . hMAF, a small human transcription factor that heterodimerizes specifically with Nrf1 and Nrf2 . The Journal of Biological Chemistry . 272 . 26 . 16490–7 . Jun 1997 . 9195958 . 10.1074/jbc.272.26.16490 . free .
• Blank V, Knoll JH, Andrews NC . Molecular characterization and localization of the human MAFG gene . Genomics . 44 . 1 . 147–9 . Aug 1997 . 9286713 . 10.1006/geno.1997.4847 .
• Dhakshinamoorthy S, Jaiswal AK . 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 Journal of Biological Chemistry . 275 . 51 . 40134–41 . Dec 2000 . 11013233 . 10.1074/jbc.M003531200 . free .
• Kataoka K, Yoshitomo-Nakagawa K, Shioda S, Nishizawa M . A set of Hox proteins interact with the Maf oncoprotein to inhibit its DNA binding, transactivation, and transforming activities . The Journal of Biological Chemistry . 276 . 1 . 819–26 . Jan 2001 . 11036080 . 10.1074/jbc.M007643200 . free .
• Hung HL, Kim AY, Hong W, Rakowski C, Blobel GA . Stimulation of NF-E2 DNA binding by CREB-binding protein (CBP)-mediated acetylation . The Journal of Biological Chemistry . 276 . 14 . 10715–21 . Apr 2001 . 11154691 . 10.1074/jbc.M007846200 . free .
• Kusunoki H, Motohashi H, Katsuoka F, Morohashi A, Yamamoto M, Tanaka T . Solution structure of the DNA-binding domain of MafG . Nature Structural Biology . 9 . 4 . 252–6 . Apr 2002 . 11875518 . 10.1038/nsb771 . 23687470 .
• Dhakshinamoorthy S, Jaiswal AK . c-Maf negatively regulates ARE-mediated detoxifying enzyme genes expression and anti-oxidant induction . Oncogene . 21 . 34 . 5301–12 . Aug 2002 . 12149651 . 10.1038/sj.onc.1205642 . 20476280 .
• Tramier M, Gautier I, Piolot T, Ravalet S, Kemnitz K, Coppey J, Durieux C, Mignotte V, Coppey-Moisan M . Picosecond-hetero-FRET microscopy to probe protein-protein interactions in live cells . Biophysical Journal . 83 . 6 . 3570–7 . Dec 2002 . 12496124 . 1302432 . 10.1016/S0006-3495(02)75357-5 . 2002BpJ....83.3570T .
• Yamamoto T, Kyo M, Kamiya T, Tanaka T, Engel JD, Motohashi H, Yamamoto M . Predictive base substitution rules that determine the binding and transcriptional specificity of Maf recognition elements . Genes to Cells . 11 . 6 . 575–91 . Jun 2006 . 16716189 . 10.1111/j.1365-2443.2006.00965.x . 2027.42/71635 . 5546846 . free .

Notes and References

1. Kataoka K, Igarashi K, Itoh K, Fujiwara KT, Noda M, Yamamoto M, Nishizawa M . Small Maf proteins heterodimerize with Fos and may act as competitive repressors of the NF-E2 transcription factor . Molecular and Cellular Biology . 15 . 4 . 2180–90 . Apr 1995 . 7891713 . 230446 . 10.1128/mcb.15.4.2180.
2. Web site: Entrez Gene: MAFG v-maf musculoaponeurotic fibrosarcoma oncogene homolog G (avian).
3. Sep 1993. Two new members of the maf oncogene family, mafK and mafF, encode nuclear b-Zip proteins lacking putative trans-activator domain. Oncogene. 8. 9. 2371–80. 8361754. Fujiwara KT, Kataoka K, Nishizawa M.
4. Petryszak R, Burdett T, Fiorelli B, Fonseca NA, Gonzalez-Porta M, Hastings E, Huber W, Jupp S, Keays M, Kryvych N, McMurry J, Marioni JC, Malone J, Megy K, Rustici G, Tang AY, Taubert J, Williams E, Mannion O, Parkinson HE, Brazma A . Expression Atlas update--a database of gene and transcript expression from microarray- and sequencing-based functional genomics experiments . Nucleic Acids Research . 42 . Database issue . D926–32 . Jan 2014 . 24304889 . 10.1093/nar/gkt1270 . 3964963.
5. Crawford DR, Leahy KP, Wang Y, Schools GP, Kochheiser JC, Davies KJ . Oxidative stress induces the levels of a MafG homolog in hamster HA-1 cells . Free Radical Biology & Medicine . 21 . 4 . 521–5 . 1996 . 8886803 . 10.1016/0891-5849(96)00160-8.
6. Katsuoka F, Motohashi H, Engel JD, Yamamoto M . Nrf2 transcriptionally activates the mafG gene through an antioxidant response element . The Journal of Biological Chemistry . 280 . 6 . 4483–90 . Feb 2005 . 15574414 . 10.1074/jbc.M411451200 . free .
7. de Aguiar Vallim. TQ. 2015. AFG is a transcriptional repressor of bile acid synthesis and metabolism.. Cell Metab.. 10.1016/j.cmet.2015.01.007. 25651182. 21. 2. 4317590. 298–310.
8. Igarashi K, Kataoka K, Itoh K, Hayashi N, Nishizawa M, Yamamoto M . Regulation of transcription by dimerization of erythroid factor NF-E2 p45 with small Maf proteins . Nature . 367 . 6463 . 568–72 . Feb 1994 . 8107826 . 10.1038/367568a0 . 1994Natur.367..568I . 4339431 .
9. Johnsen O, Murphy P, Prydz H, Kolsto AB . Interaction of the CNC-bZIP factor TCF11/LCR-F1/Nrf1 with MafG: binding-site selection and regulation of transcription . Nucleic Acids Research . 26 . 2 . 512–20 . Jan 1998 . 9421508 . 10.1093/nar/26.2.512 . 147270.
10. Itoh K, Chiba T, Takahashi S, Ishii T, Igarashi K, Katoh Y, Oyake T, Hayashi N, Satoh K, Hatayama I, Yamamoto M, Nabeshima Y . An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements . Biochemical and Biophysical Research Communications . 236 . 2 . 313–22 . Jul 1997 . 9240432 . 10.1006/bbrc.1997.6943.
11. Kobayashi A, Ito E, Toki T, Kogame K, Takahashi S, Igarashi K, Hayashi N, Yamamoto M . Molecular cloning and functional characterization of a new Cap'n' collar family transcription factor Nrf3 . The Journal of Biological Chemistry . 274 . 10 . 6443–52 . Mar 1999 . 10037736 . 10.1074/jbc.274.10.6443. free .
12. Oyake T, Itoh K, Motohashi H, Hayashi N, Hoshino H, Nishizawa M, Yamamoto M, Igarashi K . Bach proteins belong to a novel family of BTB-basic leucine zipper transcription factors that interact with MafK and regulate transcription through the NF-E2 site . Molecular and Cellular Biology . 16 . 11 . 6083–95 . Nov 1996 . 8887638 . 10.1128/mcb.16.11.6083 . 231611.
13. Kataoka K, Igarashi K, Itoh K, Fujiwara KT, Noda M, Yamamoto M, Nishizawa M . Small Maf proteins heterodimerize with Fos and may act as competitive repressors of the NF-E2 transcription factor . Molecular and Cellular Biology . 15 . 4 . 2180–90 . Apr 1995 . 7891713 . 10.1128/mcb.15.4.2180. 230446.
14. Kurokawa H, Motohashi H, Sueno S, Kimura M, Takagawa H, Kanno Y, Yamamoto M, Tanaka T . Structural basis of alternative DNA recognition by Maf transcription factors . Molecular and Cellular Biology . 29 . 23 . 6232–44 . Dec 2009 . 19797082 . 10.1128/MCB.00708-09 . 2786689.
15. Otsuki A, Suzuki M, Katsuoka F, Tsuchida K, Suda H, Morita M, Shimizu R, Yamamoto M . Unique cistrome defined as CsMBE is strictly required for Nrf2-sMaf heterodimer function in cytoprotection . Free Radical Biology & Medicine . 91 . 45–57 . Feb 2016 . 26677805 . 10.1016/j.freeradbiomed.2015.12.005 .
16. Friling RS, Bensimon A, Tichauer Y, Daniel V . Xenobiotic-inducible expression of murine glutathione S-transferase Ya subunit gene is controlled by an electrophile-responsive element . Proceedings of the National Academy of Sciences of the United States of America . 87 . 16 . 6258–62 . Aug 1990 . 2166952 . 10.1073/pnas.87.16.6258. 54512. 1990PNAS...87.6258F . free .
17. Rushmore TH, Morton MR, Pickett CB . The antioxidant responsive element. Activation by oxidative stress and identification of the DNA consensus sequence required for functional activity . The Journal of Biological Chemistry . 266 . 18 . 11632–9 . Jun 1991 . 10.1016/S0021-9258(18)99004-6 . 1646813 . free .
18. Mignotte V, Eleouet JF, Raich N, Romeo PH . Cis- and trans-acting elements involved in the regulation of the erythroid promoter of the human porphobilinogen deaminase gene . Proceedings of the National Academy of Sciences of the United States of America . 86 . 17 . 6548–52 . Sep 1989 . 2771941 . 10.1073/pnas.86.17.6548. 297881. 1989PNAS...86.6548M . free .
19. Romeo PH, Prandini MH, Joulin V, Mignotte V, Prenant M, Vainchenker W, Marguerie G, Uzan G . Megakaryocytic and erythrocytic lineages share specific transcription factors . Nature . 344 . 6265 . 447–9 . Mar 1990 . 2320113 . 10.1038/344447a0 . 1990Natur.344..447R . 4277397 .
20. Newman JR, Keating AE . Comprehensive identification of human bZIP interactions with coiled-coil arrays . Science . 300 . 5628 . 2097–101 . Jun 2003 . 12805554 . 10.1126/science.1084648 . 2003Sci...300.2097N . 36715183 . free .
21. Shavit JA, Motohashi H, Onodera K, Akasaka J, Yamamoto M, Engel JD . Impaired megakaryopoiesis and behavioral defects in mafG-null mutant mice . Genes & Development . 12 . 14 . 2164–74 . Jul 1998 . 9679061 . 10.1101/gad.12.14.2164 . 317009.
22. Shivdasani RA, Rosenblatt MF, Zucker-Franklin D, Jackson CW, Hunt P, Saris CJ, Orkin SH . Transcription factor NF-E2 is required for platelet formation independent of the actions of thrombopoietin/MGDF in megakaryocyte development . Cell . 81 . 5 . 695–704 . Jun 1995 . 7774011 . 10.1016/0092-8674(95)90531-6. 14195541 . free .
23. Katsuoka F, Motohashi H, Ishii T, Aburatani H, Engel JD, Yamamoto M . Genetic evidence that small maf proteins are essential for the activation of antioxidant response element-dependent genes . Molecular and Cellular Biology . 25 . 18 . 8044–51 . Sep 2005 . 16135796 . 10.1128/MCB.25.18.8044-8051.2005 . 1234339.
24. Fang M, Ou J, Hutchinson L, Green MR . The BRAF oncoprotein functions through the transcriptional repressor MAFG to mediate the CpG Island Methylator phenotype . Molecular Cell . 55 . 6 . 904–15 . Sep 2014 . 25219500 . 10.1016/j.molcel.2014.08.010 . 4170521.
25. Katsuoka F, Motohashi H, Tamagawa Y, Kure S, Igarashi K, Engel JD, Yamamoto M . Small Maf compound mutants display central nervous system neuronal degeneration, aberrant transcription, and Bach protein mislocalization coincident with myoclonus and abnormal startle response . Molecular and Cellular Biology . 23 . 4 . 1163–74 . Feb 2003 . 12556477 . 10.1128/mcb.23.4.1163-1174.2003 . 141134.
26. Agrawal SA, Anand D, Siddam AD, Kakrana A, Dash S, Scheiblin DA, Dang CA, Terrell AM, Waters SM, Singh A, Motohashi H, Yamamoto M, Lachke SA . Compound mouse mutants of bZIP transcription factors Mafg and Mafk reveal a regulatory network of non-crystallin genes associated with cataract . Human Genetics . 134 . 7 . 717–35 . Jul 2015 . 25896808 . 10.1007/s00439-015-1554-5 . 4486474.
27. Onodera K, Shavit JA, Motohashi H, Yamamoto M, Engel JD . Perinatal synthetic lethality and hematopoietic defects in compound mafG::mafK mutant mice . The EMBO Journal . 19 . 6 . 1335–45 . Mar 2000 . 10716933 . 10.1093/emboj/19.6.1335 . 305674.
28. Yamazaki H, Katsuoka F, Motohashi H, Engel JD, Yamamoto M . Embryonic lethality and fetal liver apoptosis in mice lacking all three small Maf proteins . Molecular and Cellular Biology . 32 . 4 . 808–16 . Feb 2012 . 22158967 . 10.1128/MCB.06543-11 . 3272985.