Small Maf

The following genes encode small Maf proteins

• {{gene|MAFF}} (Human), Maff (Mouse), maft renamed maff (Zebrafish)
• {{gene|MAFG}} (Human), Mafg (Mouse), mafg (Zebrafish)
• {{gene|MAFK}} (Human), Mafk (Mouse), mafk (Zebrafish)

File:W-F1.jpg

sMaf proteins were identified as members of the Maf family transcription factors. The Maf family is divided into two subfamilies, as follows: the large Maf subfamily (c-Maf, MafA, MafB, and NRL); and the small Maf subfamily (MafF, MafG and MafK) (Fig. 1). The first member of the Maf family is c-Maf, which was cloned as a cellular counterpart of the v-Maf oncogene isolated from avian musculoaponeurotic fibrosarcoma.{{Cite journal|last=Nishizawa|first=M|date=1989|title=v-maf, a viral oncogene that encodes a "leucine zipper" motif|journal=Proc. Natl. Acad. Sci. USA|doi=10.1073/pnas.86.20.7711|pmid=2554284|volume=86|issue=20|pmc=298140|pages=7711–5|bibcode=1989PNAS...86.7711N|doi-access=free}} The MafF, MafG, and MafK genes were later isolated. Because MafF, MafG and MafK are well-conserved 18 kDa proteins that lack a transcriptional activation domain, they are classified into the small Maf subfamily, which is structurally and functionally distinct from the large Maf subfamily.

Three sMaf genes are widely expressed in various cell types and tissues under differential transcriptional regulation.{{Cite journal|last=Toki|first=T|date=1997|title=Human small Maf proteins form heterodimers with CNC family transcription factors and recognize the NF-E2 motif|journal=Oncogene|doi=10.1038/sj.onc.1201024|pmid=9150357|volume=14|issue=16|pages=1901–10|doi-access=free}}{{Cite journal|last=Onodera|first=K|date=1999|title=Characterization of the murine mafF gene|journal=J. Biol. Chem.|doi=10.1074/jbc.274.30.21162|pmid=10409670|volume=274|issue=30|pages=21162–9|doi-access=free}} In mouse, each sMaf gene harbors multiple first exons, which partly contribute to their tissue-specific or stimulus-specific expression patterns.{{Cite journal|last=Motohashi|first=H|date=1996|title=Mesodermal- vs. neuronal-specific expression of MafK is elicited by different promoters|journal=Genes Cells|doi=10.1046/j.1365-2443.1996.d01-230.x|pmid=9140066|volume=1|issue=2|pages=223–38|doi-access=free}}{{Cite journal|last=Motohashi|first=H|date=1998|title=A core region of the mafK gene IN promoter directs neurone-specific transcription in vivo|journal=Genes Cells|doi=10.1046/j.1365-2443.1998.00222.x|pmid=9893024|volume=3|issue=10|pages=671–84|s2cid=33684152|doi-access=free}}{{Cite journal|last=Katsuoka|first=F|date=2005|title=Nrf2 transcriptionally activates the mafG gene through an antioxidant response element|journal=J. Biol. Chem.|doi=10.1074/jbc.M411451200|pmid=15574414|volume=280|issue=6|pages=4483–90|doi-access=free}} Human MAFF is induced by proinflammatory cytokines.{{Cite journal|last=Massrieh|first=W|date=2006|title=Regulation of the MAFF transcription factor by proinflammatory cytokines in myometrial cells|journal=Biol. Reprod.|doi=10.1095/biolreprod.105.045450|pmid=16371591|volume=74|issue=4|pages=699–705|s2cid=11823930|doi-access=free}} Mouse Mafg gene is induced by oxidative stresses (e.g. reactive oxygen species and electrophilic compounds) or the presence of bile acids.{{Cite journal|last=de Aguiar Vallim|first=TQ|date=2015|title=MAFG is a transcriptional repressor of bile acid synthesis and metabolism|journal=Cell Metab.|doi=10.1016/j.cmet.2015.01.007|pmid=25651182|volume=21|issue=2|pmc=4317590|pages=298–310}} Mouse Mafk gene is under the regulation of GATA factors (GATA-1 and GATA-2 in hematopoietic tissues; and GATA-4 and GATA-6 in cardiac tissues).{{Cite journal|last=Katsuoka|first=F|date=2000|title=One enhancer mediates mafK transcriptional activation in both hematopoietic and cardiac muscle cells|journal=EMBO J.|doi=10.1093/emboj/19.12.2980|pmid=10856242|volume=19|issue=12|pmc=203348|pages=2980–91}}

File:W-F2.jpg

All members of the Maf family including sMafs have a bZIP structure that consists of the basic region for DNA binding and the leucine zipper structure for dimer formation (Fig. 2). The basic region of each Maf family protein contains a tyrosine residue, which is critical for the unique DNA-binding modes of these proteins (see below for details).{{Cite journal|last=Kimura|first=M|date=2007|title=Molecular basis distinguishing the DNA binding profile of Nrf2-Maf heterodimer from that of Maf homodimer|journal=J. Biol. Chem.|doi=10.1074/jbc.M706863200|pmid=17875642|volume=282|issue=46|pages=33681–90|doi-access=free}} In addition, each Maf family protein possesses an extended homology region (EHR), which contributes to stable DNA binding.{{Cite journal|last=Kusunoki|first=H|date=2002|title=Solution structure of the DNA-binding domain of MafG|journal=Nat. Struct. Biol.|doi=10.1038/nsb771|pmid=11875518|volume=9|issue=4|pages=252–6|s2cid=23687470}}{{Cite journal|last=Kurokawa|first=H|date=2009|title=Structural basis of alternative DNA recognition by Maf transcription factors|journal=Mol. Cell. Biol.|doi=10.1128/MCB.00708-09|pmid=19797082|volume=29|issue=23|pmc=2786689|pages=6232–44}} The C-terminal region of sMaf includes a region required for its proper subnuclear localization.{{Cite journal|last=Motohashi|first=H|date=2011|title=Molecular determinants for small Maf protein control of platelet production|journal=Mol. Cell. Biol.|doi=10.1128/MCB.00798-10|pmid=20974807|volume=31|issue=1|pmc=3019851|pages=151–62}} Two modifications have been reported for MafG: SUMOylation through a SUMOylation motif at the N-terminal region;{{Cite journal|last=Motohashi|first=H|date=2006|title=MafG sumoylation is required for active transcriptional repression|journal=Mol. Cell. Biol.|doi=10.1128/MCB.02193-05|pmid=16738329|volume=26|issue=12|pmc=1489127|pages=4652–63}} phosphorylation through an ERK phosphorylation site in the C-terminal region.{{Cite journal|last=Fang|first=M|date=2014|title=The BRAF oncoprotein functions through the transcriptional repressor MAFG to mediate the CpG Island Methylator phenotype|journal=Mol. Cell|doi=10.1016/j.molcel.2014.08.010|pmid=25219500|volume=55|issue=6|pmc=4170521|pages=904–15}}

sMaf proteins form homodimers by themselves and heterodimers with two other bZIP families of transcription factors, namely CNC (cap 'n' collar) proteins (p45 NF-E2 (NFE2), Nrf1 (NFE2L1), Nrf2 (NFE2L2), and Nrf3 (NFE2L3) – not to be confused with Nuclear Respiratory factors) and Bach proteins (Bach1 and Bach2). Because these proteins cannot bind DNA by themselves, sMaf proteins are indispensable partner molecules of the CNC and Bach transcription factors.

File:W-F3.jpg

sMaf homodimers bind to a palindromic DNA sequence called the Maf recognition element (MARE: TGCTGACTCAGCA) and its related sequences. Structural analyses have demonstrated that the basic region of a Maf factor recognizes the flanking GC sequences. 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 (Fig. 3).{{Cite journal|last=Hirotsu|first=Y|date=2012|title=Nrf2-MafG heterodimers contribute globally to antioxidant and metabolic networks|journal=Nucleic Acids Res.|doi=10.1093/nar/gks827|pmid=22965115|volume=40|issue=20|pmc=3488259|pages=10228–39}}{{Cite journal|last=Warnatz|first=HJ|date=2011|title=The BTB and CNC homology 1 (BACH1) target genes are involved in the oxidative stress response and in control of the cell cycle|journal=J. Biol. Chem.|doi=10.1074/jbc.M111.220178|pmid=21555518|volume=286|issue=26|pmc=3123115|pages=23521–32|doi-access=free}}{{Cite journal|last=Otsuki|first=A|date=2015|title=Unique cistrome defined as CsMBE is strictly required for Nrf2-sMaf heterodimer function in cytoprotection.|url=https://zenodo.org/record/1002612|journal=Free Radical Bio.|doi=10.1016/j.freeradbiomed.2015.12.005|pmid=26677805|volume=91|pages=45–57}} The latter DNA sequences have been recognized as antioxidant/electrophile response elements{{Cite journal|last=Friling|first=RS|date=1990|title=Xenobiotic-inducible expression of murine glutathione S-transferase Ya subunit gene is controlled by an electrophile-responsive element|journal=Proc. Natl. Acad. Sci. USA|doi=10.1073/pnas.87.16.6258|pmid=2166952|volume=87|issue=16|pmc=54512|pages=6258–62|bibcode=1990PNAS...87.6258F|doi-access=free}}{{Cite journal|last=Rushmore|first=TH|date=1991|title=The antioxidant responsive element. Activation by oxidative stress and identification of the DNA consensus sequence required for functional activity|journal=J. Biol. Chem.|pmid=1646813|volume=266|issue=18|pages=11632–9|doi=10.1016/S0021-9258(18)99004-6|doi-access=free}} or NF-E2-binding motifs,{{Cite journal|last=Mignotte|first=V|date=1989|title=Cis- and trans-acting elements involved in the regulation of the erythroid promoter of the human porphobilinogen deaminase gene|journal=Proc. Natl. Acad. Sci. USA|doi=10.1073/pnas.86.17.6548|pmid=2771941|volume=86|issue=17|pmc=297881|pages=6548–52|bibcode=1989PNAS...86.6548M|doi-access=free}}{{Cite journal|last=Romeo|first=PH|date=1990|title=Megakaryocytic and erythrocytic lineages share specific transcription factors|journal=Nature|doi=10.1038/344447a0|pmid=2320113|volume=344|issue=6265|pages=447–9|bibcode=1990Natur.344..447R|s2cid=4277397}} to which Nrf2-sMaf heterodimers and p45 NF-E2-sMaf heterodimers bind, respectively. It has been proposed that the latter sequences are 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.{{Cite journal|last=Newman|first=JR|date=2003|title=Comprehensive identification of human bZIP interactions with coiled-coil arrays|journal=Science|doi=10.1126/science.1084648|pmid=12805554|volume=300|issue=5628|pages=2097–101|bibcode=2003Sci...300.2097N|s2cid=36715183|doi-access=free}} However, the biological significance of these heterodimers remains unknown.

Because sMafs lack any canonical transcriptional activation domains, the sMaf homodimer act as a negative regulator. Overexpression of MafG is known to inhibit proplatelet formation, which is thought to reflect a process of platelet production.{{Cite journal|last=Motohashi|first=H|date=2000|title=MARE-dependent transcriptional regulation is determined by the abundance of small Maf proteins|journal=Cell|doi=10.1016/s0092-8674(00)00190-2|pmid=11136972|volume=103|issue=6|pages=865–75|s2cid=16876406|doi-access=free}} SUMOylation is required for MafG homodimer-mediated transcriptional repression.

The p45 NF-E2-sMaf heterodimers are critical for platelet production. Knockout mouse studies have shown that MafG knockout mice show mild thrombocytopenia,{{Cite journal|last=Shavit|first=J|date=1998|title=Impaired megakaryopoiesis and behavioral defects in mafG-null mutant mice|journal=Genes Dev.|doi=10.1101/gad.12.14.2164|pmid=9679061|volume=12|issue=14|pmc=317009|pages=2164–74}} whereas MafG and MafK double mutant mice show severe thrombocytopenia.{{Cite journal|last=Onodera|first=K|date=2000|title=Perinatal synthetic lethality and hematopoietic defects in compound mafG::mafK mutant mice|journal=EMBO J.|doi=10.1093/emboj/19.6.1335|pmid=10716933|volume=19|issue=6|pmc=305674|pages=1335–45}} Similar results were also observed in p45 NF-E2 knockout mice.{{Cite journal|last=Shivdasani|first=RA|date=1995|title=Transcription factor NF-E2 is required for platelet formation independent of the actions of thrombopoietin/MGDF in megakaryocyte development|journal=Cell|doi=10.1016/0092-8674(95)90531-6|pmid=7774011|volume=81|issue=5|pages=695–704|s2cid=14195541|doi-access=free}} The p45 NF-E2-sMaf heterodimer regulates genes responsible for platelet production and function.{{Cite journal|last=Fujita|first=R|date=2013|title=NF-E2 p45 is important for establishing normal function of platelets|journal=Mol. Cell. Biol.|doi=10.1128/MCB.01274-12|pmid=23648484|volume=33|issue=14|pmc=3700136|pages=2659–70}}

The Nrf1-sMaf heterodimers are critical for neuronal homeostasis. Knockout mouse studies have shown that Mafg knockout mice display mild ataxia. Mafg and Mafk mutant mice (Mafg^−/−::Mafk^+/−) show more severe ataxia with progressive neuronal degeneration.{{Cite journal|last=Katsuoka|first=F|date=2003|title=Small Maf compound mutants display central nervous system neuronal degeneration, aberrant transcription, and Bach protein mislocalization coincident with myoclonus and abnormal startle response|journal=Mol. Cell. Biol.|doi=10.1128/mcb.23.4.1163-1174.2003|pmid=12556477|volume=23|issue=4|pmc=141134|pages=1163–74}} Similar results have also been observed in Nrf1 central nervous-specific knockout mice.{{Cite journal|last=Kobayashi|first=A|date=2011|title=Central nervous system-specific deletion of transcription factor Nrf1 causes progressive motor neuronal dysfunction|journal=Genes Cells|doi=10.1111/j.1365-2443.2011.01522.x|pmid=21554501|volume=16|issue=6|pages=692–703|doi-access=free}}{{Cite journal|last=Lee|first=CS|date=2011|title=Loss of nuclear factor E2-related factor 1 in the brain leads to dysregulation of proteasome gene expression and neurodegeneration|journal=Proc. Natl. Acad. Sci. USA|doi=10.1073/pnas.1019209108|pmid=21536885|volume=108|issue=20|pmc=3100960|pages=8408–13|bibcode=2011PNAS..108.8408L|doi-access=free}} The Nrf1-sMaf heterodimers regulate genes responsible for proteasomal genes and metabolism genes.{{Cite journal|last=Hirotsu|first=Y|date=2012|title=NF-E2-related factor 1 (Nrf1) serves as a novel regulator of hepatic lipid metabolism through regulation of the Lipin1 and PGC-1β genes|journal=Mol. Cell. Biol.|doi=10.1128/MCB.06706-11|pmid=22586274|volume=32|issue=14|pmc=3416188|pages=2760–70}}

The Nrf2-sMaf heterodimers are critical for oxidative and electrophilic stress response. Nrf2 is known as a master regulator of antioxidant and xenobiotic metabolizing enzyme genes. Induction of these cytoprotective genes is impaired in Nrf2 knockout mice. While MafG, MafK and MafF triple knockout mice die in embryonic stage, cultured cells derived from the triple knockout embryo fail to induce Nrf2-dependent cytoprotective genes in response to stimuli.{{Cite journal|last=Katsuoka|first=F|date=2005|title=Genetic evidence that small maf proteins are essential for the activation of antioxidant response element-dependent genes|journal=Mol. Cell. Biol.|doi=10.1128/MCB.25.18.8044-8051.2005|pmid=16135796|volume=25|issue=18|pmc=1234339|pages=8044–51}}

The Bach1-sMaf heterodimer is critical for heme metabolism. Knockout mouse studies showed that heme oxygenase-1 gene expression is upregulated in Bach1 knockout mice.{{Cite journal|last=Sun|first=J|date=2002|title=Hemoprotein Bach1 regulates enhancer availability of heme oxygenase-1 gene|journal=EMBO J.|doi=10.1093/emboj/cdf516|pmid=12356737|volume=21|issue=19|pmc=129038|pages=5216–24}} Similar results were also observed in MafG and MafK double mutant mice (Mafg^−/−::Mafk^+/−). These data show that the Bach1-sMaf heterodimer negatively regulates heme oxygenase-1 gene.

The Bach2-sMaf heterodimers are critical for B cell differentiation.{{Cite journal|last=Muto|first=A|date=1998|title=Identification of Bach2 as a B-cell-specific partner for small maf proteins that negatively regulate the immunoglobulin heavy chain gene 3' enhancer|journal=EMBO J.|doi=10.1093/emboj/17.19.5734|pmid=9755173|volume=17|issue=19|pmc=1170901|pages=5734–43}} Bach2 knockout mice studies have demonstrated that Bach2 is required for class switching and somatic hypermutation of immunoglobulin genes.{{Cite journal|last=Muto|first=A|date=2004|title=The transcriptional programme of antibody class switching involves the repressor Bach2|url=https://tsukuba.repo.nii.ac.jp/?action=repository_action_common_download&item_id=14102&item_no=1&attribute_id=17&file_no=1|journal=Nature|doi=10.1038/nature02596|pmid=15152264|volume=429|issue=6991|pages=566–71|bibcode=2004Natur.429..566M|hdl=2241/1881|s2cid=4430935|hdl-access=free}} However, these phenotypes have not been examined in sMaf knockout mice.

MafG and MafK double mutant mice (Mafg^−/−::Mafk^+/−) have cataracts.{{Cite journal|last=Agrawal|first=SA|date=2015|title=Compound mouse mutants of bZIP transcription factors Mafg and Mafk reveal a regulatory network of non-crystallin genes associated with cataract|journal=Hum. Genet.|doi=10.1007/s00439-015-1554-5|pmid=25896808|volume=134|issue=7|pmc=4486474|pages=717–35}} However, the interaction of CNC partner(s) with sMafs in this context remains undetermined. MafG, MafK and MafF triple knockout mice die during embryogenesis, demonstrating that sMafs are indispensable for embryonic development.{{Cite journal|last=Yamazaki|first=H|date=2012|title=Embryonic lethality and fetal liver apoptosis in mice lacking all three small Maf proteins|journal=Mol. Cell. Biol.|doi=10.1128/MCB.06543-11|pmid=22158967|volume=32|issue=4|pmc=3272985|pages=808–16}} Because Nrf1 and Nrf2 double mutant mice also die during embryogenesis,{{Cite journal|last=Leung|first=L|date=2003|title=Deficiency of the Nrf1 and Nrf2 transcription factors results in early embryonic lethality and severe oxidative stress|journal=J. Biol. Chem.|doi=10.1074/jbc.M308439200|pmid=12968018|volume=278|issue=48|pages=48021–9|doi-access=free}} the loss of function of both Nrf1-sMaf and Nrf2-sMaf may contribute to the lethality.

sMafs have been suggested to be involved in various diseases as heterodimeric partners of CNC and Bach proteins. Because Nrf2-sMaf heterodimers regulate a battery of antioxidant and xenobiotic metabolizing enzymes, impaired function of sMafs is expected to make cells vulnerable to various stresses and increase the risk of various diseases, such as cancers. SNPs associated with the cancer onset were reported in MAFF and MAFG genes.{{Cite journal|last=Martínez-Hernández|first=A|date=2014|title=Small MAF genes variants and chronic myeloid leukemia|journal=Eur. J. Haematol.|doi=10.1111/ejh.12211|pmid=24118457|volume=92|issue=1|pages=35–41|s2cid=24331218}}{{Cite journal|last=Wang|first=X|date=2010|title=Genetic variation and antioxidant response gene expression in the bronchial airway epithelium of smokers at risk for lung cancer|journal=PLOS ONE|doi=10.1371/journal.pone.0011934|pmid=20689807|volume=5|issue=8|pmc=2914741|pages=e11934|bibcode=2010PLoSO...511934W|doi-access=free}} In addition, Nrf2 is known to be critical for anti-inflammatory responses.{{Cite journal|last=Mimura|first=J|date=2015|title=Role of Nrf2 in the pathogenesis of atherosclerosis|journal=Free Radic. Biol. Med.|doi=10.1016/j.freeradbiomed.2015.06.019|pmid=26117321|volume=88|issue=Pt B|pages=221–32}}{{Cite journal|last=Yamazaki|first=H|date=2015|title=Role of the Keap1/Nrf2 pathway in neurodegenerative diseases|journal=Pathol. Int.|doi=10.1111/pin.12261|pmid=25707882|volume=65|issue=5|pages=210–9|s2cid=31560777}} Thus, sMaf insufficiencies are expected to result in prolonged inflammation that can cause diseases, such as neurodegeneration and atherosclerosis.

Conversely, sMafs also appear to contribute to cancer malignancy. Certain cancers contain somatic mutations in NRF2(NFE2L2) or KEAP1 that cause constitutive activation of Nrf2 and promote cell proliferation.{{Cite journal|last=Suzuki|first=T|date=2015|title=Molecular basis of the Keap1-Nrf2 system|journal=Free Radic. Biol. Med.|doi=10.1016/j.freeradbiomed.2015.06.006|pmid=26117331|volume=88|issue=Pt B|pages=93–100|doi-access=free}} It has also been reported that the Bach1-MafG heterodimer contributes to cancer malignancy by repressing tumor suppressor genes. Thus, as partners of Nrf2 and Bach1, sMafs are expected to play critical roles in cancer cells.

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Category:Proteins

{{Transcription factors and intracellular receptors}}