Biology:MAFG

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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.[1] 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.[1] Similar to other sMafs, MafG lacks any canonical transcriptional activation domains.[1]

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.[6] 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.[3][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).[15]

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.[8][21][22] Nrf2-sMaf heterodimer regulates a battery of cytoprotective genes, such as antioxidant/xenobiotic metabolizing enzyme genes.[10][23] The Bach1-sMaf heterodimer regulates the heme oxygenase-1 gene.[12] 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.[21] 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.[23]

Genotype Mouse Phenotype
Maff Mafg Mafk
−/− Mild motor ataxia, mild thrombocytopenia [21]
−/− +/− Severe motor ataxia, progressive neuronal degeneration, severe thrombocytopenia, and cataract [25][26]
−/− −/− More severe neuronal phenotypes, and perinatal lethal [27]
−/− +/− −/− No severe abnormality [28] (Fertile)
−/− −/− −/− Growth retardation, fetal liver hypoplasia, and lethal around embryonic day, 13.5 [28]
+/− (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.

Notes

References

  1. ↑ 1.0 1.1 1.2 1.3 "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. doi:10.1128/mcb.15.4.2180. PMID 7891713. 
  2. ↑ 2.0 2.1 "Entrez Gene: MAFG v-maf musculoaponeurotic fibrosarcoma oncogene homolog G (avian)". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4097. 
  3. ↑ 3.0 3.1 "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. Sep 1993. PMID 8361754. 
  4. ↑ "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. doi:10.1093/nar/gkt1270. PMID 24304889. 
  5. ↑ "Oxidative stress induces the levels of a MafG homolog in hamster HA-1 cells". Free Radical Biology & Medicine 21 (4): 521–5. 1996. doi:10.1016/0891-5849(96)00160-8. PMID 8886803. 
  6. ↑ 6.0 6.1 "Nrf2 transcriptionally activates the mafG gene through an antioxidant response element". The Journal of Biological Chemistry 280 (6): 4483–90. Feb 2005. doi:10.1074/jbc.M411451200. PMID 15574414. 
  7. ↑ de Aguiar Vallim, TQ (2015). "AFG is a transcriptional repressor of bile acid synthesis and metabolism.". Cell Metab. 21 (2): 298–310. doi:10.1016/j.cmet.2015.01.007. PMID 25651182. 
  8. ↑ 8.0 8.1 "Regulation of transcription by dimerization of erythroid factor NF-E2 p45 with small Maf proteins". Nature 367 (6463): 568–72. Feb 1994. doi:10.1038/367568a0. PMID 8107826. Bibcode: 1994Natur.367..568I. 
  9. ↑ "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. doi:10.1093/nar/26.2.512. PMID 9421508. 
  10. ↑ 10.0 10.1 "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. doi:10.1006/bbrc.1997.6943. PMID 9240432. 
  11. ↑ "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. doi:10.1074/jbc.274.10.6443. PMID 10037736. 
  12. ↑ 12.0 12.1 "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. doi:10.1128/mcb.16.11.6083. PMID 8887638. 
  13. ↑ "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. doi:10.1128/mcb.15.4.2180. PMID 7891713. 
  14. ↑ "Structural basis of alternative DNA recognition by Maf transcription factors". Molecular and Cellular Biology 29 (23): 6232–44. Dec 2009. doi:10.1128/MCB.00708-09. PMID 19797082. 
  15. ↑ 15.0 15.1 "Unique cistrome defined as CsMBE is strictly required for Nrf2-sMaf heterodimer function in cytoprotection". Free Radical Biology & Medicine 91: 45–57. Feb 2016. doi:10.1016/j.freeradbiomed.2015.12.005. PMID 26677805. https://zenodo.org/record/1002612. 
  16. ↑ "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. doi:10.1073/pnas.87.16.6258. PMID 2166952. Bibcode: 1990PNAS...87.6258F. 
  17. ↑ "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. doi:10.1016/S0021-9258(18)99004-6. PMID 1646813. 
  18. ↑ "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. doi:10.1073/pnas.86.17.6548. PMID 2771941. Bibcode: 1989PNAS...86.6548M. 
  19. ↑ "Megakaryocytic and erythrocytic lineages share specific transcription factors". Nature 344 (6265): 447–9. Mar 1990. doi:10.1038/344447a0. PMID 2320113. Bibcode: 1990Natur.344..447R. 
  20. ↑ "Comprehensive identification of human bZIP interactions with coiled-coil arrays". Science 300 (5628): 2097–101. Jun 2003. doi:10.1126/science.1084648. PMID 12805554. Bibcode: 2003Sci...300.2097N. 
  21. ↑ 21.0 21.1 21.2 "Impaired megakaryopoiesis and behavioral defects in mafG-null mutant mice". Genes & Development 12 (14): 2164–74. Jul 1998. doi:10.1101/gad.12.14.2164. PMID 9679061. 
  22. ↑ "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. doi:10.1016/0092-8674(95)90531-6. PMID 7774011. 
  23. ↑ 23.0 23.1 "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. doi:10.1128/MCB.25.18.8044-8051.2005. PMID 16135796. 
  24. ↑ "The BRAF oncoprotein functions through the transcriptional repressor MAFG to mediate the CpG Island Methylator phenotype". Molecular Cell 55 (6): 904–15. Sep 2014. doi:10.1016/j.molcel.2014.08.010. PMID 25219500. 
  25. ↑ 25.0 25.1 "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. doi:10.1128/mcb.23.4.1163-1174.2003. PMID 12556477. 
  26. ↑ 26.0 26.1 "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. doi:10.1007/s00439-015-1554-5. PMID 25896808. 
  27. ↑ 27.0 27.1 "Perinatal synthetic lethality and hematopoietic defects in compound mafG::mafK mutant mice". The EMBO Journal 19 (6): 1335–45. Mar 2000. doi:10.1093/emboj/19.6.1335. PMID 10716933. 
  28. ↑ 28.0 28.1 28.2 "Embryonic lethality and fetal liver apoptosis in mice lacking all three small Maf proteins". Molecular and Cellular Biology 32 (4): 808–16. Feb 2012. doi:10.1128/MCB.06543-11. PMID 22158967. 

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