MAFA (gene)

Transcription factor MafA is a protein that in humans is encoded by the MAFA gene. It is a member of the Maf family of transcription factors.

MAFA
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4EOT
Identifiers
Aliases	MAFA, RIPE3b1, hMafA, MAF bZIP transcription factor A, INSDM
External IDs	OMIM: 610303 MGI: 2673307 HomoloGene: 65867 GeneCards: MAFA
Gene location (Human) Chr. Chromosome 8 (human) Band 8q24.3 Start 143,419,182 bp End 143,430,732 bp
Gene location (Mouse) Chr. Chromosome 15 (mouse) Band 15|15 D3 Start 75,617,339 bp End 75,620,077 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in gastrocnemius muscle skeletal muscle tissue islet of Langerhans body of pancreas placenta gastric mucosa ganglionic eminence popliteal artery left ventricle stromal cell of endometrium Top expressed in islet of Langerhans vastus lateralis muscle triceps brachii muscle sternocleidomastoid muscle temporal muscle ankle gastrocnemius muscle tibialis anterior muscle digastric muscle extensor digitorum longus muscle More reference expression data BioGPS More reference expression data
Gene ontology Molecular function DNA-binding transcription factor activity protein heterodimerization activity DNA binding DNA-binding transcription activator activity, RNA polymerase II-specific RNA polymerase II cis-regulatory region sequence-specific DNA binding protein homodimerization activity DNA-binding transcription factor activity, RNA polymerase II-specific sequence-specific DNA binding Cellular component nucleus Biological process regulation of transcription, DNA-templated response to glucose insulin secretion transcription by RNA polymerase II positive regulation of transcription by RNA polymerase II positive regulation of transcription, DNA-templated nitric oxide mediated signal transduction transcription, DNA-templated Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 389692 378435 Ensembl ENSG00000182759 ENSMUSG00000047591 UniProt Q8NHW3 Q8CF90 RefSeq (mRNA) NM_201589 NM_194350 RefSeq (protein) NP_963883 NP_919331 Location (UCSC) Chr 8: 143.42 – 143.43 Mb Chr 15: 75.62 – 75.62 Mb PubMed search
Wikidata
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MAFA is phosphorylated sequentially on four serine/threonine residues by GSK-3 kinase. These phosphorylations activate MAFA transcription and trigger its degradation in the proteasome. Altering these post-translationnal modifications leads to severe pathological consequences. Mutation of these  residues  is perinatally lethal in mice, and  mutation of the Ser64Phe priming site was reported to induce familial diabetes mellitus and insulinomatosis in humans.

MAFA assists in insulin regulation

An in vivo study on mice proved MafA binds to the promoter in an insulin gene to regulate insulin transcription in response to serum glucose levels. MafA is a β cell-specific activator, which differentiates it from other transcription factors involved with insulin gene expression. It helps regulate the β cells involved with insulin secretion primarily by maintaining β cell metabolism. The amount of MafA in the β cells is regulated by levels of glucose and oxidative stress.

Interactions

MafA (gene) has been shown to interact with NEUROD1 and Pdx1. MafA works with Pdx1 to activate the insulin gene.

MAFA in neurons

In addition to its expression in pancreatic ßcells, MAFA is also expressed in specific subsets of  excitatory and inhibitory neurons. In the peripheric nervous system, it is expressed in touch mechanoreceptors.  In the central nervous system,  Mafa is expressed in sensory neurons in the spinal cord and trigeminal nucleus, as well as in the olfactory bulb. It is also present in ventral inhibitory neurons of the spinal cord (Renshaw cells) and in brainstem inhibitory neurons controlling  mouse neonatal apneas.

Further reading

• Benkhelifa S, Provot S, Nabais E, et al. (2001). "Phosphorylation of MafA is essential for its transcriptional and biological properties". Mol. Cell. Biol. 21 (14): 4441–52. doi:10.1128/MCB.21.14.4441-4452.2001. PMC 87104. PMID 11416124.
• Olbrot M, Rud J, Moss LG, Sharma A (2002). "Identification of beta-cell-specific insulin gene transcription factor RIPE3b1 as mammalian MafA". Proc. Natl. Acad. Sci. U.S.A. 99 (10): 6737–42. Bibcode:2002PNAS...99.6737O. doi:10.1073/pnas.102168499. PMC 124472. PMID 12011435.
• Kataoka K, Han SI, Shioda S, et al. (2003). "MafA is a glucose-regulated and pancreatic beta-cell-specific transcriptional activator for the insulin gene". J. Biol. Chem. 277 (51): 49903–10. doi:10.1074/jbc.M206796200. PMID 12368292.
• Matsuoka TA, Artner I, Henderson E, et al. (2004). "The MafA transcription factor appears to be responsible for tissue-specific expression of insulin". Proc. Natl. Acad. Sci. U.S.A. 101 (9): 2930–3. Bibcode:2004PNAS..101.2930M. doi:10.1073/pnas.0306233101. PMC 365722. PMID 14973194.
• Kaneto H, Matsuoka TA, Nakatani Y, et al. (2005). "A crucial role of MafA as a novel therapeutic target for diabetes". J. Biol. Chem. 280 (15): 15047–52. doi:10.1074/jbc.M412013200. PMID 15664997.
• Harmon JS, Stein R, Robertson RP (2005). "Oxidative stress-mediated, post-translational loss of MafA protein as a contributing mechanism to loss of insulin gene expression in glucotoxic beta cells". J. Biol. Chem. 280 (12): 11107–13. doi:10.1074/jbc.M410345200. PMID 15664999.
• Zhao L, Guo M, Matsuoka TA, et al. (2005). "The islet beta cell-enriched MafA activator is a key regulator of insulin gene transcription". J. Biol. Chem. 280 (12): 11887–94. doi:10.1074/jbc.M409475200. PMID 15665000.
• Aramata S, Han SI, Yasuda K, Kataoka K (2005). "Synergistic activation of the insulin gene promoter by the beta-cell enriched transcription factors MafA, Beta2, and Pdx1". Biochim. Biophys. Acta. 1730 (1): 41–6. doi:10.1016/j.bbaexp.2005.05.009. PMID 15993959.
• Raum JC, Gerrish K, Artner I, et al. (2006). "FoxA2, Nkx2.2, and PDX-1 regulate islet beta-cell-specific mafA expression through conserved sequences located between base pairs -8118 and -7750 upstream from the transcription start site". Mol. Cell. Biol. 26 (15): 5735–43. doi:10.1128/MCB.00249-06. PMC 1592775. PMID 16847327.