MAFA (gene)

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; OMA:MAFA - orthologs
Gene location (Human) Chr. Chromosome 8 (human) [1] Band 8q24.3 Start 143,419,182 bp [1] End 143,430,732 bp [1]
Gene location (Mouse) Chr. Chromosome 15 (mouse) [2] Band 15|15 D3 Start 75,617,339 bp [2] End 75,620,077 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in muscle of thigh gastrocnemius muscle skeletal muscle tissue gonad islet of Langerhans testicle right testis left testis body of pancreas placenta Top expressed in islet of Langerhans vastus lateralis muscle triceps brachii muscle sternocleidomastoid muscle temporal muscle ankle gastrocnemius muscle tibialis anterior muscle muscle of thigh digastric 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 [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Transcription factor MafA is a protein that in humans is encoded by the MAFA gene. ^[5] It is a member of the Maf family of transcription factors. ^[6]

MAFA is phosphorylated sequentially on four serine/threonine residues by GSK-3 kinase. ^[7] 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, ^[8] and  mutation of the Ser64Phe priming site was reported to induce familial diabetes mellitus and insulinomatosis in humans. ^[9]

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. ^[10] MafA is a β cell-specific activator, which differentiates it from other transcription factors involved with insulin gene expression. ^[11] It helps regulate the β cells involved with insulin secretion primarily by maintaining β cell metabolism. ^[12] The amount of MafA in the β cells is regulated by levels of glucose and oxidative stress. ^[6]

Interactions

MafA (gene) has been shown to interact with NEUROD1 ^[13] and Pdx1. ^[13] MafA works with Pdx1 to activate the insulin gene. ^[6]

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. ^{[14] [15]}  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. ^[8]

References

1. GRCh38: Ensembl release 89: ENSG00000182759 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000047591 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "Entrez Gene: MAFA v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (avian)".
6. Aramata; Han (2007). "Roles and Regulation of Transcription Factor MafA in Islet β-cells". Endocr. J. 54 (5): 659–66. doi: 10.1507/endocrj.kr-101 . PMID   17785922.
7. Rocques, Nathalie; Abou Zeid, Nancy; Sii-Felice, Karine; Lecoin, Laure; Felder-Schmittbuhl, Marie-Paule; Eychène, Alain; Pouponnot, Celio (November 2007). "GSK-3-Mediated Phosphorylation Enhances Maf-Transforming Activity". Molecular Cell. 28 (4): 584–597. doi: 10.1016/j.molcel.2007.11.009 . PMID   18042454.
8. Lecoin, Laure; Dempsey, Bowen; Garancher, Alexandra; Bourane, Steeve; Ruffault, Pierre-Louis; Morin-Surun, Marie-Pierre; Rocques, Nathalie; Goulding, Martyn; Eychène, Alain; Pouponnot, Celio; Fortin, Gilles; Champagnat, Jean (June 2022). "Mafa-dependent GABAergic activity promotes mouse neonatal apneas". Nature Communications. 13 (1): 3284. Bibcode:2022NatCo..13.3284L. doi:10.1038/s41467-022-30825-3. ISSN   2041-1723. PMC   9174494 . PMID   35672398.
9. Iacovazzo, Donato; Flanagan, Sarah E.; Walker, Emily; Quezado, Rosana; de Sousa Barros, Fernando Antonio; Caswell, Richard; Johnson, Matthew B.; Wakeling, Matthew; Brändle, Michael; Guo, Min; Dang, Mary N.; Gabrovska, Plamena; Niederle, Bruno; Christ, Emanuel; Jenni, Stefan (30 January 2018). "MAFA missense mutation causes familial insulinomatosis and diabetes mellitus". Proceedings of the National Academy of Sciences. 115 (5): 1027–1032. Bibcode:2018PNAS..115.1027I. doi: 10.1073/pnas.1712262115 . ISSN   0027-8424. PMC   5798333 . PMID   29339498.
10. Zhang; Moriguchi (2005). "MafA Is a Key Regulator of Glucose-Stimulated Insulin Secretion". Mol. Cell. Biol. 25 (12): 4969–4976. doi:10.1128/MCB.25.12.4969-4976.2005. PMC   1140590 . PMID   15923615.
11. Matsuoka; Artner (March 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.
12. Wang; Kataoka (2007). "MAFA controls genes implicated in insulin biosynthesis and secretion". Diabetologia. 50 (2): 348–58. doi:10.1007/s00125-006-0490-2. PMC   2196442 . PMID   17149590.
13. Zhao, Li; Guo Min; Matsuoka Taka-Aki; Hagman Derek K; Parazzoli Susan D; Poitout Vincent; Stein Roland (March 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 . ISSN   0021-9258. PMID   15665000.
14. Bourane, Steeve; Garces, Alain; Venteo, Stephanie; Pattyn, Alexandre; Hubert, Thomas; Fichard, Agnes; Puech, Sylvie; Boukhaddaoui, Hassan; Baudet, Christel; Takahashi, Satoru; Valmier, Jean; Carroll, Patrick (December 2009). "Low-Threshold Mechanoreceptor Subtypes Selectively Express MafA and Are Specified by Ret Signaling". Neuron. 64 (6): 857–870. doi: 10.1016/j.neuron.2009.12.004 . PMID   20064392. S2CID   14370290.
15. Lecoin, Laure; Rocques, Nathalie; El-Yakoubi, Warif; Achour, Sarrah Ben; Larcher, Magalie; Pouponnot, Celio; Eychène, Alain (2010). "MafA transcription factor identifies the early ret-expressing sensory neurons" . Developmental Neurobiology. 70 (7): 485–497. doi:10.1002/dneu.20790. PMID   20213756. S2CID   421285.

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.