MAFK
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Location (UCSC) | Chr 7: 1.53 – 1.54 Mb | Chr 5: 139.78 – 139.79 Mb | |||||||
PubMed search | [3] | [4] |
View/Edit Human | View/Edit Mouse |
Transcription factor MafK is a bZip Maf transcription factor protein that in humans is encoded by the MAFK gene.[5][6]
MafK 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 MAFK is “v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog K”.
Discovery
MafK was first cloned and identified in chicken in 1993 as a member of the small Maf (sMaf) genes. MafK was also identified as p18 NF-E2, a component of NF-E2 complex binding to a specific motif (NF-E2) in the regulatory regions of β-globin and other erythroid-related genes.[7] MAFK has been identified in many vertebrates, including humans. There are three functionally redundant sMaf proteins in vertebrates, MafF, MafG, and MafK.[6]
Structure
MafK has a bZIP structure that consists of a basic region for DNA binding and a leucine zipper structure for dimer formation.[5] Similar to other sMafs, MafK lacks any canonical transcriptional activation domains.[5]
Expression
MAFK is broadly but differentially expressed in various tissues. MAFK expression was detected in all 16 tissues examined by the human BodyMap Project, but relatively abundant in adipose, lung and skeletal muscle tissues.[8] Mouse Mafk is regulated by different GATA factors in both hematopoietic and cardiac tissues.[9] MAFK expression is influenced by TGF-β[10] and Wnt signaling,[11] and rat Mafk expression is influenced by NGF[12] and AKT[13] in neuronal cells.
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)][14][15][16][17] and Bach proteins (BACH1 and BACH2).[18]
sMaf homodimers bind to a palindromic DNA sequence called the Maf recognition element (MARE: TGCTGACTCAGCA) and its related sequences.[5][19] Structural analyses have demonstrated that the basic region of a Maf factor recognizes the flanking GC sequences.[20] 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.[21] The latter DNA sequences have been recognized as antioxidant/electrophile response elements[22][23] or NF-E2-binding motifs[24][25] 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).[21]
It has also been reported that sMafs form heterodimers with other bZIP transcription factors, such as c-Jun and c-Fos.[26]
Target genes
sMafs regulate different target genes depending on their partners. For instance, the p45-NF-E2-sMaf heterodimer regulates genes responsible for platelet production.[14][27][28] Although it has not been confirmed by mouse genetic studies, many studies suggest that p45-NFE2-sMaf heterodimer is involved in the regulation of β-globin and other erythroid-related genes.[7][14] Nrf2-sMaf heterodimer regulates a battery of cytoprotective genes, such as antioxidant/xenobiotic metabolizing enzyme genes.[16][29] The Bach1-sMaf heterodimer regulates the heme oxygenase-1 gene.[18] 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 MafK are seemingly healthy under laboratory conditions,[27] while mice lacking MafG exhibit mild neuronal phenotype and mild thrombocytopenia.[27] However, mice lacking Mafg and one allele of Mafk (Mafg−/−::Mafk+/−) exhibit progressive neuronal degeneration, thrombocytopenia and cataract,[30][31] and mice lacking MafG and MafK (Mafg−/−::Mafk−/−) exhibit more severe neuronal degeneration and die in the perinatal stage.[32] Mice lacking MafF, MafG and MafK are embryonic lethal.[33] Embryonic fibroblasts that are derived from Maff−/−::Mafg−/−::Mafk−/− mice fail to activate Nrf2-dependent cytoprotective genes in response to stress.[29]
Genotype | Mouse Phenotype | ||
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Maff | Mafg | Mafk | |
−/− | No apparent phenotype under laboratory conditions [27] | ||
−/− | Mild motor ataxia, mild thrombocytopenia [27] | ||
−/− | +/− | Severe motor ataxia, progressive neuronal degeneration, severe thrombocytopenia, and cataract [30][31] | |
−/− | −/− | More severe neuronal phenotypes, and perinatal lethal [32] | |
−/− | +/− | −/− | No severe abnormality [33] (Fertile) |
−/− | −/− | −/− | Growth retardation, fetal liver hypoplasia, and lethal around embryonic day, 13.5 [33] |
+/− ( 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
Wikidata Q37014084 . |
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000198517 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000018143 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ PMID 8361754.
- ^ a b "Entrez Gene: MAFK v-maf musculoaponeurotic fibrosarcoma oncogene homolog K (avian)".
- ^ PMID 8265578.
- PMID 24304889.
- PMID 10856242.
- PMID 23737527.
- PMID 26214410.
- PMID 12388604.
- PMID 20233453.
- ^ S2CID 4339431.
- PMID 9421508.
- ^ PMID 9240432.
- PMID 10037736.
- ^ PMID 8887638.
- PMID 7891713.
- PMID 19797082.
- ^ PMID 26677805.
- PMID 2166952.
- PMID 1646813.
- PMID 2771941.
- S2CID 4277397.
- S2CID 36715183.
- ^ PMID 9679061.
- S2CID 14195541.
- ^ PMID 16135796.
- ^ PMID 12556477.
- ^ PMID 25896808.
- ^ PMID 10716933.
- ^ PMID 22158967.
Further reading
- Ney PA, Andrews NC, Jane SM, Safer B, Purucker ME, Weremowicz S, Morton CC, Goff SC, Orkin SH, Nienhuis AW (Sep 1993). "Purification of the human NF-E2 complex: cDNA cloning of the hematopoietic cell-specific subunit and evidence for an associated partner". Molecular and Cellular Biology. 13 (9): 5604–12. PMID 8355703.
- Oyake T, Itoh K, Motohashi H, Hayashi N, Hoshino H, Nishizawa M, Yamamoto M, Igarashi K (Nov 1996). "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. PMID 8887638.
- Toki T, Itoh J, Kitazawa J, Arai K, Hatakeyama K, Akasaka J, Igarashi K, Nomura N, Yokoyama M, Yamamoto M, Ito E (Apr 1997). "Human small Maf proteins form heterodimers with CNC family transcription factors and recognize the NF-E2 motif". Oncogene. 14 (16): 1901–10. PMID 9150357.
- Quevillon S, Robinson JC, Berthonneau E, Siatecka M, Mirande M (Jan 1999). "Macromolecular assemblage of aminoacyl-tRNA synthetases: identification of protein-protein interactions and characterization of a core protein". Journal of Molecular Biology. 285 (1): 183–95. PMID 9878398.
- Kobayashi A, Ito E, Toki T, Kogame K, Takahashi S, Igarashi K, Hayashi N, Yamamoto M (Mar 1999). "Molecular cloning and functional characterization of a new Cap'n' collar family transcription factor Nrf3". The Journal of Biological Chemistry. 274 (10): 6443–52. PMID 10037736.
- Nguyen T, Huang HC, Pickett CB (May 2000). "Transcriptional regulation of the antioxidant response element. Activation by Nrf2 and repression by MafK". The Journal of Biological Chemistry. 275 (20): 15466–73. PMID 10747902.
- Dhakshinamoorthy S, Jaiswal AK (Dec 2000). "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. PMID 11013233.
- Newman JR, Keating AE (Jun 2003). "Comprehensive identification of human bZIP interactions with coiled-coil arrays". Science. 300 (5628): 2097–101. S2CID 36715183.
External links
- MAFK+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- FactorBook MafK