FOXC2 (original) (raw)

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Protein-coding gene in the species Homo sapiens

FOXC2
Available structuresPDBOrtholog search: PDBe RCSB List of PDB id codes1D5V
Identifiers
Aliases FOXC2, FKHL14, LD, MFH-1, MFH1, forkhead box C2
External IDs OMIM: 602402; MGI: 1347481; HomoloGene: 21091; GeneCards: FOXC2; OMA:FOXC2 - orthologs
Gene location (Human)Chromosome 16 (human)Chr.Chromosome 16 (human)[1]Chromosome 16 (human)Genomic location for FOXC2Genomic location for FOXC2Band16q24.1Start86,566,829 bp[1]End86,569,728 bp[1]
Gene location (Mouse)Chromosome 8 (mouse)Chr.Chromosome 8 (mouse)[2]Chromosome 8 (mouse)Genomic location for FOXC2Genomic location for FOXC2Band8 E1|8 70.33 cMStart121,842,910 bp[2]End121,845,634 bp[2]
RNA expression patternBgeeHuman Mouse (ortholog)Top expressed invena cavapalpebral conjunctivapopliteal arterytrigeminal gangliontibial arteriesurethraascending aortaspinal gangliaDescending thoracic aortacardiac muscle tissue of right atriumTop expressed inaortic archesascending aortafifth metatarsal bonerenal corpuscleoptic nerveaortic valvefourth metatarsal bonesomitesclerotomelumbar spinal ganglionMore reference expression dataBioGPSn/a
Gene ontologyMolecular function sequence-specific DNA binding DNA binding DNA-binding transcription factor activity DNA-binding transcription activator activity, RNA polymerase II-specific protein binding identical protein binding transcription factor activity, RNA polymerase II distal enhancer sequence-specific binding chromatin DNA binding promoter-specific chromatin binding DNA-binding transcription factor activity, RNA polymerase II-specific RNA polymerase II transcription regulatory region sequence-specific DNA binding RNA polymerase II cis-regulatory region sequence-specific DNA binding Cellular component nucleus nucleoplasm nuclear body Biological process Notch signaling pathway somitogenesis embryonic skeletal system morphogenesis skeletal system development insulin receptor signaling pathway ureteric bud development regulation of transcription, DNA-templated positive regulation of cell migration involved in sprouting angiogenesis neural crest cell development paraxial mesoderm formation paraxial mesodermal cell fate commitment ossification lymphangiogenesis collagen fibril organization kidney development glomerular mesangial cell development heart morphogenesis negative regulation of transcription by RNA polymerase II cardiac muscle cell proliferation lymph vessel development transcription, DNA-templated embryonic heart tube development positive regulation of endothelial cell migration positive regulation of transcription, DNA-templated multicellular organism development ventricular cardiac muscle tissue morphogenesis heart development blood vessel remodeling vascular endothelial growth factor receptor signaling pathway blood vessel development positive regulation of vascular wound healing artery morphogenesis branching involved in blood vessel morphogenesis glomerular visceral epithelial cell differentiation response to hormone embryonic viscerocranium morphogenesis embryonic cranial skeleton morphogenesis camera-type eye development glomerular endothelium development positive regulation of cell adhesion mediated by integrin mesoderm development regulation of organ growth metanephros development cell population proliferation positive regulation of transcription by RNA polymerase II negative regulation of apoptotic process involved in outflow tract morphogenesis transcription by RNA polymerase II cell differentiation regulation of transcription by RNA polymerase II anatomical structure morphogenesis negative regulation of cold-induced thermogenesis Sources:Amigo / QuickGO
OrthologsSpeciesHuman MouseEntrez230314234EnsemblENSG00000176692ENSMUSG00000046714UniProtQ99958Q61850RefSeq (mRNA)NM_005251NM_013519RefSeq (protein)NP_005242NP_038547Location (UCSC)Chr 16: 86.57 – 86.57 MbChr 8: 121.84 – 121.85 MbPubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Forkhead box protein C2 (FOXC2) also known as forkhead-related protein FKHL14 (FKHL14), transcription factor FKH-14, or mesenchyme fork head protein 1 (MFH1) is a protein that in humans is encoded by the FOXC2 gene.[5][6] FOXC2 is a member of the fork head box (FOX) family of transcription factors.

Structure and function

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The protein is 501 amino acids in length. The gene has no introns; the single exon is approximately 1.5kb in size.[6][7]

FOX transcription factors are expressed during development and are associated with a number of cellular and developmental differentiation processes. FOXC2 is required during early development of the kidneys, including differentiation of podocytes and maturation of the glomerular basement membrane. It is also involved in the early development of the heart.[8]

An increased expression of FOXC2 in adipocytes can increase the amount of brown adipose tissue leading to lower weight and an increased sensitivity to insulin.[9][10]

Absence of FOXC2 has been shown to lead to the failure of lymphatic valves to form and problems with lymphatic remodelling. A number of mutations in the FOXC2 gene have been associated with Lymphedema–distichiasis syndrome,[11][12] It has also been suggested that there may be a link between polymorphisms in FOXC2 and varicose veins.[12][13]

FOXC2 is also involved in cancer metastases. In particular, expression of FOXC2 is induced when epithelial cells undergo an epithelial-mesenchymal transition (EMT) and become mesenchymal looking cells. EMT can be induced by a number of genes including Snail, Twist, Goosecoid, and TGF-beta 1.[14] Overexpression of FOXC2 has been noted in subtypes of breast cancer which are highly metastatic.[8] Suppression of FOXC2 expression using shRNA in a highly metastatic breast cancer model blocks their metastatic ability.[15]

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000176692 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000046714 – 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. ^ Kaestner KH, Bleckmann SC, Monaghan AP, Schlöndorff J, Mincheva A, Lichter P, Schütz G (June 1996). "Clustered arrangement of winged helix genes fkh-6 and MFH-1: possible implications for mesoderm development". Development. 122 (6): 1751–8. doi:10.1242/dev.122.6.1751. PMID 8674414.
  6. ^ a b Miura N, Iida K, Kakinuma H, Yang XL, Sugiyama T (May 1997). "Isolation of the mouse (MFH-1) and human (FKHL 14) mesenchyme fork head-1 genes reveals conservation of their gene and protein structures". Genomics. 41 (3): 489–92. doi:10.1006/geno.1997.4695. PMID 9169153.
  7. ^ Fang J, Dagenais SL, Erickson RP, Arlt MF, Glynn MW, Gorski JL, Seaver LH, Glover TW (Dec 2000). "Mutations in FOXC2 (MFH-1), a forkhead family transcription factor, are responsible for the hereditary lymphedema-distichiasis syndrome". Am J Hum Genet. 67 (6): 1382–8. doi:10.1086/316915. PMC 1287915. PMID 11078474.
  8. ^ a b Hader C, Marlier A, Cantley L (2010). "Mesenchymal-epithelial transition in epithelial response to injury: the role of Foxc2". Oncogene. 29 (7): 1031–40. doi:10.1038/onc.2009.397. PMC 2824778. PMID 19935708.
  9. ^ Lidell ME, Seifert EL, Westergren R, Heglind M, Gowing A, Sukonina V, Arani Z, Itkonen P, Wallin S, Westberg F, Fernandez-Rodriguez J, Laakso M, Nilsson T, Peng XR, Harper ME, Enerbäck S (Feb 2011). "The adipocyte-expressed forkhead transcription factor Foxc2 regulates metabolism through altered mitochondrial function". Diabetes. 60 (2): 427–35. doi:10.2337/db10-0409. PMC 3028341. PMID 21270254.
  10. ^ Cederberg A, Gronning LM, Ahren B, Tasken K, Carlsson P, Enerback S (2001). "FOXC2 is a winged helix gene that counteracts obesity, hypertriglyceridemia, and diet-induced insulin resistance". Cell. 106 (5): 563–73. doi:10.1016/s0092-8674(01)00474-3. PMID 11551504. S2CID 7411570.
  11. ^ Connell F, Brice G, Mortimer P (2008). "Phenotypic characterization of primary lymphedema". Ann. N. Y. Acad. Sci. 1131 (1): 140–6. Bibcode:2008NYASA1131..140C. doi:10.1196/annals.1413.013. PMID 18519967. S2CID 20912436.
  12. ^ a b Norrmén C, Ivanov KI, Cheng J, Zangger N, Delorenzi M, Jaquet M, Miura N, Puolakkainen P, Horsley V, Hu J, Augustin HG, Ylä-Herttuala S, Alitalo K, Petrova TV (May 2009). "FOXC2 controls formation and maturation of lymphatic collecting vessels through cooperation with NFATc1". J. Cell Biol. 185 (3): 439–57. doi:10.1083/jcb.200901104. PMC 2700385. PMID 19398761.
  13. ^ Ng MY, Andrew T, Spector TD, Jeffery S (March 2005). "Linkage to the FOXC2 region of chromosome 16 for varicose veins in otherwise healthy, unselected sibling pairs". J. Med. Genet. 42 (3): 235–9. doi:10.1136/jmg.2004.024075. PMC 1736007. PMID 15744037.
  14. ^ Battula VL, Evans KW, Hollier BG, Shi Y, Marini FC, Ayyanan A, Wang RY, Brisken C, Guerra R, Andreeff M, Mani SA (June 2010). "Epithelial-Mesenchymal Transition-Derived Cells Exhibit Multi-Lineage Differentiation Potential Similar to Mesenchymal Stem Cells". Stem Cells. 28 (8): 1435–45. doi:10.1002/stem.467. PMC 3523728. PMID 20572012.
  15. ^ Mani SA, Yang J, Brooks M, Schwaninger G, Zhou A, Miura N, Kutok JL, Hartwell K, Richardson AL, Weinberg RA (June 2007). "Mesenchyme Forkhead 1 (FOXC2) plays a key role in metastasis and is associated with aggressive basal-like breast cancers". Proc. Natl. Acad. Sci. U.S.A. 104 (24): 10069–74. Bibcode:2007PNAS..10410069M. doi:10.1073/pnas.0703900104. PMC 1891217. PMID 17537911.