Biology:FOXC2
 Generic protein structure example |
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.[1][2] FOXC2 is a member of the fork head box (FOX) family of transcription factors.
Structure and function
The protein is 501 amino acids in length. The gene has no introns; the single exon is approximately 1.5kb in size.[2][3]
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.[4]
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.[5][6]
Role in disease
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,[7][8] It has also been suggested that there may be a link between polymorphisms in FOXC2 and varicose veins.[8][9]
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.[10] Overexpression of FOXC2 has been noted in subtypes of breast cancer which are highly metastatic.[4] Suppression of FOXC2 expression using shRNA in a highly metastatic breast cancer model blocks their metastatic ability.[11]
References
- ↑ "Clustered arrangement of winged helix genes fkh-6 and MFH-1: possible implications for mesoderm development". Development 122 (6): 1751–8. June 1996. doi:10.1242/dev.122.6.1751. PMID 8674414.
- ↑ 2.0 2.1 "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. May 1997. doi:10.1006/geno.1997.4695. PMID 9169153.
- ↑ "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. Dec 2000. doi:10.1086/316915. PMID 11078474.
- ↑ 4.0 4.1 "Mesenchymal-epithelial transition in epithelial response to injury: the role of Foxc2". Oncogene 29 (7): 1031–40. 2010. doi:10.1038/onc.2009.397. PMID 19935708.
- ↑ "The adipocyte-expressed forkhead transcription factor Foxc2 regulates metabolism through altered mitochondrial function.". Diabetes 60 (2): 427–35. Feb 2011. doi:10.2337/db10-0409. PMID 21270254.
- ↑ "FOXC2 is a winged helix gene that counteracts obesity, hypertriglyceridemia, and diet-induced insulin resistance.". Cell 106 (5): 563–73. 2001. doi:10.1016/s0092-8674(01)00474-3. PMID 11551504.
- ↑ "Phenotypic characterization of primary lymphedema". Ann. N. Y. Acad. Sci. 1131 (1): 140–6. 2008. doi:10.1196/annals.1413.013. PMID 18519967. Bibcode: 2008NYASA1131..140C.
- ↑ 8.0 8.1 "FOXC2 controls formation and maturation of lymphatic collecting vessels through cooperation with NFATc1". J. Cell Biol. 185 (3): 439–57. May 2009. doi:10.1083/jcb.200901104. PMID 19398761.
- ↑ "Linkage to the FOXC2 region of chromosome 16 for varicose veins in otherwise healthy, unselected sibling pairs". J. Med. Genet. 42 (3): 235–9. March 2005. doi:10.1136/jmg.2004.024075. PMID 15744037.
- ↑ "Epithelial-Mesenchymal Transition-Derived Cells Exhibit Multi-Lineage Differentiation Potential Similar to Mesenchymal Stem Cells". Stem Cells 28 (8): 1435–45. June 2010. doi:10.1002/stem.467. PMID 20572012.
- ↑ "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. June 2007. doi:10.1073/pnas.0703900104. PMID 17537911. Bibcode: 2007PNAS..10410069M.
Further reading
- "A novel missense mutation and two microrearrangements in the FOXC2 gene of three families with lymphedema-distichiasis syndrome.". Lymphology 43 (1): 14–8. 2010. PMID 20552815.
- "Lymphedema-distichiasis syndrome without FOXC2 mutation: evidence for chromosome 16 duplication upstream of FOXC2.". Lymphology 42 (4): 152–60. 2009. PMID 20218083.
- "Abnormal Shh and FOXC2 expression correlates with aberrant lymphatic development in human fetuses with increased nuchal translucency.". Prenat. Diagn. 29 (9): 840–6. 2009. doi:10.1002/pd.2316. PMID 19548265.
- "The Foxc2 transcription factor regulates tumor angiogenesis.". Biochem. Biophys. Res. Commun. 392 (2): 201–6. 2010. doi:10.1016/j.bbrc.2010.01.015. PMID 20060810.
- "Lymphedema-distichiasis syndrome: a distinct type of primary lymphedema caused by mutations in the FOXC2 gene.". Int. J. Dermatol. 47 (Suppl 1): 52–5. 2008. doi:10.1111/j.1365-4632.2008.03962.x. PMID 18986489.
- Kume T (2008). "Foxc2 transcription factor: a newly described regulator of angiogenesis.". Trends Cardiovasc. Med. 18 (6): 224–8. doi:10.1016/j.tcm.2008.11.003. PMID 19185813.
- "Association of a polymorphism of the apolipoprotein E gene with chronic kidney disease in Japanese individuals with metabolic syndrome.". Genomics 93 (3): 221–6. 2009. doi:10.1016/j.ygeno.2008.11.001. PMID 19056482.
- "A recurrent ITGA9 missense mutation in human fetuses with severe chylothorax: possible correlation with poor response to fetal therapy.". Prenat. Diagn. 28 (11): 1057–63. 2008. doi:10.1002/pd.2130. PMID 18973153.
- "High-density association study of 383 candidate genes for volumetric BMD at the femoral neck and lumbar spine among older men.". J. Bone Miner. Res. 24 (12): 2039–49. 2009. doi:10.1359/jbmr.090524. PMID 19453261.
- "Multiple genetic variants along candidate pathways influence plasma high-density lipoprotein cholesterol concentrations.". J. Lipid Res. 49 (12): 2582–9. 2008. doi:10.1194/jlr.M800232-JLR200. PMID 18660489.
- "Novel missense mutations in the FOXC2 gene alter transcriptional activity.". Hum. Mutat. 30 (12): E1002–9. 2009. doi:10.1002/humu.21127. PMID 19760751.
- "Gestational diabetes mellitus shares polymorphisms of genes associated with insulin resistance and type 2 diabetes in the Greek population.". Gynecological Endocrinology 27 (4): 267–272. 2010. doi:10.3109/09513590.2010.490609. PMID 20540670.
- "Human variation in alcohol response is influenced by variation in neuronal signaling genes". Alcohol. Clin. Exp. Res. 34 (5): 800–12. 2010. doi:10.1111/j.1530-0277.2010.01152.x. PMID 20201926.
- "A case of lymphedema-distichiasis syndrome carrying a new de novo frameshift FOXC2 mutation". Ophthalmic Genet. 31 (2): 98–100. 2010. doi:10.3109/13816811003620517. PMID 20450314.
- "Sporadic in utero generalized edema caused by mutations in the lymphangiogenic genes VEGFR3 and FOXC2". J. Pediatr. 155 (1): 90–3. 2009. doi:10.1016/j.jpeds.2009.02.023. PMID 19394045.
- Janssens, A. Cecile J.W., ed (2008). "Gender differences in genetic risk profiles for cardiovascular disease". PLOS ONE 3 (10): e3615. doi:10.1371/journal.pone.0003615. PMID 18974842. Bibcode: 2008PLoSO...3.3615S.
- "Novel FOXC2 missense mutation identified in patient with lymphedema-distichiasis syndrome and review". Lymphology 41 (3): 98–102. 2008. PMID 19013876.
- "Obesity-related polymorphisms and their associations with the ability to regulate fat oxidation in obese Europeans: the NUGENOB study". Obesity (Silver Spring) 18 (7): 1369–77. 2010. doi:10.1038/oby.2009.377. PMID 19876004.
- "Prox-1 and FOXC2 gene expression in adipose tissue: A potential contributory role of the lymphatic system to familial combined hyperlipidaemia". Atherosclerosis 206 (2): 343–5. 2009. doi:10.1016/j.atherosclerosis.2009.02.026. PMID 19339011.
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