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{{PBB|geneid=2303}}
{{Short description|Protein-coding gene in the species Homo sapiens}}
{{Infobox_gene}}


'''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]].<ref name="pmid8674414">{{cite journal | author = Kaestner KH, Bleckmann SC, Monaghan AP, Schlöndorff J, Mincheva A, Lichter P, Schütz G | title = Clustered arrangement of winged helix genes fkh-6 and MFH-1: possible implications for mesoderm development | journal = Development | volume = 122 | issue = 6 | pages = 1751–8 |date=June 1996 | pmid = 8674414 | doi = | url = | issn = }}</ref><ref name="pmid9169153">{{cite journal | author = Miura N, Iida K, Kakinuma H, Yang XL, Sugiyama T | title = Isolation of the mouse (MFH-1) and human (FKHL 14) mesenchyme fork head-1 genes reveals conservation of their gene and protein structures | journal = Genomics | volume = 41 | issue = 3 | pages = 489–92 |date=May 1997 | pmid = 9169153 | doi = 10.1006/geno.1997.4695 | url = | issn = }}</ref> FOXC2 is a member of the [[FOX proteins|fork head box]] (FOX) family of [[transcription factor]]s.
'''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]].<ref name="pmid8674414">{{cite journal | vauthors = Kaestner KH, Bleckmann SC, Monaghan AP, Schlöndorff J, Mincheva A, Lichter P, Schütz G | title = Clustered arrangement of winged helix genes fkh-6 and MFH-1: possible implications for mesoderm development | journal = Development | volume = 122 | issue = 6 | pages = 1751–8 |date=June 1996 | doi = 10.1242/dev.122.6.1751 | pmid = 8674414 }}</ref><ref name="pmid9169153">{{cite journal | vauthors = Miura N, Iida K, Kakinuma H, Yang XL, Sugiyama T | title = Isolation of the mouse (MFH-1) and human (FKHL 14) mesenchyme fork head-1 genes reveals conservation of their gene and protein structures | journal = Genomics | volume = 41 | issue = 3 | pages = 489–92 |date=May 1997 | pmid = 9169153 | doi = 10.1006/geno.1997.4695 }}</ref> FOXC2 is a member of the [[FOX proteins|fork head box]] (FOX) family of [[transcription factor]]s.


==Structure and function==
==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.<ref name="pmid9169153"/><ref name="pmid11078474">{{cite journal | title=Mutations in FOXC2 (MFH-1), a forkhead family transcription factor, are responsible for the hereditary lymphedema-distichiasis syndrome. | vauthors=Fang J, Dagenais SL, Erickson RP, Arlt MF, Glynn MW, Gorski JL, Seaver LH, Glover TW | journal=Am J Hum Genet |date=Dec 2000 | volume=67 | issue=6 | pages=1382–8 | pmid=11078474 | pmc=1287915 | doi=10.1086/316915}}</ref>
⚫
The protein is 501 amino acids in length. The gene has no [[introns]]; the single [[exon]] is approximately 1.5kb is size.<ref name="pmid9169153"/><ref name="pmid11078474">{{cite journal | title=Mutations in FOXC2 (MFH-1), a forkhead family transcription factor, are responsible for the hereditary lymphedema-distichiasis syndrome. | author=Fang J, Dagenais SL, Erickson RP, Arlt MF, Glynn MW, Gorski JL, Seaver LH, Glover TW. | journal=Am J Hum Genet. |date=Dec 2000 | volume=67 | issue=6 | pages=1382-8 | PMID=11078474 | pmc=1287915 | doi=10.1086/316915}}</ref>


FOX transcription factors are expressed during development and are associated with a number of cellular and developmental [[Cellular differentiation|differentiation]] processes. FOXC2 is required during early development of the kidneys, including differentiation of [[podocyte]]s and maturation of the [[glomerular basement membrane]]. It is also involved in the early development of the heart.<ref name="pmid19935708">{{cite journal |author=Hader C, Marlier A, Cantley L |title=Mesenchymal-epithelial transition in epithelial response to injury: the role of Foxc2 |journal=Oncogene |volume=29 |issue= 7 |pages= 1031–40 |year= 2010 |pmid= 19935708 |pmc=2824778 |doi= 10.1038/onc.2009.397 }}</ref>
FOX transcription factors are expressed during development and are associated with a number of cellular and developmental [[Cellular differentiation|differentiation]] processes. FOXC2 is required during early development of the kidneys, including differentiation of [[podocyte]]s and maturation of the [[glomerular basement membrane]]. It is also involved in the early development of the heart.<ref name="pmid19935708">{{cite journal |vauthors=Hader C, Marlier A, Cantley L |title=Mesenchymal-epithelial transition in epithelial response to injury: the role of Foxc2 |journal=Oncogene |volume=29 |issue= 7 |pages= 1031–40 |year= 2010 |pmid= 19935708 |pmc=2824778 |doi= 10.1038/onc.2009.397 }}</ref>


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.<ref name="pmid21270254">{{cite journal | title=The adipocyte-expressed forkhead transcription factor Foxc2 regulates metabolism through altered mitochondrial function. | author=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. | journal=Diabetes. |date=Feb 2011 | volume=60 | issue=2 | pages=427-35 | doi=10.2337/db10-0409 | PMID=21270254 | pmc=3028341}}</ref><ref name="pmid11551504">{{cite journal | title=FOXC2 is a winged helix gene that counteracts obesity, hypertriglyceridemia, and diet-induced insulin resistance. | author=Cederberg A, Gronning LM, Ahren B, Tasken K, Carlsson P, Enerback S. | journal=Cell | year=2001 | volume=106 | pages=563–73 | PMID=11551504 | issue=5 | doi=10.1016/s0092-8674(01)00474-3}}</ref>
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.<ref name="pmid21270254">{{cite journal | title=The adipocyte-expressed forkhead transcription factor Foxc2 regulates metabolism through altered mitochondrial function. | vauthors=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 | journal=Diabetes |date=Feb 2011 | volume=60 | issue=2 | pages=427–35 | doi=10.2337/db10-0409 | pmid=21270254 | pmc=3028341}}</ref><ref name="pmid11551504">{{cite journal | title=FOXC2 is a winged helix gene that counteracts obesity, hypertriglyceridemia, and diet-induced insulin resistance. | vauthors=Cederberg A, Gronning LM, Ahren B, Tasken K, Carlsson P, Enerback S | journal=Cell | year=2001 | volume=106 | pages=563–73 | pmid=11551504 | issue=5 | doi=10.1016/s0092-8674(01)00474-3| s2cid=7411570 | doi-access=free }}</ref>


==Role in disease==
==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]],<ref name="pmid18519967">{{cite journal | author = Connell F, Brice G, Mortimer P | title = Phenotypic characterization of primary lymphedema | journal = Ann. N. Y. Acad. Sci. | volume = 1131 | issue = | pages = 140–6 | year = 2008 | pmid = 18519967 | doi = 10.1196/annals.1413.013 | url = | issn = }}</ref><ref name="pmid19398761">{{cite journal | title=FOXC2 controls formation and maturation of lymphatic collecting vessels through cooperation with NFATc1 | author=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. | journal=J Cell Biol. |date=May 2009 | volume=185 | issue=3 | pages=439-57 | doi=10.1083/jcb.200901104 | PMID=19398761 | pmc=2700385}}</ref> It has also been suggested that there may be a link between polymorphisms in FOXC2 and varicose veins.<ref name="pmid15744037">{{cite journal | author = Ng MY, Andrew T, Spector TD, Jeffery S | title = Linkage to the FOXC2 region of chromosome 16 for varicose veins in otherwise healthy, unselected sibling pairs | journal = J. Med. Genet. | volume = 42 | issue = 3 | pages = 235–9 |date=March 2005 | pmid = 15744037 | pmc = 1736007 | doi = 10.1136/jmg.2004.024075 | url = | issn = }}</ref>
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]],<ref name="pmid18519967">{{cite journal | vauthors = Connell F, Brice G, Mortimer P | title = Phenotypic characterization of primary lymphedema | journal = Ann. N. Y. Acad. Sci. | volume = 1131 | pages = 140–6 | year = 2008 | issue = 1 | pmid = 18519967 | doi = 10.1196/annals.1413.013 | bibcode = 2008NYASA1131..140C | s2cid = 20912436 }}</ref><ref name="pmid19398761">{{cite journal | title=FOXC2 controls formation and maturation of lymphatic collecting vessels through cooperation with NFATc1 | vauthors=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 | journal=J. Cell Biol. |date=May 2009 | volume=185 | issue=3 | pages=439–57 | doi=10.1083/jcb.200901104 | pmid=19398761 | pmc=2700385}}</ref> It has also been suggested that there may be a link between polymorphisms in FOXC2 and varicose veins.<ref name="pmid19398761"/><ref name="pmid15744037">{{cite journal | vauthors = Ng MY, Andrew T, Spector TD, Jeffery S | title = Linkage to the FOXC2 region of chromosome 16 for varicose veins in otherwise healthy, unselected sibling pairs | journal = J. Med. Genet. | volume = 42 | issue = 3 | pages = 235–9 |date=March 2005 | pmid = 15744037 | pmc = 1736007 | doi = 10.1136/jmg.2004.024075 }}</ref>
<ref name="pmid19398761"/>


FOXC2 is also involved in [[cancer]] [[metastases]]. In particular, expression of FOXC2 is induced when [[epithelium|epithelial cells]] undergo an [[epithelial-mesenchymal transition]] (EMT) and become [[mesenchymal stem cell|mesenchymal]] looking cells. EMT can be induced by a number of genes including [[SNAI1|Snail]], [[twist transcription factor|Twist]], [[GSC (gene)|Goosecoid]], and [[TGF beta 1|TGF-beta 1]].<ref name="pmid20572012">{{cite journal | author = Battula VL, Evans KW, Hollier BG, Shi Y, Marini FC, Ayyanan A, Wang RY, Brisken C, Guerra R, Andreeff M, Mani SA | title = Epithelial-Mesenchymal Transition-Derived Cells Exhibit Multi-Lineage Differentiation Potential Similar to Mesenchymal Stem Cells | journal = Stem Cells | volume = 28| issue = 8| pages = 1435–45|date=June 2010 | pmid = 20572012 | doi = 10.1002/stem.467 | url = | issn = | pmc=3523728}}</ref> Overexpression of FOXC2 has been noted in subtypes of breast cancer which are highly metastatic.<ref name="pmid19935708"/> Suppression of FOXC2 expression using [[small hairpin RNA|shRNA]] in a highly metastatic [[breast cancer]] model blocks their metastatic ability.<ref name="pmid17537911">{{cite journal | author = Mani SA, Yang J, Brooks M, Schwaninger G, Zhou A, Miura N, Kutok JL, Hartwell K, Richardson AL, Weinberg RA | title = Mesenchyme Forkhead 1 (FOXC2) plays a key role in metastasis and is associated with aggressive basal-like breast cancers | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 104 | issue = 24 | pages = 10069–74 |date=June 2007 | pmid = 17537911 | pmc = 1891217 | doi = 10.1073/pnas.0703900104 | url = | issn = }}</ref>
FOXC2 is also involved in [[cancer]] [[metastases]]. In particular, expression of FOXC2 is induced when [[epithelium|epithelial cells]] undergo an [[epithelial-mesenchymal transition]] (EMT) and become [[mesenchymal stem cell|mesenchymal]] looking cells. EMT can be induced by a number of genes including [[SNAI1|Snail]], [[twist transcription factor|Twist]], [[GSC (gene)|Goosecoid]], and [[TGF beta 1|TGF-beta 1]].<ref name="pmid20572012">{{cite journal | vauthors = Battula VL, Evans KW, Hollier BG, Shi Y, Marini FC, Ayyanan A, Wang RY, Brisken C, Guerra R, Andreeff M, Mani SA | title = Epithelial-Mesenchymal Transition-Derived Cells Exhibit Multi-Lineage Differentiation Potential Similar to Mesenchymal Stem Cells | journal = Stem Cells | volume = 28| issue = 8| pages = 1435–45|date=June 2010 | pmid = 20572012 | doi = 10.1002/stem.467 | pmc=3523728}}</ref> Overexpression of FOXC2 has been noted in subtypes of breast cancer which are highly metastatic.<ref name="pmid19935708"/> Suppression of FOXC2 expression using [[small hairpin RNA|shRNA]] in a highly metastatic [[breast cancer]] model blocks their metastatic ability.<ref name="pmid17537911">{{cite journal | vauthors = Mani SA, Yang J, Brooks M, Schwaninger G, Zhou A, Miura N, Kutok JL, Hartwell K, Richardson AL, Weinberg RA | title = Mesenchyme Forkhead 1 (FOXC2) plays a key role in metastasis and is associated with aggressive basal-like breast cancers | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 104 | issue = 24 | pages = 10069–74 |date=June 2007 | pmid = 17537911 | pmc = 1891217 | doi = 10.1073/pnas.0703900104 | bibcode = 2007PNAS..10410069M | doi-access = free }}</ref>


==References==
==References==
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==Further reading==
==Further reading==
{{refbegin | 2}}
{{refbegin | 2}}
*{{cite journal |author=Fauret AL, Tuleja E, Jeunemaitre X, Vignes S |title=A novel missense mutation and two microrearrangements in the FOXC2 gene of three families with lymphedema-distichiasis syndrome. |journal=Lymphology |volume=43 |issue= 1 |pages= 14–8 |year= 2010 |pmid= 20552815 |doi= }}
*{{cite journal |vauthors=Fauret AL, Tuleja E, Jeunemaitre X, Vignes S |title=A novel missense mutation and two microrearrangements in the FOXC2 gene of three families with lymphedema-distichiasis syndrome. |journal=Lymphology |volume=43 |issue= 1 |pages= 14–8 |year= 2010 |pmid= 20552815 }}
*{{cite journal |author=Witte MH, Erickson RP, Khalil M, et al. |title=Lymphedema-distichiasis syndrome without FOXC2 mutation: evidence for chromosome 16 duplication upstream of FOXC2. |journal=Lymphology |volume=42 |issue= 4 |pages= 152–60 |year= 2009 |pmid= 20218083 |doi= }}
*{{cite journal |vauthors=Witte MH, Erickson RP, Khalil M, etal |title=Lymphedema-distichiasis syndrome without FOXC2 mutation: evidence for chromosome 16 duplication upstream of FOXC2. |journal=Lymphology |volume=42 |issue= 4 |pages= 152–60 |year= 2009 |pmid= 20218083 }}
*{{cite journal |author=de Mooij YM, van den Akker NM, Bekker MN, et al. |title=Abnormal Shh and FOXC2 expression correlates with aberrant lymphatic development in human fetuses with increased nuchal translucency. |journal=Prenat. Diagn. |volume=29 |issue= 9 |pages= 840–6 |year= 2009 |pmid= 19548265 |doi= 10.1002/pd.2316 }}
*{{cite journal |vauthors=de Mooij YM, van den Akker NM, Bekker MN, etal |title=Abnormal Shh and FOXC2 expression correlates with aberrant lymphatic development in human fetuses with increased nuchal translucency. |journal=Prenat. Diagn. |volume=29 |issue= 9 |pages= 840–6 |year= 2009 |pmid= 19548265 |doi= 10.1002/pd.2316 |s2cid=2293233 |doi-access=free }}
*{{cite journal |author=Sano H, Leboeuf JP, Novitskiy SV, et al. |title=The Foxc2 transcription factor regulates tumor angiogenesis. |journal=Biochem. Biophys. Res. Commun. |volume=392 |issue= 2 |pages= 201–6 |year= 2010 |pmid= 20060810 |pmc=2822046 |doi= 10.1016/j.bbrc.2010.01.015 }}
*{{cite journal |vauthors=Sano H, Leboeuf JP, Novitskiy SV, etal |title=The Foxc2 transcription factor regulates tumor angiogenesis. |journal=Biochem. Biophys. Res. Commun. |volume=392 |issue= 2 |pages= 201–6 |year= 2010 |pmid= 20060810 |pmc=2822046 |doi= 10.1016/j.bbrc.2010.01.015 }}
*{{cite journal |author=Vreeburg M, Heitink MV, Damstra RJ, et al. |title=Lymphedema-distichiasis syndrome: a distinct type of primary lymphedema caused by mutations in the FOXC2 gene. |journal=Int. J. Dermatol. |volume=47 Suppl 1 |issue= |pages= 52–5 |year= 2008 |pmid= 18986489 |doi= 10.1111/j.1365-4632.2008.03962.x }}
*{{cite journal |vauthors=Vreeburg M, Heitink MV, Damstra RJ, etal |title=Lymphedema-distichiasis syndrome: a distinct type of primary lymphedema caused by mutations in the FOXC2 gene. |journal=Int. J. Dermatol. |volume=47 |pages= 52–5 |year= 2008 |issue=Suppl 1 |pmid= 18986489 |doi= 10.1111/j.1365-4632.2008.03962.x |s2cid=10265549 }}
*{{cite journal |author=Kume T |title=Foxc2 transcription factor: a newly described regulator of angiogenesis. |journal=Trends Cardiovasc. Med. |volume=18 |issue= 6 |pages= 224–8 |year= 2008 |pmid= 19185813 |pmc=2674371 |doi= 10.1016/j.tcm.2008.11.003 }}
*{{cite journal |author=Kume T |title=Foxc2 transcription factor: a newly described regulator of angiogenesis. |journal=Trends Cardiovasc. Med. |volume=18 |issue= 6 |pages= 224–8 |year= 2008 |pmid= 19185813 |pmc=2674371 |doi= 10.1016/j.tcm.2008.11.003 }}
*{{cite journal |author=Yoshida T, Kato K, Fujimaki T, et al. |title=Association of a polymorphism of the apolipoprotein E gene with chronic kidney disease in Japanese individuals with metabolic syndrome. |journal=Genomics |volume=93 |issue= 3 |pages= 221–6 |year= 2009 |pmid= 19056482 |doi= 10.1016/j.ygeno.2008.11.001 }}
*{{cite journal |vauthors=Yoshida T, Kato K, Fujimaki T, etal |title=Association of a polymorphism of the apolipoprotein E gene with chronic kidney disease in Japanese individuals with metabolic syndrome. |journal=Genomics |volume=93 |issue= 3 |pages= 221–6 |year= 2009 |pmid= 19056482 |doi= 10.1016/j.ygeno.2008.11.001 |doi-access= free }}
*{{cite journal |author=Ma GC, Liu CS, Chang SP, et al. |title=A recurrent ITGA9 missense mutation in human fetuses with severe chylothorax: possible correlation with poor response to fetal therapy. |journal=Prenat. Diagn. |volume=28 |issue= 11 |pages= 1057–63 |year= 2008 |pmid= 18973153 |doi= 10.1002/pd.2130 }}
*{{cite journal |vauthors=Ma GC, Liu CS, Chang SP, etal |title=A recurrent ITGA9 missense mutation in human fetuses with severe chylothorax: possible correlation with poor response to fetal therapy. |journal=Prenat. Diagn. |volume=28 |issue= 11 |pages= 1057–63 |year= 2008 |pmid= 18973153 |doi= 10.1002/pd.2130 |s2cid=206346009 }}
*{{cite journal |author=Yerges LM, Klei L, Cauley JA, et al. |title=High-density association study of 383 candidate genes for volumetric BMD at the femoral neck and lumbar spine among older men. |journal=J. Bone Miner. Res. |volume=24 |issue= 12 |pages= 2039–49 |year= 2009 |pmid= 19453261 |pmc=2791518 |doi= 10.1359/jbmr.090524 }}
*{{cite journal |vauthors=Yerges LM, Klei L, Cauley JA, etal |title=High-density association study of 383 candidate genes for volumetric BMD at the femoral neck and lumbar spine among older men. |journal=J. Bone Miner. Res. |volume=24 |issue= 12 |pages= 2039–49 |year= 2009 |pmid= 19453261 |pmc=2791518 |doi= 10.1359/jbmr.090524 }}
*{{cite journal |author=Lu Y, Dollé ME, Imholz S, et al. |title=Multiple genetic variants along candidate pathways influence plasma high-density lipoprotein cholesterol concentrations. |journal=J. Lipid Res. |volume=49 |issue= 12 |pages= 2582–9 |year= 2008 |pmid= 18660489 |doi= 10.1194/jlr.M800232-JLR200 }}
*{{cite journal |vauthors=Lu Y, Dollé ME, Imholz S|title=Multiple genetic variants along candidate pathways influence plasma high-density lipoprotein cholesterol concentrations. |journal=J. Lipid Res. |volume=49 |issue= 12 |pages= 2582–9 |year= 2008 |pmid= 18660489 |doi= 10.1194/jlr.M800232-JLR200 |display-authors=etal|doi-access=free }}
*{{cite journal |author=van Steensel MA, Damstra RJ, Heitink MV, et al. |title=Novel missense mutations in the FOXC2 gene alter transcriptional activity. |journal=Hum. Mutat. |volume=30 |issue= 12 |pages= E1002–9 |year= 2009 |pmid= 19760751 |doi= 10.1002/humu.21127 }}
*{{cite journal |vauthors=van Steensel MA, Damstra RJ, Heitink MV, etal |title=Novel missense mutations in the FOXC2 gene alter transcriptional activity. |journal=Hum. Mutat. |volume=30 |issue= 12 |pages= E1002–9 |year= 2009 |pmid= 19760751 |doi= 10.1002/humu.21127 |s2cid=7674502 |doi-access=free }}
*{{cite journal |author=Pappa KI, Gazouli M, Economou K, et al. |title=Gestational diabetes mellitus shares polymorphisms of genes associated with insulin resistance and type 2 diabetes in the Greek population. |journal=Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology |volume= 27|issue= 4|pages= HASH(0x28c7db0) |year= 2010 |pmid= 20540670 |doi= 10.3109/09513590.2010.490609 }}
*{{cite journal |vauthors=Pappa KI, Gazouli M, Economou K, etal |title=Gestational diabetes mellitus shares polymorphisms of genes associated with insulin resistance and type 2 diabetes in the Greek population. |journal=Gynecological Endocrinology |volume= 27|issue= 4|pages= 267–272 |year= 2010 |pmid= 20540670 |doi= 10.3109/09513590.2010.490609 |s2cid=28980963 }}
*{{cite journal |author=Joslyn G, Ravindranathan A, Brush G, et al. |title=Human variation in alcohol response is influenced by variation in neuronal signaling genes |journal=Alcohol. Clin. Exp. Res. |volume=34 |issue= 5 |pages= 800–12 |year= 2010 |pmid= 20201926 |doi= 10.1111/j.1530-0277.2010.01152.x }}
*{{cite journal |vauthors=Joslyn G, Ravindranathan A, Brush G, etal |title=Human variation in alcohol response is influenced by variation in neuronal signaling genes |journal=Alcohol. Clin. Exp. Res. |volume=34 |issue= 5 |pages= 800–12 |year= 2010 |pmid= 20201926 |doi= 10.1111/j.1530-0277.2010.01152.x |doi-access= free }}
*{{cite journal |author=Fabretto A, Shardlow A, Faletra F, et al. |title=A case of lymphedema-distichiasis syndrome carrying a new de novo frameshift FOXC2 mutation |journal=Ophthalmic Genet. |volume=31 |issue= 2 |pages= 98–100 |year= 2010 |pmid= 20450314 |doi= 10.3109/13816811003620517 }}
*{{cite journal |vauthors=Fabretto A, Shardlow A, Faletra F, etal |title=A case of lymphedema-distichiasis syndrome carrying a new de novo frameshift FOXC2 mutation |journal=Ophthalmic Genet. |volume=31 |issue= 2 |pages= 98–100 |year= 2010 |pmid= 20450314 |doi= 10.3109/13816811003620517 |s2cid=22263077 |hdl=11368/2935146 |hdl-access=free }}
*{{cite journal |author=Ghalamkarpour A, Debauche C, Haan E, et al. |title=Sporadic in utero generalized edema caused by mutations in the lymphangiogenic genes VEGFR3 and FOXC2 |journal=J. Pediatr. |volume=155 |issue= 1 |pages= 90–3 |year= 2009 |pmid= 19394045 |doi= 10.1016/j.jpeds.2009.02.023 }}
*{{cite journal |vauthors=Ghalamkarpour A, Debauche C, Haan E, etal |title=Sporadic in utero generalized edema caused by mutations in the lymphangiogenic genes VEGFR3 and FOXC2 |journal=J. Pediatr. |volume=155 |issue= 1 |pages= 90–3 |year= 2009 |pmid= 19394045 |doi= 10.1016/j.jpeds.2009.02.023 }}
*{{cite journal |author=Silander K, Alanne M, Kristiansson K, et al. |title=Gender differences in genetic risk profiles for cardiovascular disease |journal=PLoS ONE |volume=3 |issue= 10 |pages= e3615 |year= 2008 |pmid= 18974842 |pmc=2574036 |doi= 10.1371/journal.pone.0003615 |editor1-last=Janssens |editor1-first=A. Cecile J.W. }}
*{{cite journal |vauthors=Silander K, Alanne M, Kristiansson K, etal |title=Gender differences in genetic risk profiles for cardiovascular disease |journal=PLOS ONE |volume=3 |issue= 10 |pages= e3615 |year= 2008 |pmid= 18974842 |pmc=2574036 |doi= 10.1371/journal.pone.0003615 |bibcode=2008PLoSO...3.3615S |editor1-last=Janssens |editor1-first=A. Cecile J.W. |doi-access=free }}
*{{cite journal |author=Dellinger MT, Thome K, Bernas MJ, et al. |title=Novel FOXC2 missense mutation identified in patient with lymphedema-distichiasis syndrome and review |journal=Lymphology |volume=41 |issue= 3 |pages= 98–102 |year= 2008 |pmid= 19013876 |doi= }}
*{{cite journal |vauthors=Dellinger MT, Thome K, Bernas MJ, etal |title=Novel FOXC2 missense mutation identified in patient with lymphedema-distichiasis syndrome and review |journal=Lymphology |volume=41 |issue= 3 |pages= 98–102 |year= 2008 |pmid= 19013876 }}
*{{cite journal |author=Corpeleijn E, Petersen L, Holst C, et al. |title=Obesity-related polymorphisms and their associations with the ability to regulate fat oxidation in obese Europeans: the NUGENOB study |journal=Obesity (Silver Spring) |volume=18 |issue= 7 |pages= 1369–77 |year= 2010 |pmid= 19876004 |doi= 10.1038/oby.2009.377 }}
*{{cite journal |vauthors=Corpeleijn E, Petersen L, Holst C, etal |title=Obesity-related polymorphisms and their associations with the ability to regulate fat oxidation in obese Europeans: the NUGENOB study |journal=Obesity (Silver Spring) |volume=18 |issue= 7 |pages= 1369–77 |year= 2010 |pmid= 19876004 |doi= 10.1038/oby.2009.377 |s2cid=205527246 |doi-access=free }}
*{{cite journal |author=Horra A, Salazar J, Ferré R, et al. |title=Prox-1 and FOXC2 gene expression in adipose tissue: A potential contributory role of the lymphatic system to familial combined hyperlipidaemia |journal=Atherosclerosis |volume=206 |issue= 2 |pages= 343–5 |year= 2009 |pmid= 19339011 |doi= 10.1016/j.atherosclerosis.2009.02.026 }}
*{{cite journal |vauthors=Horra A, Salazar J, Ferré R|title=Prox-1 and FOXC2 gene expression in adipose tissue: A potential contributory role of the lymphatic system to familial combined hyperlipidaemia |journal=Atherosclerosis |volume=206 |issue= 2 |pages= 343–5 |year= 2009 |pmid= 19339011 |doi= 10.1016/j.atherosclerosis.2009.02.026 |display-authors=etal}}
{{refend}}
{{refend}}


==External links==
==External links==
*[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=lds GeneReviews/NCBI/NIH/UW entry on Lymphedema-Distichiasis Syndrome]
*[https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=lds GeneReviews/NCBI/NIH/UW entry on Lymphedema-Distichiasis Syndrome]


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{{DEFAULTSORT:Foxc2}}
{{DEFAULTSORT:Foxc2}}
[[Category:Forkhead transcription factors]]
[[Category:Forkhead transcription factors]]


{{genetics-stub}}

Latest revision as of 14:01, 21 December 2023

FOXC2
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesFOXC2, FKHL14, LD, MFH-1, MFH1, forkhead box C2
External IDsOMIM: 602402 MGI: 1347481 HomoloGene: 21091 GeneCards: FOXC2
Orthologs
SpeciesHumanMouse
Entrez

2303

14234

Ensembl

ENSG00000176692

ENSMUSG00000046714

UniProt

Q99958

Q61850

RefSeq (mRNA)

NM_005251

NM_013519

RefSeq (protein)

NP_005242

NP_038547

Location (UCSC)Chr 16: 86.57 – 86.57 MbChr 8: 121.84 – 121.85 Mb
PubMed 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[edit]

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]

Role in disease[edit]

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]

References[edit]

  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.

Further reading[edit]

External links[edit]

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