Forkhead box C1 explained

Forkhead box C1, also known as FOXC1, is a protein which in humans is encoded by the FOXC1 gene.^{[1] [2] [3]}

Function

This gene belongs to the forkhead family of transcription factors which is characterized by a distinct DNA-binding fork head domain. The specific function of this gene has not yet been determined; however, it has been shown to play a role in the regulation of embryonic and ocular development.

Heart development and somitogenesis

FOXC1 and its close relative, FOXC2 are both critical components in the development of the heart and blood vessels, as well as the segmentation of the paraxial mesoderm and the formation of somites. Expression of the Fox proteins range from low levels in the posterior pre-somitic mesoderm (PSM) to the highest levels in the anterior PSM. Homozygous mutant embryos for both Fox proteins failed to form somites 1–8, which indicates the importance of these proteins early on in somite development.^[4]

In cardiac morphogenesis, FOXC1 and FOXC2 are required for the proper development of the cardiac outflow tract. The outflow tract forms from a cell population known as the secondary heart field. The Fox proteins are transcribed in the secondary heart field where they regulate the expression of key signaling molecules such as Fgf8, Fgf10, Tbx1, Isl1, and Bmp4.^[5]

Clinical significance

Mutations in this gene cause various glaucoma phenotypes including primary congenital glaucoma, autosomal dominant iridogoniodysgenesis anomaly, and Axenfeld–Rieger syndrome type 3. FOXC1 mutations are also found in association with Dandy–Walker malformation.^[6]

Role in cancer

FOXC1 induces the epithelial to mesenchymal transition (EMT), which is a process where epithelial cells separate from surrounding cells and begin migration. This process is involved in metastasis, giving FOXC1 a crucial role in cancer. The over expression of FOXC1 results in the up-regulation of fibronectin, vimentin, and N-cadherin, which contribute to cellular migration in nasopharyngeal carcinoma (NPC). The knockout of FOXC1 in human NPC cells down-regulated vimentin, fibronectin, and N-cadherin expression.^[7]

FOXC1 transcription factor regulates EMT in basal-like breast cancer (BLBC). Activation of SMO-independent Hedgehog signaling by FOXC1 alters the cancer stem cell (CSC) properties in BLBC cells.^[8] These CSCs, which are regulated by FOXC1 signaling, contribute to tumor proliferation, tissue invasion, and relapse.^[9]

See also

• FOX proteins

References

Further reading

• Sperling R, Bustin M . Dynamic equilibrium in histone assembly: self-assembly of single histones and histone pairs . Biochemistry . 14 . 15 . 3322–31 . July 1975 . 1170889 . 10.1021/bi00686a006 .
• Pierrou S, Hellqvist M, Samuelsson L, Enerbäck S, Carlsson P . Cloning and characterization of seven human forkhead proteins: binding site specificity and DNA bending . The EMBO Journal . 13 . 20 . 5002–12 . October 1994 . 7957066 . 395442 . 10.1002/j.1460-2075.1994.tb06827.x.
• Hromas R, Moore J, Johnston T, Socha C, Klemsz M . Drosophila forkhead homologues are expressed in a lineage-restricted manner in human hematopoietic cells . Blood . 81 . 11 . 2854–9 . June 1993 . 8499623 . 10.1182/blood.V81.11.2854.2854. free .
• Larsson C, Hellqvist M, Pierrou S, White I, Enerbäck S, Carlsson P . Chromosomal localization of six human forkhead genes, freac-1 (FKHL5), -3 (FKHL7), -4 (FKHL8), -5 (FKHL9), -6 (FKHL10), and -8 (FKHL12) . Genomics . 30 . 3 . 464–9 . December 1995 . 8825632 . 10.1006/geno.1995.1266 .
• Longhurst TJ, O'Neill GM, Harvie RM, Davey RA . The anthracycline resistance-associated (ara) gene, a novel gene associated with multidrug resistance in a human leukaemia cell line . British Journal of Cancer . 74 . 9 . 1331–5 . November 1996 . 8912525 . 2074757 . 10.1038/bjc.1996.545 .
• Mears AJ, Mirzayans F, Gould DB, Pearce WG, Walter MA . Autosomal dominant iridogoniodysgenesis anomaly maps to 6p25 . American Journal of Human Genetics . 59 . 6 . 1321–7 . December 1996 . 8940278 . 1914875 .
• Gould DB, Mears AJ, Pearce WG, Walter MA . Autosomal dominant Axenfeld-Rieger anomaly maps to 6p25 . American Journal of Human Genetics . 61 . 3 . 765–8 . September 1997 . 9326342 . 1715932 . 10.1016/S0002-9297(07)64340-7 .
• Jordan T, Ebenezer N, Manners R, McGill J, Bhattacharya S . Familial glaucoma iridogoniodysplasia maps to a 6p25 region implicated in primary congenital glaucoma and iridogoniodysgenesis anomaly . American Journal of Human Genetics . 61 . 4 . 882–8 . October 1997 . 9382099 . 1715988 . 10.1086/514874 .
• Nishimura DY, Swiderski RE, Alward WL, Searby CC, Patil SR, Bennet SR, Kanis AB, Gastier JM, Stone EM, Sheffield VC . The forkhead transcription factor gene FKHL7 is responsible for glaucoma phenotypes which map to 6p25 . Nature Genetics . 19 . 2 . 140–7 . June 1998 . 9620769 . 10.1038/493 . 34692231 .
• Mears AJ, Jordan T, Mirzayans F, Dubois S, Kume T, Parlee M, Ritch R, Koop B, Kuo WL, Collins C, Marshall J, Gould DB, Pearce W, Carlsson P, Enerbäck S, Morissette J, Bhattacharya S, Hogan B, Raymond V, Walter MA . Mutations of the forkhead/winged-helix gene, FKHL7, in patients with Axenfeld-Rieger anomaly . American Journal of Human Genetics . 63 . 5 . 1316–28 . November 1998 . 9792859 . 1377542 . 10.1086/302109 .
• Swiderski RE, Reiter RS, Nishimura DY, Alward WL, Kalenak JW, Searby CS, Stone EM, Sheffield VC, Lin JJ . Expression of the Mf1 gene in developing mouse hearts: implication in the development of human congenital heart defects . Developmental Dynamics . 216 . 1 . 16–27 . September 1999 . 10474162 . 10.1002/(SICI)1097-0177(199909)216:1<16::AID-DVDY4>3.0.CO;2-1 . free .
• Mirzayans F, Gould DB, Héon E, Billingsley GD, Cheung JC, Mears AJ, Walter MA . Axenfeld-Rieger syndrome resulting from mutation of the FKHL7 gene on chromosome 6p25 . European Journal of Human Genetics . 8 . 1 . 71–4 . January 2000 . 10713890 . 10.1038/sj.ejhg.5200354 . free .
• Lehmann OJ, Ebenezer ND, Jordan T, Fox M, Ocaka L, Payne A, Leroy BP, Clark BJ, Hitchings RA, Povey S, Khaw PT, Bhattacharya SS . Chromosomal duplication involving the forkhead transcription factor gene FOXC1 causes iris hypoplasia and glaucoma . American Journal of Human Genetics . 67 . 5 . 1129–35 . November 2000 . 11007653 . 1288555 . 10.1016/S0002-9297(07)62943-7 .
• Nishimura DY, Searby CC, Alward WL, Walton D, Craig JE, Mackey DA, Kawase K, Kanis AB, Patil SR, Stone EM, Sheffield VC . A spectrum of FOXC1 mutations suggests gene dosage as a mechanism for developmental defects of the anterior chamber of the eye . American Journal of Human Genetics . 68 . 2 . 364–72 . February 2001 . 11170889 . 1235270 . 10.1086/318183 .
• Wang WH, McNatt LG, Shepard AR, Jacobson N, Nishimura DY, Stone EM, Sheffield VC, Clark AF . Optimal procedure for extracting RNA from human ocular tissues and expression profiling of the congenital glaucoma gene FOXC1 using quantitative RT-PCR . Molecular Vision . 7 . 89–94 . April 2001 . 11320352 .
• Kawase C, Kawase K, Taniguchi T, Sugiyama K, Yamamoto T, Kitazawa Y, Alward WL, Stone EM, Nishimura DY, Sheffield VC . Screening for mutations of Axenfeld-Rieger syndrome caused by FOXC1 gene in Japanese patients . Journal of Glaucoma . 10 . 6 . 477–82 . December 2001 . 11740218 . 10.1097/00061198-200112000-00007 . 43165728 .
• Dintilhac A, Bernués J . HMGB1 interacts with many apparently unrelated proteins by recognizing short amino acid sequences . The Journal of Biological Chemistry . 277 . 9 . 7021–8 . March 2002 . 11748221 . 10.1074/jbc.M108417200 . 39560486 . free .
• Berry FB, Saleem RA, Walter MA . FOXC1 transcriptional regulation is mediated by N- and C-terminal activation domains and contains a phosphorylated transcriptional inhibitory domain . The Journal of Biological Chemistry . 277 . 12 . 10292–7 . March 2002 . 11782474 . 10.1074/jbc.M110266200 . free .
• Borges AS, Susanna R, Carani JC, Betinjane AJ, Alward WL, Stone EM, Sheffield VC, Nishimura DY . Genetic analysis of PITX2 and FOXC1 in Rieger Syndrome patients from Brazil . Journal of Glaucoma . 11 . 1 . 51–6 . February 2002 . 11821690 . 10.1097/00061198-200202000-00010 . 26094053 . free .
• Freyaldenhoven BS, Fried C, Wielckens K . FOXD4a and FOXD4b, two new winged helix transcription factors, are expressed in human leukemia cell lines . Gene . 294 . 1–2 . 131–140 . July 2002 . 12234674 . 10.1016/S0378-1119(02)00702-3 .

Notes and References

1. Web site: Entrez Gene: FOXC1 forkhead box C1.
2. Pierrou S, Hellqvist M, Samuelsson L, Enerbäck S, Carlsson P . Cloning and characterization of seven human forkhead proteins: binding site specificity and DNA bending . The EMBO Journal . 13 . 20 . 5002–12 . October 1994 . 7957066 . 395442 . 10.1002/j.1460-2075.1994.tb06827.x.
3. Nishimura DY, Swiderski RE, Alward WL, Searby CC, Patil SR, Bennet SR, Kanis AB, Gastier JM, Stone EM, Sheffield VC . The forkhead transcription factor gene FKHL7 is responsible for glaucoma phenotypes which map to 6p25 . Nature Genetics . 19 . 2 . 140–7 . June 1998 . 9620769 . 10.1038/493 . 34692231 .
4. Kume T, Jiang H, Topczewska JM, Hogan BL . The murine winged helix transcription factors, Foxc1 and Foxc2, are both required for cardiovascular development and somitogenesis . Genes & Development . 15 . 18 . 2470–82 . September 2001 . 11562355 . 312788 . 10.1101/gad.907301 .
5. Seo S, Kume T . 2006. Forkhead transcription factors, Foxc1 and Foxc2, are required for the morphogenesis of the cardiac outflow tract . 10.1016/j.ydbio.2006.06.012 . Developmental Biology . 296. 2. 421–436 . 16839542.
6. Haldipur P, Gillies GS, Janson OK, Chizhikov VV, Mithal DS, Miller RJ, Millen KJ . Foxc1 dependent mesenchymal signalling drives embryonic cerebellar growth . eLife . 3 . e03962 . December 2014 . 25513817 . 4281880 . 10.7554/eLife.03962 . free .
7. Ou-Yang L, Xiao SJ, Liu P, Yi SJ, Zhang XL, Ou-Yang S, Tan SK, Lei X . Forkhead box C1 induces epithelial‑mesenchymal transition and is a potential therapeutic target in nasopharyngeal carcinoma . Molecular Medicine Reports . 12 . 6 . 8003–9 . December 2015 . 26461269 . 4758279 . 10.3892/mmr.2015.4427 .
8. Han B, Qu Y, Jin Y, Yu Y, Deng N, Wawrowsky K, Zhang X, Li N, Bose S, Wang Q, Sakkiah S, Abrol R, Jensen TW, Berman BP, Tanaka H, Johnson J, Gao B, Hao J, Liu Z, Buttyan R, Ray PS, Hung MC, Giuliano AE, Cui X . FOXC1 Activates Smoothened-Independent Hedgehog Signaling in Basal-like Breast Cancer . Cell Reports . 13 . 5 . 1046–1058 . November 2015 . 26565916 . 4806384 . 10.1016/j.celrep.2015.09.063 .
9. Han B, Qu Y, Jin Y, Yu Y, Deng N, Wawrowsky K, Zhang X, Li N, Bose S, Wang Q, Sakkiah S, Abrol R, Jensen TW, Berman BP, Tanaka H, Johnson J, Gao B, Hao J, Liu Z, Buttyan R, Ray PS, Hung MC, Giuliano AE, Cui X . FOXC1 Activates Smoothened-Independent Hedgehog Signaling in Basal-like Breast Cancer . Cell Reports . 13 . 5 . 1046–1058 . November 2015 . 26565916 . 4806384 . 10.1016/j.celrep.2015.09.063 .