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FOXC1  -  forkhead box C1

Homo sapiens

Synonyms: ARA, FKHL7, FREAC-3, FREAC3, Forkhead box protein C1, ...
 
 
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Disease relevance of FOXC1

  • In addition, screens of primary endometrial and ovarian cancers revealed homozygous deletion of FOXC1 in 6.7% of them, one nonsense and one missense mutation of FOXC1, and transcriptional silencing in 11.7% of primary cancers [1].
  • In A7 melanoma cells possessing elevated levels of nuclear FLNA, FOXC1 is unable to activate transcription and is partitioned to an HP1alpha, heterochromatin-rich region of the nucleus [2].
  • Here, we show that mouse embryos compound mutant for Foxc1 and Foxc2, two closely related Fox transcription factors, exhibit arteriovenous malformations and lack of induction of arterial markers whereas venous markers such as COUP-TFII are normally expressed, suggesting that mutant endothelial cells fail to acquire an arterial fate [3].
  • The mapping of ARA to this region and its homology to MRP raises questions about its potential role in the biology of the inv(16) leukemias [4].
  • In conclusion, ARA AMP exerts a considerable but transient antiviral effect on hepatitis B virus [5].
 

High impact information on FOXC1

  • The forkhead transcription factor gene FKHL7 is responsible for glaucoma phenotypes which map to 6p25 [6].
  • One of these, FKHL7, encoding a forkhead transcription factor, is in close proximity to the breakpoint in the balanced translocation patient and is deleted in a second PCG patient with partial 6p monosomy [6].
  • Molecular modeling of the FOXC1 forkhead domain predicted that the missense mutations did not alter FOXC1 structure [7].
  • However, the F112S and I126M mutations decrease the transactivation ability of FOXC1 [7].
  • A spectrum of FOXC1 mutations suggests gene dosage as a mechanism for developmental defects of the anterior chamber of the eye [8].
 

Chemical compound and disease context of FOXC1

  • This study compared the response to adenine arabinoside 5'-monophosphate (ARA AMP) in 60 patients with chronic hepatitis B according to the pretreatment serum hepatitis B virus DNA concentration [5].
  • We studied the relationship between the timing of discontinuing chronic angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor subtype 1 antagonists (ARA) and hypotension after the induction of general anesthesia in a general surgical population [9].
  • Hypotension refractory to repeated ephedrine or phenylephrine administration occurred significantly (P < or = 0.05) more in the ARA group (4 of 12) compared with the BB/CB group (0 of 45) or the ACEI group (1 of 27), but it was treated successfully by using a vasopressin system agonist [10].
  • Etoposide in combination with intermediate dose cytosine arabinoside (ID ARA C) given with the intention of further myeloablative therapy for the treatment of refractory or recurrent hematological malignancy [11].
  • These cardiac abnormalities proved to be statistically correlated with the number of ARA criteria (p = 0.045), the number of lupus flares (p = 0.004), the serum levels of cholesterol (p = 0.04) and of triglycerides (p = 0.025) as well as the duration of hypercholesterolemia (p = 0.005) and of hypertriglyceridemia (p = 0.007) [12].
 

Biological context of FOXC1

  • Structural and functional analyses of disease-causing missense mutations in the forkhead domain of FOXC1 [13].
  • These experiments extend our previous hypothesis that reduced transactivation of appropriate target genes by FOXC1, underlie AR malformations mapping to human chromosome 6p25 [13].
  • METHODS: Four pedigrees with early-onset glaucoma phenotypes secondary to segmental chromosomal duplications or deletions encompassing FOXC1 and 18 individuals from 9 FOXC2 mutation pedigrees underwent detailed ocular phenotyping [14].
  • In this report, we clinically characterize the spectrum of ocular and systemic manifestations in one family resulting from a previously reported point mutation (Phe112Ser) in FOXC1 [15].
  • Removal of residues 215-366 resulted in a transcriptionally hyperactive FOXC1 protein, which displayed a reduced level of phosphorylation [16].
 

Anatomical context of FOXC1

 

Associations of FOXC1 with chemical compounds

  • Moreover, these data implicate specific members of the FOX family of TFs (FOXC1, C2, P1, P4, and O1A) not previously suggested in heart failure pathogenesis [17].
  • We report here that FOXC1 is a short-lived protein (t 1/2< 30 min), and serine 272 is a critical residue in maintaining proper stability of FOXC1 [20].
  • FOXC1-enriched chromatin complexes were isolated by using the tight electrostatic interaction between histidine residues of the recombinant FOXC1 protein and nickel [21].
  • BACKGROUND: Autoantibodies against transglutaminase 2 (TG2) are thought to be responsible for the endomysial (EMA), reticulin (ARA), and jejunal antibody (JEA) tissue binding of serum samples from coeliac patients but the exclusive role of TG2 in these staining patterns has not yet been established [22].
  • An uncontrolled pilot study of adenine arabinoside monophosphate intramuscularly (ARA-AMP) for 5 days at 10 mg/kg/day and 23 days at 5 mg/kg/day in divided doses, was conducted in 15 consecutive patients known to be HBeAg-positive for a minimum of 12 months [23].
 

Physical interactions of FOXC1

  • Direct sequencing of PAX6 and the DNA-binding domain of FOXC1 failed to detect a mutation [24].
  • Ultimately, PITX2 loss of function mutations have a compound effect: the reduced expression of PITX2-target genes coupled with the extensive activation of FOXC1-regulated targets [25].
  • Here we demonstrate that FOXC1 interacts with the actin-binding protein filamin A (FLNA) [2].
 

Regulatory relationships of FOXC1

  • FOXC1 positively regulates FGF19 expression in corneal and periocular mesenchymal cells in cell culture and in zebrafish embryos [26].
  • Together, these data reveal a mechanism by which structural proteins such as FLNA can influence the activity of a developmentally and pathologically important transcription factor such as FOXC1 [2].
  • Regulation of FOXC1 stability and transcriptional activity by an epidermal growth factor-activated mitogen-activated protein kinase signaling cascade [20].
 

Other interactions of FOXC1

  • Haploinsufficiency of the transcription factors FOXC1 and FOXC2 results in aberrant ocular development [27].
  • In view of PITX2's contribution to corneal development and the altered CCT in some FOXC1-related cases, this study was undertaken to investigate whether a related phenotype is associated with the PITX2/Pitx2 mutation [28].
  • Investigations of other glaucoma-related genes, such as PITX2, FOXC1, and CYP1B1, are enabling a better understanding of anterior segment development and its relation to glaucoma [29].
  • Pigment-free total RNA was isolated and used for quantitative real-time RT-PCR using FOXC1 and GAPDH (internal standard) primers to assess the quality and expression of FOXC1 [18].
  • Three forkhead genes (FOXF1 and FOXQ1 from within the critical region, and FOXC1 proximal to this region) were evaluated as potential candidate disease genes for this disorder [30].
 

Analytical, diagnostic and therapeutic context of FOXC1

  • Site-directed mutagenesis was used to introduce this mutation into the FOXC1 cDNA [31].
  • RESULTS: An expression profile of FOXC1 in human ocular tissues was determined using quantitative PCR of RNA isolated using a simple and effective procedure for ocular tissue preservation and pigment-free RNA isolation [18].
  • Optimal procedure for extracting RNA from human ocular tissues and expression profiling of the congenital glaucoma gene FOXC1 using quantitative RT-PCR [18].
  • Immunofluorescence further shows PITX2A and FOXC1 to be colocalized within a common nuclear subcompartment [25].
  • Fifteen patients were treated with ARA-AMP 10 mg/kg/day given as intramuscular injections 12 hours apart for five days followed by 5 mg/kg/day for 23 days [32].

References

  1. Identification of FOXC1 as a TGF-beta1 responsive gene and its involvement in negative regulation of cell growth. Zhou, Y., Kato, H., Asanoma, K., Kondo, H., Arima, T., Kato, K., Matsuda, T., Wake, N. Genomics (2002) [Pubmed]
  2. FOXC1 transcriptional regulatory activity is impaired by PBX1 in a filamin A-mediated manner. Berry, F.B., O'Neill, M.A., Coca-Prados, M., Walter, M.A. Mol. Cell. Biol. (2005) [Pubmed]
  3. The forkhead transcription factors, Foxc1 and Foxc2, are required for arterial specification and lymphatic sprouting during vascular development. Seo, S., Fujita, H., Nakano, A., Kang, M., Duarte, A., Kume, T. Dev. Biol. (2006) [Pubmed]
  4. ARA, a novel ABC transporter, is located at 16p13.1, is deleted in inv(16) leukemias, and is shown to be expressed in primitive hematopoietic precursors. Kuss, B.J., O'Neill, G.M., Eyre, H., Doggett, N.A., Callen, D.F., Davey, R.A. Genomics (1998) [Pubmed]
  5. Adenine arabinoside 5'-monophosphate in patients with chronic hepatitis B: comparison of the efficacy in patients with high and low viral replication. Marcellin, P., Pouteau, M., Loriot, M.A., Boyer, N., Degos, F., Calès, P., Bettan, L., Bacq, Y., Coppére, H., Grange, J.D. Gut (1995) [Pubmed]
  6. The forkhead transcription factor gene FKHL7 is responsible for glaucoma phenotypes which map to 6p25. Nishimura, D.Y., Swiderski, R.E., Alward, W.L., Searby, C.C., Patil, S.R., Bennet, S.R., Kanis, A.B., Gastier, J.M., Stone, E.M., Sheffield, V.C. Nat. Genet. (1998) [Pubmed]
  7. Analyses of the effects that disease-causing missense mutations have on the structure and function of the winged-helix protein FOXC1. Saleem, R.A., Banerjee-Basu, S., Berry, F.B., Baxevanis, A.D., Walter, M.A. Am. J. Hum. Genet. (2001) [Pubmed]
  8. A spectrum of FOXC1 mutations suggests gene dosage as a mechanism for developmental defects of the anterior chamber of the eye. Nishimura, D.Y., Searby, C.C., Alward, W.L., Walton, D., Craig, J.E., Mackey, D.A., Kawase, K., Kanis, A.B., Patil, S.R., Stone, E.M., Sheffield, V.C. Am. J. Hum. Genet. (2001) [Pubmed]
  9. Angiotensin system inhibitors in a general surgical population. Comfere, T., Sprung, J., Kumar, M.M., Draper, M., Wilson, D.P., Williams, B.A., Danielson, D.R., Liedl, L., Warner, D.O. Anesth. Analg. (2005) [Pubmed]
  10. The hemodynamic effects of anesthetic induction in vascular surgical patients chronically treated with angiotensin II receptor antagonists. Brabant, S.M., Bertrand, M., Eyraud, D., Darmon, P.L., Coriat, P. Anesth. Analg. (1999) [Pubmed]
  11. Etoposide in combination with intermediate dose cytosine arabinoside (ID ARA C) given with the intention of further myeloablative therapy for the treatment of refractory or recurrent hematological malignancy. Whelan, J.S., Davis, C.L., Rohatiner, A.Z., Leahy, M., MacCallum, P.K., Gupta, R.K., Matthews, J., Norton, A.J., Amess, J.A., Lister, T.A. Hematological oncology. (1992) [Pubmed]
  12. Cardiologic abnormalities in patients with long-term lupus nephritis. Moroni, G., La Marchesina, U., Banfi, G., Nador, F., Vigano, E., Marconi, M., Lotto, A., Ponticelli, C. Clin. Nephrol. (1995) [Pubmed]
  13. Structural and functional analyses of disease-causing missense mutations in the forkhead domain of FOXC1. Saleem, R.A., Banerjee-Basu, S., Berry, F.B., Baxevanis, A.D., Walter, M.A. Hum. Mol. Genet. (2003) [Pubmed]
  14. Novel anterior segment phenotypes resulting from forkhead gene alterations: evidence for cross-species conservation of function. Lehmann, O.J., Tuft, S., Brice, G., Smith, R., Blixt, A., Bell, R., Johansson, B., Jordan, T., Hitchings, R.A., Khaw, P.T., John, S.W., Carlsson, P., Bhattacharya, S.S. Invest. Ophthalmol. Vis. Sci. (2003) [Pubmed]
  15. A family with Axenfeld-Rieger syndrome and Peters Anomaly caused by a point mutation (Phe112Ser) in the FOXC1 gene. Honkanen, R.A., Nishimura, D.Y., Swiderski, R.E., Bennett, S.R., Hong, S., Kwon, Y.H., Stone, E.M., Sheffield, V.C., Alward, W.L. Am. J. Ophthalmol. (2003) [Pubmed]
  16. FOXC1 transcriptional regulation is mediated by N- and C-terminal activation domains and contains a phosphorylated transcriptional inhibitory domain. Berry, F.B., Saleem, R.A., Walter, M.A. J. Biol. Chem. (2002) [Pubmed]
  17. Transcriptional genomics associates FOX transcription factors with human heart failure. Hannenhalli, S., Putt, M.E., Gilmore, J.M., Wang, J., Parmacek, M.S., Epstein, J.A., Morrisey, E.E., Margulies, K.B., Cappola, T.P. Circulation (2006) [Pubmed]
  18. Optimal procedure for extracting RNA from human ocular tissues and expression profiling of the congenital glaucoma gene FOXC1 using quantitative RT-PCR. Wang, W.H., McNatt, L.G., Shepard, A.R., Jacobson, N., Nishimura, D.Y., Stone, E.M., Sheffield, V.C., Clark, A.F. Mol. Vis. (2001) [Pubmed]
  19. Screening for mutations in BMP4 and FOXC1 genes in congenital anomalies of the kidney and urinary tract in humans. Nakano, T., Niimura, F., Hohenfellner, K., Miyakita, E., Ichikawa, I. Tokai J. Exp. Clin. Med. (2003) [Pubmed]
  20. Regulation of FOXC1 stability and transcriptional activity by an epidermal growth factor-activated mitogen-activated protein kinase signaling cascade. Berry, F.B., Mirzayans, F., Walter, M.A. J. Biol. Chem. (2006) [Pubmed]
  21. Identification of target genes regulated by FOXC1 using nickel agarose-based chromatin enrichment. Tamimi, Y., Lines, M., Coca-Prados, M., Walter, M.A. Invest. Ophthalmol. Vis. Sci. (2004) [Pubmed]
  22. Missing endomysial and reticulin binding of coeliac antibodies in transglutaminase 2 knockout tissues. Korponay-Szabó, I.R., Laurila, K., Szondy, Z., Halttunen, T., Szalai, Z., Dahlbom, I., Rantala, I., Kovács, J.B., Fésüs, L., Mäki, M. Gut (2003) [Pubmed]
  23. Differential effect of ARA-AMP on serum DNA polymerase activity and serum HBV-DNA in chronic hepatitis B virus infection. A possible reason for lack of efficacy. Alexander, G.J., Fagan, E.A., Rolando, N., Guarner, P., Callender, M.E., Eddleston, A.L., Williams, R. J. Hepatol. (1986) [Pubmed]
  24. A novel syndrome of congenital lid and punctal anomalies, corneal and chorioretinal dystrophy. Lee, T.K., Hébert, M., MacDonald, I.M. Ophthalmic Genet. (2003) [Pubmed]
  25. Functional interactions between FOXC1 and PITX2 underlie the sensitivity to FOXC1 gene dose in Axenfeld-Rieger syndrome and anterior segment dysgenesis. Berry, F.B., Lines, M.A., Oas, J.M., Footz, T., Underhill, D.A., Gage, P.J., Walter, M.A. Hum. Mol. Genet. (2006) [Pubmed]
  26. FGF19 is a target for FOXC1 regulation in ciliary body-derived cells. Tamimi, Y., Skarie, J.M., Footz, T., Berry, F.B., Link, B.A., Walter, M.A. Hum. Mol. Genet. (2006) [Pubmed]
  27. Haploinsufficiency of the transcription factors FOXC1 and FOXC2 results in aberrant ocular development. Smith, R.S., Zabaleta, A., Kume, T., Savinova, O.V., Kidson, S.H., Martin, J.E., Nishimura, D.Y., Alward, W.L., Hogan, B.L., John, S.W. Hum. Mol. Genet. (2000) [Pubmed]
  28. Reduced human and murine corneal thickness in an axenfeld-rieger syndrome subtype. Asai-Coakwell, M., Backhouse, C., Casey, R.J., Gage, P.J., Lehmann, O.J. Invest. Ophthalmol. Vis. Sci. (2006) [Pubmed]
  29. Genetic basis of glaucoma. WuDunn, D. Current opinion in ophthalmology. (2002) [Pubmed]
  30. Subtelomeric deletions of chromosome 6p: molecular and cytogenetic characterization of three new cases with phenotypic overlap with Ritscher-Schinzel (3C) syndrome. Descipio, C., Schneider, L., Young, T.L., Wasserman, N., Yaeger, D., Lu, F., Wheeler, P.G., Williams, M.S., Bason, L., Jukofsky, L., Menon, A., Geschwindt, R., Chudley, A.E., Saraiva, J., Schinzel, A.A., Guichet, A., Dobyns, W.E., Toutain, A., Spinner, N.B., Krantz, I.D. Am. J. Med. Genet. A (2005) [Pubmed]
  31. Identification and analysis of a novel mutation in the FOXC1 forkhead domain. Saleem, R.A., Murphy, T.C., Liebmann, J.M., Walter, M.A. Invest. Ophthalmol. Vis. Sci. (2003) [Pubmed]
  32. Randomised controlled trial of adenine arabinoside 5'-monophosphate (ARA-AMP) in chronic hepatitis B virus infection. Weller, I.V., Lok, A.S., Mindel, A., Karayiannis, P., Galpin, S., Monjardino, J., Sherlock, S., Thomas, H.C. Gut (1985) [Pubmed]
 
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