Biology:FOXJ1

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Forkhead box protein J1 is a protein that in humans is encoded by the FOXJ1 gene.[1] It is a member of the Forkhead/winged helix (FOX) family of transcription factors that is involved in ciliogenesis.[2] FOXJ1 is expressed in ciliated cells of the lung,[3] choroid plexus,[4] reproductive tract,[5] embryonic kidney and pre-somite embryo stage.[6]

Gene Location

The human FOXJ1 gene is located on the long arm of chromosome 17, region 2, band 5, sub-band 1.[7]

Structure

FOXJ1 has a conserved 100 amino acid long DNA binding domain.[8]

Function

This gene encodes a member of the forkhead family of transcription factors. Similar genes in zebrafish and mouse have been shown to regulate the transcription of genes that control the production of motile cilia. The mouse ortholog also functions in the determination of left-right asymmetry.[1]

Ciliogenesis

Primary ciliogenesis is FOXJ1 dependent and this transcription factor is required for motile ciliated cell differentiation. The onset of FOXJ1 expression is indicative of cells fated to become motile ciliated cells.[9] Cells commit towards ciliogenesis prior to FOXJ1 activation. Activation promotes basal body trafficking, docking at the apical membrane and subsequent axoneme growth.[10] The protein p73 a member of the p53 protein family directly regulates FOXJ1 and is a requirement for ciliated cell formation. The 10,000bp long transcription start site of FOXJ1 features three sequence specific binding sites for p73.[11]

Immune system

In mammalian cells, FOXJ1 has been shown to suppress NFκB, a key regulator in the immune response[12] and also inhibits the humoral response in B-cells. This occurs via regulation of an inhibitory component of NFκB called IκBβ and IL-6.[13]

Development

FOXJ1 is expressed at various points during embryonic development in relation to teeth germination, enamel, oral and tongue epithelium formation, and formation of sub-mandibular salivary glands and hair follicles.[14] Absence of FOXJ1 expression decreases calpastatin, an inhibitor of the protease calpain. Calpain dysregulation affects basal body anchoring to the apical cytoskeleton affecting axeonemal formation.[15] Expression of FOXJ1 is inhibited by IL-13.[16]

Clinical significance

Polymorphisms in this gene are associated with systemic lupus erythematosus and allergic rhinitis.[1]

Viral infections of the respiratory system have been found to lower the expression of FOXJ1. This affects ciliogenesis and impacts mucocillary action.[17]

Breast cancer

Studies into human breast tissue lines and primary breast tumors have observed that the gene FOXJ1 are aberrantly hypermethylated in primary tumors. This hypermethylation serves to silence production of the FOXJ1 protein and has been proposed as a potentially important event in tumor formation.[18]

Clear renal cell carcinoma

FOXJ1 expression has been shown to be elevated in clear cell renal carcinoma patients and indicative of tumor stage, histological grade and tumor size. High expression of FOXJ1 in CRCC patients was associated with poor prognosis. There is potential for FOXJ1 to act as an oncogene marker for CRCC patients and has value as a therapeutic target.[19]

Axenfeld–Rieger syndrome

Axenfeld–Rieger syndrome patients have a point mutation in PITX2 a regulatory protein of the FOXJ1 gene. PITX2 alongside LEF-1 and β-Catenin regulate FOXJ1. FOXJ1 in turn interacts with PITX2 to form a positive feedback mechanism. In the PITX2 point mutant whilst able to bind with FOXJ1 lacks the ability to activate the FOXJ1 promoter, this results in improper oro-facial morphogenesis a factor in ARS.[20]

Hydrocephalus

Mutations in this gene have been associated with an autosomal dominant syndrome that includes hydrocephalus and randomization of left/right body asymmetry.[21]

References

  1. ↑ 1.0 1.1 1.2 "Entrez Gene: forkhead box J1". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2302. 
  2. ↑ "Foxj1 transcription factors are master regulators of the motile ciliogenic program". Nature Genetics 40 (12): 1445–53. December 2008. doi:10.1038/ng.263. PMID 19011630. 
  3. ↑ "Forkhead transcription factor HFH-4 expression is temporally related to ciliogenesis". American Journal of Respiratory Cell and Molecular Biology 21 (2): 168–76. August 1999. doi:10.1165/ajrcmb.21.2.3691. PMID 10423398. 
  4. ↑ "The winged helix transcription factor HFH-4 is expressed during choroid plexus epithelial development in the mouse embryo". Proceedings of the National Academy of Sciences of the United States of America 94 (7): 3094–9. April 1997. doi:10.1073/pnas.94.7.3094. PMID 9096351. Bibcode: 1997PNAS...94.3094L. 
  5. ↑ "Primary structure of hepatocyte nuclear factor/forkhead homologue 4 and characterization of gene expression in the developing respiratory and reproductive epithelium". Proceedings of the National Academy of Sciences of the United States of America 92 (10): 4249–53. May 1995. doi:10.1073/pnas.92.10.4249. PMID 7753791. Bibcode: 1995PNAS...92.4249H. 
  6. ↑ "A human forkhead/winged-helix transcription factor expressed in developing pulmonary and renal epithelium". The American Journal of Physiology 274 (3 Pt 1): L351–9. March 1998. doi:10.1152/ajplung.1998.274.3.L351. PMID 9530170. 
  7. ↑ "Update of human and mouse forkhead box (FOX) gene families". Human Genomics 4 (5): 345–52. June 2010. doi:10.1186/1479-7364-4-5-345. PMID 20650821. 
  8. ↑ "Identification of nine tissue-specific transcription factors of the hepatocyte nuclear factor 3/forkhead DNA-binding-domain family". Proceedings of the National Academy of Sciences of the United States of America 90 (9): 3948–52. May 1993. doi:10.1073/pnas.90.9.3948. PMID 7683413. Bibcode: 1993PNAS...90.3948C. 
  9. ↑ "Temporal relationship between primary and motile ciliogenesis in airway epithelial cells". American Journal of Respiratory Cell and Molecular Biology 43 (6): 731–9. December 2010. doi:10.1165/rcmb.2009-0328OC. PMID 20118219. 
  10. ↑ "Role of f-box factor foxj1 in differentiation of ciliated airway epithelial cells". American Journal of Physiology. Lung Cellular and Molecular Physiology 286 (4): L650–7. April 2004. doi:10.1152/ajplung.00170.2003. PMID 12818891. 
  11. ↑ "p73 Is Required for Multiciliogenesis and Regulates the Foxj1-Associated Gene Network". Cell Reports 14 (10): 2289–300. March 2016. doi:10.1016/j.celrep.2016.02.035. PMID 26947080. 
  12. ↑ "Modulation of Th1 activation and inflammation by the NF-kappaB repressor Foxj1". Science 303 (5660): 1017–20. February 2004. doi:10.1126/science.1093889. PMID 14963332. Bibcode: 2004Sci...303.1017L. 
  13. ↑ "Restraint of B cell activation by Foxj1-mediated antagonism of NF-kappa B and IL-6". Journal of Immunology 175 (2): 951–8. July 2005. doi:10.4049/jimmunol.175.2.951. PMID 16002694. 
  14. ↑ "Novel expression and transcriptional regulation of FoxJ1 during oro-facial morphogenesis". Human Molecular Genetics 17 (23): 3643–54. December 2008. doi:10.1093/hmg/ddn258. PMID 18723525. 
  15. ↑ "Foxj1 regulates basal body anchoring to the cytoskeleton of ciliated pulmonary epithelial cells". Journal of Cell Science 117 (Pt 8): 1329–37. March 2004. doi:10.1242/jcs.00978. PMID 14996907. 
  16. ↑ "IL-13 regulates cilia loss and foxj1 expression in human airway epithelium". American Journal of Respiratory Cell and Molecular Biology 37 (3): 339–46. September 2007. doi:10.1165/rcmb.2006-0400OC. PMID 17541011. 
  17. ↑ "Effects of paramyxoviral infection on airway epithelial cell Foxj1 expression, ciliogenesis, and mucociliary function". The American Journal of Pathology 159 (6): 2055–69. December 2001. doi:10.1016/S0002-9440(10)63057-X. PMID 11733356. 
  18. ↑ "Comparative epigenomics of human and mouse mammary tumors". Genes, Chromosomes & Cancer 48 (1): 83–97. January 2009. doi:10.1002/gcc.20620. PMID 18836996. 
  19. ↑ "Forkhead box J1 expression is upregulated and correlated with prognosis in patients with clear cell renal cell carcinoma". Oncology Letters 10 (3): 1487–1494. September 2015. doi:10.3892/ol.2015.3376. PMID 26622696. 
  20. ↑ "Novel expression and transcriptional regulation of FoxJ1 during oro-facial morphogenesis". Human Molecular Genetics 17 (23): 3643–54. December 2008. doi:10.1093/hmg/ddn258. PMID 18723525. 
  21. ↑ Wallmeier, Julia; Frank, Diana; Shoemark, Amelia; Nöthe-Menchen, Tabea; Cindric, Sandra; Olbrich, Heike; Loges, Niki T.; Aprea, Isabella et al. (November 2019). "De Novo Mutations in FOXJ1 Result in a Motile Ciliopathy with Hydrocephalus and Randomization of Left/Right Body Asymmetry". The American Journal of Human Genetics 105 (5): 1030–1039. doi:10.1016/j.ajhg.2019.09.022. ISSN 0002-9297. PMID 31630787. 

Further reading

This article incorporates text from the United States National Library of Medicine, which is in the public domain.



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