FOXJ1

{{Short description|Protein-coding gene in the species Homo sapiens}}

Forkhead box protein J1 is a protein that in humans is encoded by the FOXJ1 gene.{{cite web | title = Entrez Gene: forkhead box J1| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2302}} It is a member of the Forkhead/winged helix (FOX) family of transcription factors that is involved in ciliogenesis.{{cite journal | vauthors = Yu X, Ng CP, Habacher H, Roy S | title = Foxj1 transcription factors are master regulators of the motile ciliogenic program | journal = Nature Genetics | volume = 40 | issue = 12 | pages = 1445–53 | date = December 2008 | pmid = 19011630 | doi = 10.1038/ng.263 | s2cid = 205347068 }} FOXJ1 is expressed in ciliated cells of the lung,{{cite journal | vauthors = Blatt EN, Yan XH, Wuerffel MK, Hamilos DL, Brody SL | title = Forkhead transcription factor HFH-4 expression is temporally related to ciliogenesis | journal = American Journal of Respiratory Cell and Molecular Biology | volume = 21 | issue = 2 | pages = 168–76 | date = August 1999 | pmid = 10423398 | doi = 10.1165/ajrcmb.21.2.3691 | citeseerx = 10.1.1.317.9961 }} choroid plexus,{{cite journal | vauthors = Lim L, Zhou H, Costa RH | title = The winged helix transcription factor HFH-4 is expressed during choroid plexus epithelial development in the mouse embryo | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 94 | issue = 7 | pages = 3094–9 | date = April 1997 | pmid = 9096351 | doi=10.1073/pnas.94.7.3094 | pmc=20327| bibcode = 1997PNAS...94.3094L | doi-access = free }} reproductive tract,{{cite journal | vauthors = Hackett BP, Brody SL, Liang M, Zeitz ID, Bruns LA, Gitlin JD | title = Primary structure of hepatocyte nuclear factor/forkhead homologue 4 and characterization of gene expression in the developing respiratory and reproductive epithelium | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 92 | issue = 10 | pages = 4249–53 | date = May 1995 | pmid = 7753791 | doi=10.1073/pnas.92.10.4249 | pmc=41921| bibcode = 1995PNAS...92.4249H | doi-access = free }} embryonic kidney and pre-somite embryo stage.{{cite journal | vauthors = Pelletier GJ, Brody SL, Liapis H, White RA, Hackett BP | title = A human forkhead/winged-helix transcription factor expressed in developing pulmonary and renal epithelium | journal = The American Journal of Physiology | volume = 274 | issue = 3 Pt 1 | pages = L351–9 | date = March 1998 | pmid = 9530170 | doi = 10.1152/ajplung.1998.274.3.L351 }}

Gene Location

The human FOXJ1 gene is located on the long arm of chromosome 17, region 2, band 5, sub-band 1.{{cite journal | vauthors = Jackson BC, Carpenter C, Nebert DW, Vasiliou V | title = Update of human and mouse forkhead box (FOX) gene families | journal = Human Genomics | volume = 4 | issue = 5 | pages = 345–52 | date = June 2010 | pmid = 20650821 | doi = 10.1186/1479-7364-4-5-345 | pmc=3500164 | doi-access = free }}

Structure

FOXJ1 has a conserved 100 amino acid long DNA binding domain.{{cite journal | vauthors = Clevidence DE, Overdier DG, Tao W, Qian X, Pani L, Lai E, Costa RH | title = Identification of nine tissue-specific transcription factors of the hepatocyte nuclear factor 3/forkhead DNA-binding-domain family | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 90 | issue = 9 | pages = 3948–52 | date = May 1993 | pmid = 7683413 | doi = 10.1073/pnas.90.9.3948 | pmc=46423| bibcode = 1993PNAS...90.3948C | doi-access = free }}

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.

= 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.{{cite journal | vauthors = Jain R, Pan J, Driscoll JA, Wisner JW, Huang T, Gunsten SP, You Y, Brody SL | title = Temporal relationship between primary and motile ciliogenesis in airway epithelial cells | journal = American Journal of Respiratory Cell and Molecular Biology | volume = 43 | issue = 6 | pages = 731–9 | date = December 2010 | pmid = 20118219 | doi = 10.1165/rcmb.2009-0328OC | pmc=2993092}} Cells commit towards ciliogenesis prior to FOXJ1 activation. Activation promotes basal body trafficking, docking at the apical membrane and subsequent axoneme growth.{{cite journal | vauthors = You Y, Huang T, Richer EJ, Schmidt JE, Zabner J, Borok Z, Brody SL | s2cid = 17661686 | title = Role of f-box factor foxj1 in differentiation of ciliated airway epithelial cells | journal = American Journal of Physiology. Lung Cellular and Molecular Physiology | volume = 286 | issue = 4 | pages = L650–7 | date = April 2004 | pmid = 12818891 | doi = 10.1152/ajplung.00170.2003 }} 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.{{cite journal | vauthors = Marshall CB, Mays DJ, Beeler JS, Rosenbluth JM, Boyd KL, Santos Guasch GL, Shaver TM, Tang LJ, Liu Q, Shyr Y, Venters BJ, Magnuson MA, Pietenpol JA | title = p73 Is Required for Multiciliogenesis and Regulates the Foxj1-Associated Gene Network | journal = Cell Reports | volume = 14 | issue = 10 | pages = 2289–300 | date = March 2016 | pmid = 26947080 | doi = 10.1016/j.celrep.2016.02.035 | pmc=4794398}}

= Immune system =

In mammalian cells, FOXJ1 has been shown to suppress NFκB, a key regulator in the immune response{{cite journal | vauthors = Lin L, Spoor MS, Gerth AJ, Brody SL, Peng SL | title = Modulation of Th1 activation and inflammation by the NF-kappaB repressor Foxj1 | journal = Science | volume = 303 | issue = 5660 | pages = 1017–20 | date = February 2004 | pmid = 14963332 | doi = 10.1126/science.1093889 | bibcode = 2004Sci...303.1017L | s2cid = 85412475 }} and also inhibits the humoral response in B-cells. This occurs via regulation of an inhibitory component of NFκB called IκBβ and IL-6.{{cite journal | vauthors = Lin L, Brody SL, Peng SL | title = Restraint of B cell activation by Foxj1-mediated antagonism of NF-kappa B and IL-6 | journal = Journal of Immunology | volume = 175 | issue = 2 | pages = 951–8 | date = July 2005 | pmid = 16002694 | doi = 10.4049/jimmunol.175.2.951 | doi-access = free }}

= 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.{{cite journal | vauthors = Venugopalan SR, Amen MA, Wang J, Wong L, Cavender AC, D'Souza RN, Akerlund M, Brody SL, Hjalt TA, Amendt BA | title = Novel expression and transcriptional regulation of FoxJ1 during oro-facial morphogenesis | journal = Human Molecular Genetics | volume = 17 | issue = 23 | pages = 3643–54 | date = December 2008 | pmid = 18723525 | doi = 10.1093/hmg/ddn258 | pmc=2733810}} 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.{{cite journal | vauthors = Gomperts BN, Gong-Cooper X, Hackett BP | title = Foxj1 regulates basal body anchoring to the cytoskeleton of ciliated pulmonary epithelial cells | journal = Journal of Cell Science | volume = 117 | issue = Pt 8 | pages = 1329–37 | date = March 2004 | pmid = 14996907 | doi = 10.1242/jcs.00978 | doi-access = free }} Expression of FOXJ1 is inhibited by IL-13.{{cite journal | vauthors = Gomperts BN, Kim LJ, Flaherty SA, Hackett BP | title = IL-13 regulates cilia loss and foxj1 expression in human airway epithelium | journal = American Journal of Respiratory Cell and Molecular Biology | volume = 37 | issue = 3 | pages = 339–46 | date = September 2007 | pmid = 17541011 | doi = 10.1165/rcmb.2006-0400OC | pmc=2720122}}

Clinical significance

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

Viral infections of the respiratory system have been found to lower the expression of FOXJ1. This affects ciliogenesis and impacts mucocillary action.{{cite journal | vauthors = Look DC, Walter MJ, Williamson MR, Pang L, You Y, Sreshta JN, Johnson JE, Zander DS, Brody SL | title = Effects of paramyxoviral infection on airway epithelial cell Foxj1 expression, ciliogenesis, and mucociliary function | journal = The American Journal of Pathology | volume = 159 | issue = 6 | pages = 2055–69 | date = December 2001 | pmid = 11733356 | doi = 10.1016/S0002-9440(10)63057-X | pmc=1850590}}

= 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.{{cite journal | vauthors = Demircan B, Dyer LM, Gerace M, Lobenhofer EK, Robertson KD, Brown KD | title = Comparative epigenomics of human and mouse mammary tumors | journal = Genes, Chromosomes & Cancer | volume = 48 | issue = 1 | pages = 83–97 | date = January 2009 | pmid = 18836996 | doi = 10.1002/gcc.20620 | pmc=2929596}}

= 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.{{cite journal | vauthors = Zhu P, Piao Y, Dong X, Jin Z | title = Forkhead box J1 expression is upregulated and correlated with prognosis in patients with clear cell renal cell carcinoma | journal = Oncology Letters | volume = 10 | issue = 3 | pages = 1487–1494 | date = September 2015 | pmid = 26622696 | doi = 10.3892/ol.2015.3376 | pmc=4533638}}

= 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.{{cite journal | vauthors = Venugopalan SR, Amen MA, Wang J, Wong L, Cavender AC, D'Souza RN, Akerlund M, Brody SL, Hjalt TA, Amendt BA | title = Novel expression and transcriptional regulation of FoxJ1 during oro-facial morphogenesis | journal = Human Molecular Genetics | volume = 17 | issue = 23 | pages = 3643–54 | date = December 2008 | pmid = 18723525 | doi = 10.1093/hmg/ddn258 | pmc=2733810}}

= Hydrocephalus =

Mutations in this gene have been associated with an autosomal dominant syndrome that includes hydrocephalus and randomization of left/right body asymmetry.{{cite journal | vauthors = Wallmeier J, Frank D, Shoemark A, Nöthe-Menchen T, Cindric S, Olbrich H, Loges NT, Aprea I, Dougherty GW, Pennekamp P, Kaiser T, Mitchison HM, Hogg C, Carr SB, Zariwala MA, Ferkol T, Leigh MW, Davis SD, Atkinson J, Dutcher SK, Knowles MR, Thiele H, Altmüller J, Krenz H, Wöste M, Brentrup A, Ahrens F, Vogelberg C, Morris-Rosendahl DJ, Omran H | title = De Novo Mutations in FOXJ1 Result in a Motile Ciliopathy with Hydrocephalus and Randomization of Left/Right Body Asymmetry | journal = American Journal of Human Genetics | volume = 105 | issue = 5 | pages = 1030–1039 | date = November 2019 | pmid = 31630787 | pmc = 6849114 | doi = 10.1016/j.ajhg.2019.09.022 }}