FOXJ1

FOXJ1
Identifiers
Aliases	FOXJ1, FKHL13, HFH-4, HFH4, forkhead box J1
External IDs	MGI: 1347474 HomoloGene: 1117 GeneCards: FOXJ1
Gene ontology Molecular function • transcription regulatory region sequence-specific DNA binding • RNA polymerase II core promoter proximal region sequence-specific DNA binding • transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding • sequence-specific DNA binding • RNA polymerase II transcription factor activity, sequence-specific DNA binding • DNA binding • transcription factor activity, sequence-specific DNA binding Cellular component • nucleus Biological process • determination of left/right symmetry • positive regulation of lung ciliated cell differentiation • cell projection organization • regulation of transcription, DNA-templated • metanephric part of ureteric bud development • pattern specification process • transcription, DNA-templated • glomerular parietal epithelial cell development • regulation of epithelial cell differentiation • transcription from RNA polymerase II promoter • negative regulation of T cell proliferation • left/right pattern formation • spermatogenesis • heart development • negative regulation of T cell differentiation in thymus • negative regulation of interleukin-6 biosynthetic process • cilium morphogenesis • establishment of apical/basal cell polarity • activation of GTPase activity • negative regulation of B cell activation • positive regulation of central B cell tolerance induction • negative regulation of transcription from RNA polymerase II promoter • epithelium development • negative regulation of humoral immune response mediated by circulating immunoglobulin • brain development • humoral immune response • negative regulation of germinal center formation • central tolerance induction • cilium assembly • negative regulation of NF-kappaB transcription factor activity • lung epithelium development • actin cytoskeleton organization • leukocyte migration • positive regulation of transcription from RNA polymerase II promoter Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	2302	15223
Ensembl	ENSG00000129654	ENSMUSG00000034227
UniProt	Q92949	Q61660
RefSeq (mRNA)	NM_001454	NM_008240
RefSeq (protein)	NP_001445.2	NP_032266.3
Location (UCSC)	Chr 17: 76.14 – 76.14 Mb	Chr 11: 116.33 – 116.34 Mb
PubMed search	[1]	[2]
Wikidata

View/Edit Human

View/Edit Mouse

Forkhead box protein J1 is a protein that in humans is encoded by the FOXJ1 gene.^[3] It is a member of the Forkhead/winged helix (FOX) family of transcription factors that is involved in ciliogenesis.^[4] FOXJ1 is expressed in ciliated cells of the lung,^[5] choroid plexus,^[6] reproductive track,^[7] embryonic kidney and pre-somite embryo stage.^[8]

Gene Location

The human FOXJ1 gene is located on the long arm of chromosome 17, region 2, band 5, sub-band 1.^[9]

Structure

FOXJ1 has a conserved 100 amino acid long DNA binding domain.^[10]

Function

This gene encodes a member of the forkhead family of transcription factors. Similar genes in zebra fish 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.^[3]

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 cilliated cells.^[11] Cells commit towards ciliogenesis prior to FOXJ1 activation. Activation promotes basal body trafficking, docking at the apical membrane and subsequent axoneme growth.^[12] The protein p73 a member of the p53 protein family directly regulates FOXJ1 and is a requirement for ciliated cell formation. The ten thousand base pair long transcription start site of FOXJ1 features three sequence specific binding sites for p73.^[13]

Immune system

In mammalian cells FOXJ1 has been shown to suppress NFκB a key regulator in the immune response^[14] and also inhibits the humoral response in B-Cells. This occurs via regulation of an inhibitory component of NFκB called IκBβ and IL-6.^[15]

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.^[16] 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.^[17] Expression of FOXJ1 is inhibited by IL-13.^[18]

Clinical significance

Polymorphisms in this gene are associated with systemic lupus erythematosus and allergic rhinitis.^[3]

Viral infections of the respiratory system have been found to lower the expression of FOXJ1. This affects ciliogenesis and impacts mucocillary action.^[19]

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.^[20]

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.^[21]

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.^[22]

References

1. "Human PubMed Reference:".
2. "Mouse PubMed Reference:".
3. "Entrez Gene: forkhead box J1".
4. Yu X, Ng CP, Habacher H, Roy S (December 2008). "Foxj1 transcription factors are master regulators of the motile ciliogenic program". Nature Genetics. 40 (12): 1445–53. doi:10.1038/ng.263. PMID 19011630.
5. Blatt EN, Yan XH, Wuerffel MK, Hamilos DL, Brody SL (August 1999). "Forkhead transcription factor HFH-4 expression is temporally related to ciliogenesis". American Journal of Respiratory Cell and Molecular Biology. 21 (2): 168–76. doi:10.1165/ajrcmb.21.2.3691. PMID 10423398.
6. Lim L, Zhou H, Costa RH (April 1997). "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. PMID 9096351.
7. Hackett BP, Brody SL, Liang M, Zeitz ID, Bruns LA, Gitlin JD (May 1995). "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. PMID 7753791.
8. Pelletier GJ, Brody SL, Liapis H, White RA, Hackett BP (March 1998). "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. PMID 9530170.
9. Jackson BC, Carpenter C, Nebert DW, Vasiliou V (June 2010). "Update of human and mouse forkhead box (FOX) gene families". Human Genomics. 4 (5): 345–52. doi:10.1186/1479-7364-4-5-345. PMID 20650821.
10. Clevidence DE, Overdier DG, Tao W, Qian X, Pani L, Lai E, Costa RH (May 1993). "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. doi:10.1073/pnas.90.9.3948. PMID 7683413.
11. Jain R, Pan J, Driscoll JA, Wisner JW, Huang T, Gunsten SP, You Y, Brody SL (December 2010). "Temporal relationship between primary and motile ciliogenesis in airway epithelial cells". American Journal of Respiratory Cell and Molecular Biology. 43 (6): 731–9. doi:10.1165/rcmb.2009-0328OC. PMID 20118219.
12. You Y, Huang T, Richer EJ, Schmidt JE, Zabner J, Borok Z, Brody SL (April 2004). "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. doi:10.1152/ajplung.00170.2003. PMID 12818891.
13. 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 (March 2016). "p73 Is Required for Multiciliogenesis and Regulates the Foxj1-Associated Gene Network". Cell Reports. 14 (10): 2289–300. doi:10.1016/j.celrep.2016.02.035. PMID 26947080.
14. Lin L, Spoor MS, Gerth AJ, Brody SL, Peng SL (February 2004). "Modulation of Th1 activation and inflammation by the NF-kappaB repressor Foxj1". Science. 303 (5660): 1017–20. doi:10.1126/science.1093889. PMID 14963332.
15. Lin L, Brody SL, Peng SL (July 2005). "Restraint of B cell activation by Foxj1-mediated antagonism of NF-kappa B and IL-6". Journal of Immunology. 175 (2): 951–8. doi:10.4049/jimmunol.175.2.951. PMID 16002694.
16. Venugopalan SR, Amen MA, Wang J, Wong L, Cavender AC, D'Souza RN, Akerlund M, Brody SL, Hjalt TA, Amendt BA (December 2008). "Novel expression and transcriptional regulation of FoxJ1 during oro-facial morphogenesis". Human Molecular Genetics. 17 (23): 3643–54. doi:10.1093/hmg/ddn258. PMID 18723525.
17. Gomperts BN, Gong-Cooper X, Hackett BP (March 2004). "Foxj1 regulates basal body anchoring to the cytoskeleton of ciliated pulmonary epithelial cells". Journal of Cell Science. 117 (Pt 8): 1329–37. doi:10.1242/jcs.00978. PMID 14996907.
18. Gomperts BN, Kim LJ, Flaherty SA, Hackett BP (September 2007). "IL-13 regulates cilia loss and foxj1 expression in human airway epithelium". American Journal of Respiratory Cell and Molecular Biology. 37 (3): 339–46. doi:10.1165/rcmb.2006-0400OC. PMID 17541011.
19. Look DC, Walter MJ, Williamson MR, Pang L, You Y, Sreshta JN, Johnson JE, Zander DS, Brody SL (December 2001). "Effects of paramyxoviral infection on airway epithelial cell Foxj1 expression, ciliogenesis, and mucociliary function". The American Journal of Pathology. 159 (6): 2055–69. doi:10.1016/S0002-9440(10)63057-X. PMID 11733356.
20. Demircan B, Dyer LM, Gerace M, Lobenhofer EK, Robertson KD, Brown KD (January 2009). "Comparative epigenomics of human and mouse mammary tumors". Genes, Chromosomes & Cancer. 48 (1): 83–97. doi:10.1002/gcc.20620. PMID 18836996.
21. Zhu P, Piao Y, Dong X, Jin Z (September 2015). "Forkhead box J1 expression is upregulated and correlated with prognosis in patients with clear cell renal cell carcinoma". Oncology Letters. 10 (3): 1487–1494. doi:10.3892/ol.2015.3376. PMID 26622696.
22. Venugopalan SR, Amen MA, Wang J, Wong L, Cavender AC, D'Souza RN, Akerlund M, Brody SL, Hjalt TA, Amendt BA (December 2008). "Novel expression and transcriptional regulation of FoxJ1 during oro-facial morphogenesis". Human Molecular Genetics. 17 (23): 3643–54. doi:10.1093/hmg/ddn258. PMID 18723525.

Further reading

• Li CS, Zhang Q, Lim MK, Sheen DH, Shim SC, Kim JY, Lee SS, Yun KJ, Moon HB, Chung HT, Chae SC (December 2007). "Association of FOXJ1 polymorphisms with systemic lupus erythematosus and rheumatoid arthritis in Korean population". Experimental & Molecular Medicine. 39 (6): 805–11. doi:10.1038/emm.2007.87. PMID 18160851.
• Li CS, Chae SC, Lee JH, Zhang Q, Chung HT (2006). "Identification of single nucleotide polymorphisms in FOXJ1 and their association with allergic rhinitis". Journal of Human Genetics. 51 (4): 292–7. doi:10.1007/s10038-006-0359-8. PMID 16518568.
• Turner J, Roger J, Fitau J, Combe D, Giddings J, Heeke GV, Jones CE (March 2011). "Goblet cells are derived from a FOXJ1-expressing progenitor in a human airway epithelium". American Journal of Respiratory Cell and Molecular Biology. 44 (3): 276–84. doi:10.1165/rcmb.2009-0304OC. PMID 20539013.
• Murphy DB, Seemann S, Wiese S, Kirschner R, Grzeschik KH, Thies U (March 1997). "The human hepatocyte nuclear factor 3/fork head gene FKHL13: genomic structure and pattern of expression". Genomics. 40 (3): 462–9. doi:10.1006/geno.1996.4587. PMID 9073514.
• Maiti AK, Bartoloni L, Mitchison HM, Meeks M, Chung E, Spiden S, Gehrig C, Rossier C, DeLozier-Blanchet CD, Blouin J, Gardiner RM, Antonarakis SE (2000). "No deleterious mutations in the FOXJ1 (alias HFH-4) gene in patients with primary ciliary dyskinesia (PCD)". Cytogenetics and Cell Genetics. 90 (1-2): 119–22. doi:10.1159/000015645. PMID 11060460.
• LeSimple P, van Seuningen I, Buisine MP, Copin MC, Hinz M, Hoffmann W, Hajj R, Brody SL, Coraux C, Puchelle E (March 2007). "Trefoil factor family 3 peptide promotes human airway epithelial ciliated cell differentiation". American Journal of Respiratory Cell and Molecular Biology. 36 (3): 296–303. doi:10.1165/rcmb.2006-0270OC. PMID 17008636.
• Lim L, Zhou H, Costa RH (April 1997). "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. doi:10.1073/pnas.94.7.3094. PMC 20327. PMID 9096351.
• Pelletier GJ, Brody SL, Liapis H, White RA, Hackett BP (March 1998). "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. PMID 9530170.
• Wu C, Ma MH, Brown KR, Geisler M, Li L, Tzeng E, Jia CY, Jurisica I, Li SS (June 2007). "Systematic identification of SH3 domain-mediated human protein-protein interactions by peptide array target screening". Proteomics. 7 (11): 1775–85. doi:10.1002/pmic.200601006. PMID 17474147.

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