FOXJ1

Last updated

FOXJ1
Identifiers
Aliases FOXJ1 , FKHL13, HFH-4, HFH4, forkhead box J1, CILD43
External IDs OMIM: 602291; MGI: 1347474; HomoloGene: 1117; GeneCards: FOXJ1; OMA:FOXJ1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001454

NM_008240

RefSeq (protein)

NP_001445

NP_032266

Location (UCSC) Chr 17: 76.14 – 76.14 Mb Chr 11: 116.22 – 116.23 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Forkhead box protein J1 is a protein that in humans is encoded by the FOXJ1 gene. [5] It is a member of the Forkhead/winged helix (FOX) family of transcription factors that is involved in ciliogenesis. [6] FOXJ1 is expressed in ciliated cells of the lung, [7] choroid plexus, [8] reproductive tract, [9] embryonic kidney and pre-somite embryo stage. [10]

Contents

Gene Location

The human FOXJ1 gene is located on the long arm of chromosome 17, region 2, band 5, sub-band 1. [11]

Structure

FOXJ1 has a conserved 100 amino acid long DNA binding domain. [12]

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. [5]

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. [13] Cells commit towards ciliogenesis prior to FOXJ1 activation. Activation promotes basal body trafficking, docking at the apical membrane and subsequent axoneme growth. [14] 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. [15]

Immune system

In mammalian cells, FOXJ1 has been shown to suppress NFκB, a key regulator in the immune response [16] and also inhibits the humoral response in B-cells. This occurs via regulation of an inhibitory component of NFκB called IκBβ and IL-6. [17]

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. [18] 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. [19] Expression of FOXJ1 is inhibited by IL-13. [20]

Clinical significance

Polymorphisms in this gene are associated with systemic lupus erythematosus and allergic rhinitis. [5]

Viral infections of the respiratory system have been found to lower the expression of FOXJ1. This affects ciliogenesis and impacts mucocillary action. [21]

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. [22]

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. [23]

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. [24]

Hydrocephalus

Mutations in this gene have been associated with an autosomal dominant syndrome that includes hydrocephalus and randomization of left/right body asymmetry. [25]

Related Research Articles

FOXproteins are a family of transcription factors that play important roles in regulating the expression of genes involved in cell growth, proliferation, differentiation, and longevity. Many FOX proteins are important to embryonic development. FOX proteins also have pioneering transcription activity by being able to bind condensed chromatin during cell differentiation processes.

<span class="mw-page-title-main">FOXC2</span> Protein-coding gene in the species Homo sapiens

Forkhead box protein C2 (FOXC2) also known as forkhead-related protein FKHL14 (FKHL14), transcription factor FKH-14, or mesenchyme fork head protein 1 (MFH1) is a protein that in humans is encoded by the FOXC2 gene. FOXC2 is a member of the fork head box (FOX) family of transcription factors.

<span class="mw-page-title-main">FOXP1</span> Protein-coding gene in the species Homo sapiens

Forkhead box protein P1 is a protein that in humans is encoded by the FOXP1 gene. FOXP1 is necessary for the proper development of the brain, heart, and lung in mammals. It is a member of the large FOX family of transcription factors.

<span class="mw-page-title-main">FOXO3</span> Protein-coding gene in humans

Forkhead box O3, also known as FOXO3 or FOXO3a, is a human protein encoded by the FOXO3 gene.

<span class="mw-page-title-main">RUNX3</span> Protein-coding gene in humans

Runt-related transcription factor 3 is a protein that in humans is encoded by the RUNX3 gene.

<span class="mw-page-title-main">NK2 homeobox 1</span> Mammalian protein found in Homo sapiens

NK2 homeobox 1 (NKX2-1), also known as thyroid transcription factor 1 (TTF-1), is a protein which in humans is encoded by the NKX2-1 gene.

<span class="mw-page-title-main">PITX2</span> Protein-coding gene in the species Homo sapiens

Paired-like homeodomain transcription factor 2 also known as pituitary homeobox 2 is a protein that in humans is encoded by the PITX2 gene.

<span class="mw-page-title-main">Forkhead box C1</span> Protein-coding gene in the species Homo sapiens

Forkhead box C1, also known as FOXC1, is a protein which in humans is encoded by the FOXC1 gene.

<span class="mw-page-title-main">FOXL2</span> Transcription factor gene of the FOX family

Forkhead box protein L2 is a protein that in humans is encoded by the FOXL2 gene.

<span class="mw-page-title-main">FOXE1</span> Mammalian protein found in Homo sapiens

Forkhead box protein E1 is a protein that in humans is encoded by the FOXE1 gene.

<span class="mw-page-title-main">Thymic stromal lymphopoietin</span> Cytokine, alarmin, and growth factor.

Thymic stromal lymphopoietin (TSLP) is an interleukin (IL)-2-like cytokine, alarmin, and growth factor involved in numerous physiological and pathological processes, primarily those of the immune system. It shares a common ancestor with IL-7.

<span class="mw-page-title-main">ELF5</span> Protein-coding gene

E74-like factor 5 , is a gene found in both mice and humans. In humans it is also called ESE2.

<i>EHF</i> (gene) Protein-coding gene in the species Homo sapiens

ETS homologous factor is a protein that in humans is encoded by the EHF gene. This gene encodes a protein that belongs to an ETS transcription factor subfamily characterized by epithelial-specific expression (ESEs). The encoded protein acts as a transcriptional repressor and may be associated with asthma susceptibility. This protein may be involved in epithelial differentiation and carcinogenesis.

<span class="mw-page-title-main">FOXF1</span> Protein-coding gene in the species Homo sapiens

Forkhead box protein F1 (FOXF1) is a protein that in humans is encoded by the FOXF1 gene.

<span class="mw-page-title-main">FOXN1</span> Protein-coding gene in the species Homo sapiens

Forkhead box protein N1 is a protein that in humans is encoded by the FOXN1 gene.

<span class="mw-page-title-main">FOXA1</span> Protein-coding gene in the species Homo sapiens

Forkhead box protein A1 (FOXA1), also known as hepatocyte nuclear factor 3-alpha (HNF-3A), is a protein that in humans is encoded by the FOXA1 gene.

<span class="mw-page-title-main">FOXA2</span> Mammalian protein found in Homo sapiens

Forkhead box protein A2 (FOXA2), also known as hepatocyte nuclear factor 3-beta (HNF-3B), is a transcription factor that plays an important role during development, in mature tissues and, when dysregulated or mutated, also in cancer.

<span class="mw-page-title-main">FOXE3</span> Protein-coding gene in the species Homo sapiens

Forkhead box protein E3 (FOXE3) also known as forkhead-related transcription factor 8 (FREAC-8) is a protein that in humans is encoded by the FOXE3 gene located on the short arm of chromosome 1.

<span class="mw-page-title-main">Cadherin related family member 3</span> Protein found in humans

Cadherin related family member 3 (CDHR3), also known as CDH28 or its abbreviation CDHR3, is a protein that in humans is encoded by the CDHR3 gene. The protein is predominately expressed in respiratory epithelium and the first notion of its clinical implications was from the discovery that genetic variation of CDHR3 is strongly associated to early severe asthma exacerbations in children. Subsequent studies have suggested that CDHR3 is a receptor for a subtype of rhinovirus.

<span class="mw-page-title-main">Grainyhead-like gene family</span> Family of highly conserved genes for transcription factors in animals

Grainyhead-like genes are a family of highly conserved transcription factors that are functionally and structurally homologous across a large number of vertebrate and invertebrate species. For an estimated 100 million years or more, this genetic family has been evolving alongside life to fine tune the regulation of epithelial barrier integrity during development, fine-tuning epithelial barrier establishment, maintenance and subsequent homeostasis. The three main orthologues, Grainyhead-like 1, 2 and 3, regulate numerous genetic pathways within different organisms and perform analogous roles between them, ranging from neural tube closure, wound healing, establishment of the craniofacial skeleton and repair of the epithelium. When Grainyhead-like genes are impaired, due to genetic mutations in embryogenesis, it will cause the organism to present with developmental defects that largely affect ectodermal tissues in which they are expressed. These subsequent congenital disorders, including cleft lip and exencephaly, vary greatly in their severity and impact on the quality of life for the affected individual. There is much still to learn about the function of these genes and the more complex roles of Grainyhead-like genes are yet to be discovered.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000129654 Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000034227 Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 3 "Entrez Gene: forkhead box J1".
  6. 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. S2CID   205347068.
  7. 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. CiteSeerX   10.1.1.317.9961 . doi:10.1165/ajrcmb.21.2.3691. PMID   10423398.
  8. 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. Bibcode:1997PNAS...94.3094L. doi: 10.1073/pnas.94.7.3094 . PMC   20327 . PMID   9096351.
  9. 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. Bibcode:1995PNAS...92.4249H. doi: 10.1073/pnas.92.10.4249 . PMC   41921 . PMID   7753791.
  10. 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. doi:10.1152/ajplung.1998.274.3.L351. PMID   9530170.
  11. 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 . PMC   3500164 . PMID   20650821.
  12. Clevidence DE, Overdier DG, Tao W, Qian X, Pani L, Lai E, et al. (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. Bibcode:1993PNAS...90.3948C. doi: 10.1073/pnas.90.9.3948 . PMC   46423 . PMID   7683413.
  13. Jain R, Pan J, Driscoll JA, Wisner JW, Huang T, Gunsten SP, et al. (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. PMC   2993092 . PMID   20118219.
  14. You Y, Huang T, Richer EJ, Schmidt JE, Zabner J, Borok Z, et al. (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. S2CID   17661686.
  15. Marshall CB, Mays DJ, Beeler JS, Rosenbluth JM, Boyd KL, Santos Guasch GL, et al. (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. PMC   4794398 . PMID   26947080.
  16. 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. Bibcode:2004Sci...303.1017L. doi:10.1126/science.1093889. PMID   14963332. S2CID   85412475.
  17. 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.
  18. Venugopalan SR, Amen MA, Wang J, Wong L, Cavender AC, D'Souza RN, et al. (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. PMC   2733810 . PMID   18723525.
  19. 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.
  20. 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. PMC   2720122 . PMID   17541011.
  21. Look DC, Walter MJ, Williamson MR, Pang L, You Y, Sreshta JN, et al. (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. PMC   1850590 . PMID   11733356.
  22. 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. PMC   2929596 . PMID   18836996.
  23. 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. PMC   4533638 . PMID   26622696.
  24. Venugopalan SR, Amen MA, Wang J, Wong L, Cavender AC, D'Souza RN, et al. (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. PMC   2733810 . PMID   18723525.
  25. Wallmeier J, Frank D, Shoemark A, Nöthe-Menchen T, Cindric S, Olbrich H, et al. (November 2019). "De Novo Mutations in FOXJ1 Result in a Motile Ciliopathy with Hydrocephalus and Randomization of Left/Right Body Asymmetry". American Journal of Human Genetics. 105 (5): 1030–1039. doi:10.1016/j.ajhg.2019.09.022. PMC   6849114 . PMID   31630787.

Further reading

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