Homeobox protein Nkx-2.5

Homeobox protein Nkx-2.5 is a protein that in humans is encoded by the NKX2.5 gene.[5][6][7]

NKX2-5
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3RKQ, 4S0H
Identifiers
Aliases	NKX2-5, CHNG5, CSX, CSX1, HLHS2, NKX2.5, NKX2E, NKX4-1, VSD3, NK2 homeobox 5
External IDs	OMIM: 600584 MGI: 97350 HomoloGene: 3230 GeneCards: NKX2-5
Gene location (Human) Chr. Chromosome 5 (human)[1] Band 5q35.1 Start 173,232,109 bp[1] End 173,235,311 bp[1]
Gene location (Mouse) Chr. Chromosome 17 (mouse)[2] Band 17 A3.3|17 13.6 cM Start 26,838,664 bp[2] End 26,845,009 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • GO:0001131, GO:0001151, GO:0001130, GO:0001204 DNA-binding transcription factor activity • GO:0001077, GO:0001212, GO:0001213, GO:0001211, GO:0001205 DNA-binding transcription activator activity, RNA polymerase II-specific • transcription factor binding • protein homodimerization activity • serum response element binding • chromatin binding • GO:0001948 protein binding • DNA binding • sequence-specific DNA binding • GO:0001104 transcription cofactor activity • protein heterodimerization activity • transcription factor activity, RNA polymerase II distal enhancer sequence-specific binding • GO:0000980 RNA polymerase II cis-regulatory region sequence-specific DNA binding • GO:0001200, GO:0001133, GO:0001201 DNA-binding transcription factor activity, RNA polymerase II-specific Cellular component • cytoplasm • cell nucleus • transcription factor complex • RNA polymerase II transcription factor complex • macromolecular complex • protein-DNA complex Biological process • cardiac conduction system development • apoptotic process involved in heart morphogenesis • bundle of His development • regulation of transcription from RNA polymerase II promoter • atrioventricular node cell development • outflow tract morphogenesis • embryonic heart tube development • vasculogenesis • heart looping • atrial septum morphogenesis • positive regulation of heart contraction • proepicardium development • pulmonary myocardium development • heart contraction • ventricular cardiac muscle cell development • negative regulation of canonical Wnt signaling pathway • pharyngeal system development • atrioventricular node development • cardiac ventricle formation • regulation of transcription, DNA-templated • cardiac muscle contraction • regulation of cardiac muscle cell proliferation • heart trabecula formation • ventricular septum morphogenesis • cardiac muscle cell differentiation • Purkinje myocyte differentiation • spleen development • positive regulation of transcription, DNA-templated • heart development • positive regulation of neuron differentiation • positive regulation of cardioblast differentiation • septum secundum development • atrial cardiac muscle cell development • cardiovascular system development • cell differentiation • adult heart development • right ventricular cardiac muscle tissue morphogenesis • negative regulation of apoptotic process • negative regulation of transcription from RNA polymerase II promoter • positive regulation of transcription initiation from RNA polymerase II promoter • cardiac muscle cell proliferation • BMP signaling pathway • ventricular trabecula myocardium morphogenesis • outflow tract septum morphogenesis • negative regulation of cardiac muscle cell apoptotic process • thyroid gland development • canonical Wnt signaling pathway • negative regulation of transcription, DNA-templated • sarcomere organization • cardiac ventricle morphogenesis • regulation of cardiac conduction • positive regulation of transcription via serum response element binding • cardiac muscle tissue development • embryonic heart tube left/right pattern formation • heart morphogenesis • cardiac muscle tissue morphogenesis • multicellular organism development • positive regulation of gene expression • positive regulation of cell proliferation • positive regulation of sodium ion transport • negative regulation of myotube differentiation • regulation of cardiac muscle contraction • ventricular cardiac myofibril assembly • atrioventricular node cell fate commitment • positive regulation of transcription from RNA polymerase II promoter • transcription from RNA polymerase II promoter • haematopoiesis Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	1482	18091
Ensembl	ENSG00000183072	ENSMUSG00000015579
UniProt	P52952	P42582
RefSeq (mRNA)	NM_004387 NM_001166175 NM_001166176	NM_008700
RefSeq (protein)	NP_001159647 NP_001159648 NP_004378	NP_032726
Location (UCSC)	Chr 5: 173.23 – 173.24 Mb	Chr 17: 26.84 – 26.85 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Function

Homeobox-containing genes play critical roles in regulating tissue-specific gene expression essential for tissue differentiation, as well as determining the temporal and spatial patterns of development (Shiojima et al., 1995). It has been demonstrated that a Drosophila homeobox-containing gene called 'tinman' is expressed in the developing dorsal vessel and in the equivalent of the vertebrate heart. Mutations in tinman result in loss of heart formation in the embryo, suggesting that tinman is essential for Drosophila heart formation. Furthermore, abundant expression of Csx, the presumptive mouse homolog of tinman, is observed only in the heart from the time of cardiac differentiation. CSX, the human homolog of murine Csx, has a homeodomain sequence identical to that of Csx and is expressed only in the heart, again suggesting that CSX plays an important role in human heart formation.[7] In humans, proper NKX2-5 expression is essential for the development of atrial, ventricular, and conotruncal septation, atrioventricular (AV) valve formation, and maintenance of AV conduction. Mutations in expression are associated with congenital heart disease (CHD) and related ailments. Patients with NKX2-5 mutations commonly present AV conduction block and atrial septal defects (ASD). Recently, postnatal roles of cardiac transcription factors have been extensively investigated. Consistent with the direct transactivation of numerous cardiac genes reactivated in response to hypertrophic stimulation, cardiac transcription factors are profoundly involved in the generation of cardiac hypertrophy or in cardioprotection from cytotoxic stress in the adult heart. Nkx-2.5 transcription factor may help myocytes endure cytotoxic stress, however further exploration in this field is required.[8]

NK-2 homeobox genes are a family of genes that encode for numerous transcription factors that go on to aid in the development of many structures including the thyroid, colon, and heart.[9][10][11] Of the NK-2 genes, Nkx-2.5 transcription factor is mostly involved in cardiac development and defects with this gene can lead to congenital heart defects including, but not limited to atrial septal defects.[12] Nkx-2.5 is expressed in precursor cardiac cells and this expression is necessary in order to lead to proper cardiac development.[13] In Nkx-2.5 gene knock out mice, subjects were found to have induced congenital heart defects by leading to differentially expressed genes.[14] In the case of loss of function of Nkx-2.5, test subjects developed increased heart rate and decreased variability in heart rate.[15] This discovery indicates that Nkx-2.5 is necessary for proper cardiac formatting as well as proper cardiac function after formatting. Nkx-2.5 has also been shown to bind to the promoter of FGF-16 and regulate its expression. This finding suggests that Nkx-2.5 is implicated in cardiac injury via cytotoxic effects.[16]

Interactions

During embryogenesis, NKX2-5 is expressed in early cardiac mesoderm cells throughout the left ventricle and atrial chambers. In early cardiogenesis, cardiac precursor cells from the cardiac crescent congregate along the ventral midline of the developing embryo and form the linear heart tube. In Nkx2-5 knock out mice, cardiac development halts at the linear heart tube stage and looping morphogenesis disrupted.

NKX2.5 has been shown to interact with GATA4[17][18][19][20] and TBX5.[17][21] NKX 2.5 is a transcription factor that regulates heart development from the Cardiac Crescent of the splanchnic mesoderm in humans.[22] NKX2.5 is dependent upon the JAK-STAT pathway[23] and works along with MEF2, HAND1, and HAND2 transcription factors to direct heart looping during early heart development. NKX2.5 in vertebrates is equivalent to the ‘tinman’ gene in Drosophila and directly activates the MEF2 gene to control cardiomyocyte differentiation. NKX2.5 operates in a positive feedback loop with GATA transcription factors to regulate cardiomyocyte formation. NKX2.5 influences HAND1 and HAND2 transcription factors that control the essential asymmetrical development of the heart's ventricles. The gene has been show to play a role in the heart's conduction system, postnatally.[24] NKX2-5 is also involved in the intrinsic mechanisms that decide ventricle and atrial cellular fate. During ventricular chamber formation, NKX2-5 and NKX2-7 are required to maintain cardiomyocyte cellular identity. Repression of either gene results in the differentiating cardiomyocytes to move towards atrial chamber identity. The Nbx2.5 mutation has also been associated with preeclampsia; though research is still being conducting in this area.[25]

References

1. GRCh38: Ensembl release 89: ENSG00000183072 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000015579 - 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. Shiojima I, Komuro I, Inazawa J, Nakahori Y, Matsushita I, Abe T, Nagai R, Yazaki Y (May 1995). "Assignment of cardiac homeobox gene CSX to human chromosome 5q34". Genomics. 27 (1): 204–6. doi:10.1006/geno.1995.1027. PMID 7665173.
6. Turbay D, Wechsler SB, Blanchard KM, Izumo S (January 1996). "Molecular cloning, chromosomal mapping, and characterization of the human cardiac-specific homeobox gene hCsx". Molecular Medicine. 2 (1): 86–96. doi:10.1007/BF03402205. PMC 2230031. PMID 8900537.
7. "Entrez Gene: NKX2-5 NK2 transcription factor related, locus 5 (Drosophila)".
8. Akazawa H, Komuro I (May 2003). "Roles of cardiac transcription factors in cardiac hypertrophy". Circulation Research. 92 (10): 1079–88. doi:10.1161/01.RES.0000072977.86706.23. PMID 12775656.
9. "NKX2-3 NK2 homeobox 3 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2018-04-13.
10. Bartlett, Veenstra, Weeks, Heather, Gert, Daniel (2010). "Examining the Cardiac NK-2 Genes in Early Heart Development". Pediatric Cardiology. 31 (3): 335–341. doi:10.1007/s00246-009-9605-0. PMC 2981039. PMID 19967350.CS1 maint: multiple names: authors list (link)
11. "NKX2-1 NK2 homeobox 1 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2018-04-13.
12. Ranganayakulu G, Elliott DA, Harvey RP, Olson EN (August 1998). "Divergent roles for NK-2 class homeobox genes in cardiogenesis in flies and mice". Development. 125 (16): 3037–48. PMID 9671578.
13. Harvey RP (September 1996). "NK-2 homeobox genes and heart development". Developmental Biology. 178 (2): 203–16. doi:10.1006/dbio.1996.0212. PMID 8812123.
14. Li J, Cao Y, Wu Y, Chen W, Yuan Y, Ma X, Huang G (December 2015). "The expression profile analysis of NKX2-5 knock-out embryonic mice to explore the pathogenesis of congenital heart disease". Journal of Cardiology. 66 (6): 527–31. doi:10.1016/j.jjcc.2014.12.022. PMID 25818641.
15. Harrington JK, Sorabella R, Tercek A, Isler JR, Targoff KL (September 2017). "Nkx2.5 is essential to establish normal heart rate variability in the zebrafish embryo". American Journal of Physiology. Regulatory, Integrative and Comparative Physiology. 313 (3): R265–R271. doi:10.1152/ajpregu.00223.2016. PMC 5625277. PMID 28615160.
16. Wang J, Jin Y, Cattini PA (February 2017). "Expression of the Cardiac Maintenance and Survival Factor FGF-16 Gene Is Regulated by Csx/Nkx2.5 and Is an Early Target of Doxorubicin Cardiotoxicity". DNA and Cell Biology. 36 (2): 117–126. doi:10.1089/dna.2016.3507. PMID 27929351.
17. Garg V, Kathiriya IS, Barnes R, Schluterman MK, King IN, Butler CA, Rothrock CR, Eapen RS, Hirayama-Yamada K, Joo K, Matsuoka R, Cohen JC, Srivastava D (July 2003). "GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5". Nature. 424 (6947): 443–7. Bibcode:2003Natur.424..443G. doi:10.1038/nature01827. PMID 12845333.
18. Durocher D, Charron F, Warren R, Schwartz RJ, Nemer M (September 1997). "The cardiac transcription factors Nkx2-5 and GATA-4 are mutual cofactors". The EMBO Journal. 16 (18): 5687–96. doi:10.1093/emboj/16.18.5687. PMC 1170200. PMID 9312027.
19. Zhu W, Shiojima I, Hiroi Y, Zou Y, Akazawa H, Mizukami M, Toko H, Yazaki Y, Nagai R, Komuro I (November 2000). "Functional analyses of three Csx/Nkx-2.5 mutations that cause human congenital heart disease". The Journal of Biological Chemistry. 275 (45): 35291–6. doi:10.1074/jbc.M000525200. PMID 10948187.
20. Mattapally S, Singh M, Murthy KS, Asthana S, Banerjee SK (Feb 2018). "Computational modeling suggests impaired interactions between NKX2.5 and GATA4 in individuals carrying a novel pathogenic D16N NKX2.5 mutation". Oncotarget. 9 (17): 13713–13732. doi:10.18632/oncotarget.24459. PMC 5862610. PMID 29568389.
21. Hiroi Y, Kudoh S, Monzen K, Ikeda Y, Yazaki Y, Nagai R, Komuro I (July 2001). "Tbx5 associates with Nkx2-5 and synergistically promotes cardiomyocyte differentiation". Nature Genetics. 28 (3): 276–80. doi:10.1038/90123. PMID 11431700.
22. Carlson B (2013). Human Embryology and Developmental Biology. Saunders. pp. 104–105, 425.
23. Bodmer R (July 1993). "The gene tinman is required for specification of the heart and visceral muscles in Drosophila". Development. 118 (3): 719–29. PMID 7915669.
24. Winslow R. "In 'Tinman' Gene, Scientists See Root Of 2 Heart Defects". Wall Street Journal.
25. Fugate E. "Developing Genetic Therapies for Congenital Heart Defects". www.muschealth.org.

Further reading

• Harvey RP, Lai D, Elliott D, Biben C, Solloway M, Prall O, Stennard F, Schindeler A, Groves N, Lavulo L, Hyun C, Yeoh T, Costa M, Furtado M, Kirk E (2003). "Homeodomain factor Nkx2-5 in heart development and disease". Cold Spring Harbor Symposia on Quantitative Biology. 67: 107–14. doi:10.1101/sqb.2002.67.107. PMID 12858530.
• Chen CY, Schwartz RJ (November 1996). "Recruitment of the tinman homolog Nkx-2.5 by serum response factor activates cardiac alpha-actin gene transcription". Molecular and Cellular Biology. 16 (11): 6372–84. doi:10.1128/mcb.16.11.6372. PMC 231639. PMID 8887666.
• Durocher D, Charron F, Warren R, Schwartz RJ, Nemer M (September 1997). "The cardiac transcription factors Nkx2-5 and GATA-4 are mutual cofactors". The EMBO Journal. 16 (18): 5687–96. doi:10.1093/emboj/16.18.5687. PMC 1170200. PMID 9312027.
• Schott JJ, Benson DW, Basson CT, Pease W, Silberbach GM, Moak JP, Maron BJ, Seidman CE, Seidman JG (July 1998). "Congenital heart disease caused by mutations in the transcription factor NKX2-5". Science. 281 (5373): 108–11. Bibcode:1998Sci...281..108S. doi:10.1126/science.281.5373.108. PMID 9651244.
• Kim YH, Choi CY, Lee SJ, Conti MA, Kim Y (October 1998). "Homeodomain-interacting protein kinases, a novel family of co-repressors for homeodomain transcription factors". The Journal of Biological Chemistry. 273 (40): 25875–9. doi:10.1074/jbc.273.40.25875. PMID 9748262.
• Kasahara H, Izumo S (January 1999). "Identification of the in vivo casein kinase II phosphorylation site within the homeodomain of the cardiac tisue-specifying homeobox gene product Csx/Nkx2.5". Molecular and Cellular Biology. 19 (1): 526–36. doi:10.1128/mcb.19.1.526. PMC 83910. PMID 9858576.
• Benson DW, Silberbach GM, Kavanaugh-McHugh A, Cottrill C, Zhang Y, Riggs S, Smalls O, Johnson MC, Watson MS, Seidman JG, Seidman CE, Plowden J, Kugler JD (December 1999). "Mutations in the cardiac transcription factor NKX2.5 affect diverse cardiac developmental pathways". The Journal of Clinical Investigation. 104 (11): 1567–73. doi:10.1172/JCI8154. PMC 409866. PMID 10587520.
• Kasahara H, Lee B, Schott JJ, Benson DW, Seidman JG, Seidman CE, Izumo S (July 2000). "Loss of function and inhibitory effects of human CSX/NKX2.5 homeoprotein mutations associated with congenital heart disease". The Journal of Clinical Investigation. 106 (2): 299–308. doi:10.1172/JCI9860. PMC 314312. PMID 10903346.
• Zhu W, Shiojima I, Hiroi Y, Zou Y, Akazawa H, Mizukami M, Toko H, Yazaki Y, Nagai R, Komuro I (November 2000). "Functional analyses of three Csx/Nkx-2.5 mutations that cause human congenital heart disease". The Journal of Biological Chemistry. 275 (45): 35291–6. doi:10.1074/jbc.M000525200. PMID 10948187.
• Hiroi Y, Kudoh S, Monzen K, Ikeda Y, Yazaki Y, Nagai R, Komuro I (July 2001). "Tbx5 associates with Nkx2-5 and synergistically promotes cardiomyocyte differentiation". Nature Genetics. 28 (3): 276–80. doi:10.1038/90123. PMID 11431700.
• Goldmuntz E, Geiger E, Benson DW (November 2001). "NKX2.5 mutations in patients with tetralogy of fallot". Circulation. 104 (21): 2565–8. doi:10.1161/hc4601.098427. PMID 11714651.
• Toko H, Zhu W, Takimoto E, Shiojima I, Hiroi Y, Zou Y, Oka T, Akazawa H, Mizukami M, Sakamoto M, Terasaki F, Kitaura Y, Takano H, Nagai T, Nagai R, Komuro I (July 2002). "Csx/Nkx2-5 is required for homeostasis and survival of cardiac myocytes in the adult heart". The Journal of Biological Chemistry. 277 (27): 24735–43. doi:10.1074/jbc.M107669200. PMID 11889119.
• Habets PE, Moorman AF, Clout DE, van Roon MA, Lingbeek M, van Lohuizen M, Campione M, Christoffels VM (May 2002). "Cooperative action of Tbx2 and Nkx2.5 inhibits ANF expression in the atrioventricular canal: implications for cardiac chamber formation". Genes & Development. 16 (10): 1234–46. doi:10.1101/gad.222902. PMC 186286. PMID 12023302.
• Ikeda Y, Hiroi Y, Hosoda T, Utsunomiya T, Matsuo S, Ito T, Inoue J, Sumiyoshi T, Takano H, Nagai R, Komuro I (June 2002). "Novel point mutation in the cardiac transcription factor CSX/NKX2.5 associated with congenital heart disease". Circulation Journal. 66 (6): 561–3. doi:10.1253/circj.66.561. PMID 12074273.
• Shirai M, Osugi T, Koga H, Kaji Y, Takimoto E, Komuro I, Hara J, Miwa T, Yamauchi-Takihara K, Takihara Y (July 2002). "The Polycomb-group gene Rae28 sustains Nkx2.5/Csx expression and is essential for cardiac morphogenesis". The Journal of Clinical Investigation. 110 (2): 177–84. doi:10.1172/JCI14839. PMC 151044. PMID 12122109.
• Watanabe Y, Benson DW, Yano S, Akagi T, Yoshino M, Murray JC (November 2002). "Two novel frameshift mutations in NKX2.5 result in novel features including visceral inversus and sinus venosus type ASD". Journal of Medical Genetics. 39 (11): 807–11. doi:10.1136/jmg.39.11.807. PMC 1735007. PMID 12414819.
• Fan C, Liu M, Wang Q (March 2003). "Functional analysis of TBX5 missense mutations associated with Holt-Oram syndrome". The Journal of Biological Chemistry. 278 (10): 8780–5. doi:10.1074/jbc.M208120200. PMC 1579789. PMID 12499378.

External links

• NKX2-5+protein,+human at the US National Library of Medicine Medical Subject Headings (MeSH)

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