Homeobox protein Nkx-2.5: Difference between revisions

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{{Infobox_gene}}
{{Infobox_gene}}
'''Homeobox protein Nkx-2.5''' is a [[protein]] that in humans is encoded by the ''NKX2.5'' [[gene]].<ref name="pmid7665173">{{cite journal | vauthors = Shiojima I, Komuro I, Inazawa J, Nakahori Y, Matsushita I, Abe T, Nagai R, Yazaki Y | title = Assignment of cardiac homeobox gene CSX to human chromosome 5q34 | journal = Genomics | volume = 27 | issue = 1 | pages = 204–6 | date = May 1995 | pmid = 7665173 | pmc =  | doi = 10.1006/geno.1995.1027 }}</ref><ref name="pmid8900537">{{cite journal | vauthors = Turbay D, Wechsler SB, Blanchard KM, Izumo S | title = Molecular cloning, chromosomal mapping, and characterization of the human cardiac-specific homeobox gene hCsx | journal = Molecular Medicine | volume = 2 | issue = 1 | pages = 86–96 | date = Jan 1996 | pmid = 8900537 | pmc = 2230031 | doi =  }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: NKX2-5 NK2 transcription factor related, locus 5 (Drosophila)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1482| accessdate = }}</ref>
'''Homeobox protein Nkx-2.5''' is a [[protein]] that in humans is encoded by the ''NKX2.5'' [[gene]].<ref name="pmid7665173">{{cite journal | vauthors = Shiojima I, Komuro I, Inazawa J, Nakahori Y, Matsushita I, Abe T, Nagai R, Yazaki Y | title = Assignment of cardiac homeobox gene CSX to human chromosome 5q34 | journal = Genomics | volume = 27 | issue = 1 | pages = 204–6 | date = May 1995 | pmid = 7665173 | pmc =  | doi = 10.1006/geno.1995.1027 }}</ref><ref name="pmid8900537">{{cite journal | vauthors = Turbay D, Wechsler SB, Blanchard KM, Izumo S | title = Molecular cloning, chromosomal mapping, and characterization of the human cardiac-specific homeobox gene hCsx | journal = Molecular Medicine | volume = 2 | issue = 1 | pages = 86–96 | date = January 1996 | pmid = 8900537 | pmc = 2230031 | doi =  }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: NKX2-5 NK2 transcription factor related, locus 5 (Drosophila)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1482| access-date = }}</ref>


== Function ==
== Function ==
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[[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.<ref name="entrez"/>
[[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.<ref name="entrez"/>
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.<ref>{{cite journal | vauthors = Akazawa H, Komuro I | title = Roles of cardiac transcription factors in cardiac hypertrophy | journal = Circulation Research | volume = 92 | issue = 10 | pages = 1079–88 | date = May 2003 | pmid = 12775656 | doi = 10.1161/01.RES.0000072977.86706.23 | url = http://circres.ahajournals.org/content/92/10/1079 }}</ref>
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.<ref>{{cite journal | vauthors = Akazawa H, Komuro I | title = Roles of cardiac transcription factors in cardiac hypertrophy | journal = Circulation Research | volume = 92 | issue = 10 | pages = 1079–88 | date = May 2003 | pmid = 12775656 | doi = 10.1161/01.RES.0000072977.86706.23 | url = http://circres.ahajournals.org/content/92/10/1079 }}</ref>
NK-2 homeobox genes are a family of [[gene]]s that encode for numerous transcription factors that go on to aid in the development of many structures including the thyroid, colon, and heart.<ref>{{Cite web|url=https://www.ncbi.nlm.nih.gov/gene/159296|title=NKX2-3 NK2 homeobox 3 [Homo sapiens (human)] - Gene - NCBI|website=www.ncbi.nlm.nih.gov|access-date=2018-04-13}}</ref><ref>{{Cite journal|last=Bartlett, Veenstra, Weeks|first=Heather, Gert, Daniel|date=2010|title=Examining the Cardiac NK-2 Genes in Early Heart Development|pmc=2981039|journal=Pediatric cardiology|volume=|pages=|via=}}</ref><ref>{{Cite web|url=https://www.ncbi.nlm.nih.gov/gene/7080|title=NKX2-1 NK2 homeobox 1 [Homo sapiens (human)] - Gene - NCBI|website=www.ncbi.nlm.nih.gov|access-date=2018-04-13}}</ref> 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 defect]]s including, but not limited to atrial septal defects.<ref>{{cite journal | vauthors = Ranganayakulu G, Elliott DA, Harvey RP, Olson EN | title = Divergent roles for NK-2 class homeobox genes in cardiogenesis in flies and mice | journal = Development | volume = 125 | issue = 16 | pages = 3037–48 | date = August 1998 | pmid = 9671578 }}</ref> Nkx-2.5 is expressed in precursor cardiac cells and this expression is necessary in order to lead to proper cardiac development.<ref>{{cite journal | vauthors = Harvey RP | title = NK-2 homeobox genes and heart development | journal = Developmental Biology | volume = 178 | issue = 2 | pages = 203–16 | date = September 1996 | pmid = 8812123 | doi = 10.1006/dbio.1996.0212 }}</ref> In Nkx-2.5 [[Gene knockout|gene knock out]] mice, subjects were found to have induced congenital heart defects by leading to differentially expressed genes.<ref>{{cite journal | vauthors = Li J, Cao Y, Wu Y, Chen W, Yuan Y, Ma X, Huang G | title = The expression profile analysis of NKX2-5 knock-out embryonic mice to explore the pathogenesis of congenital heart disease | language = English | journal = Journal of Cardiology | volume = 66 | issue = 6 | pages = 527–31 | date = December 2015 | pmid = 25818641 | doi = 10.1016/j.jjcc.2014.12.022 | url = http://www.journal-of-cardiology.com/article/S0914-5087(15)00039-8/abstract }}</ref> In the case of loss of function of Nkx-2.5, test subjects developed increased heart rate and decreased variability in heart rate.<ref>{{cite journal | vauthors = Harrington JK, Sorabella R, Tercek A, Isler JR, Targoff KL | title = Nkx2.5 is essential to establish normal heart rate variability in the zebrafish embryo | journal = American Journal of Physiology. Regulatory, Integrative and Comparative Physiology | volume = 313 | issue = 3 | pages = R265-R271 | date = September 2017 | pmid = 28615160 | pmc = 5625277 | doi = 10.1152/ajpregu.00223.2016 }}</ref> 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 [[FGF16|FGF-16]] and regulate its expression.  This finding suggests that Nkx-2.5 is implicated in cardiac injury via cytotoxic effects.<ref>{{cite journal | vauthors = Wang J, Jin Y, Cattini PA | title = 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 | journal = DNA and Cell Biology | volume = 36 | issue = 2 | pages = 117–126 | date = February 2017 | pmid = 27929351 | doi = 10.1089/dna.2016.3507 }}</ref>


== Interactions ==
== 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.  
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 [[Protein-protein interaction|interact]] with [[GATA4]]<ref name=pmid12845333>{{cite journal | vauthors = 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 | title = GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5 | journal = Nature | volume = 424 | issue = 6947 | pages = 443–7 | date = Jul 2003 | pmid = 12845333 | doi = 10.1038/nature01827 }}</ref><ref name=pmid9312027>{{cite journal | vauthors = Durocher D, Charron F, Warren R, Schwartz RJ, Nemer M | title = The cardiac transcription factors Nkx2-5 and GATA-4 are mutual cofactors | journal = The EMBO Journal | volume = 16 | issue = 18 | pages = 5687–96 | date = Sep 1997 | pmid = 9312027 | pmc = 1170200 | doi = 10.1093/emboj/16.18.5687 }}</ref><ref name=pmid10948187>{{cite journal | vauthors = Zhu W, Shiojima I, Hiroi Y, Zou Y, Akazawa H, Mizukami M, Toko H, Yazaki Y, Nagai R, Komuro I | title = Functional analyses of three Csx/Nkx-2.5 mutations that cause human congenital heart disease | journal = The Journal of Biological Chemistry | volume = 275 | issue = 45 | pages = 35291–6 | date = Nov 2000 | pmid = 10948187 | doi = 10.1074/jbc.M000525200 }}</ref> and [[TBX5 (gene)|TBX5]].<ref name=pmid12845333/><ref name=pmid11431700>{{cite journal | vauthors = Hiroi Y, Kudoh S, Monzen K, Ikeda Y, Yazaki Y, Nagai R, Komuro I | title = Tbx5 associates with Nkx2-5 and synergistically promotes cardiomyocyte differentiation | journal = Nature Genetics | volume = 28 | issue = 3 | pages = 276–80 | date = Jul 2001 | pmid = 11431700 | doi = 10.1038/90123 }}</ref>
NKX2.5 has been shown to [[Protein-protein interaction|interact]] with [[GATA4]]<ref name=pmid12845333>{{cite journal | vauthors = 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 | title = GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5 | journal = Nature | volume = 424 | issue = 6947 | pages = 443–7 | date = July 2003 | pmid = 12845333 | doi = 10.1038/nature01827 }}</ref><ref name=pmid9312027>{{cite journal | vauthors = Durocher D, Charron F, Warren R, Schwartz RJ, Nemer M | title = The cardiac transcription factors Nkx2-5 and GATA-4 are mutual cofactors | journal = The EMBO Journal | volume = 16 | issue = 18 | pages = 5687–96 | date = September 1997 | pmid = 9312027 | pmc = 1170200 | doi = 10.1093/emboj/16.18.5687 }}</ref><ref name=pmid10948187>{{cite journal | vauthors = Zhu W, Shiojima I, Hiroi Y, Zou Y, Akazawa H, Mizukami M, Toko H, Yazaki Y, Nagai R, Komuro I | title = Functional analyses of three Csx/Nkx-2.5 mutations that cause human congenital heart disease | journal = The Journal of Biological Chemistry | volume = 275 | issue = 45 | pages = 35291–6 | date = November 2000 | pmid = 10948187 | doi = 10.1074/jbc.M000525200 }}</ref><ref name=pmid29568389>{{cite journal | vauthors = Mattapally S, Singh M, Murthy KS, Asthana S, Banerjee SK | title = Computational modeling suggests impaired interactions between NKX2.5 and GATA4 in individuals carrying a novel pathogenic D16N NKX2.5 mutation | journal = Oncotarget | volume = 9 | issue = 17 | pages = 13713-13732 | date = Feb 2018 | pmid = 29568389 | doi = 10.18632/oncotarget.24459 }}</ref> and [[TBX5 (gene)|TBX5]].<ref name=pmid12845333/><ref name=pmid11431700>{{cite journal | vauthors = Hiroi Y, Kudoh S, Monzen K, Ikeda Y, Yazaki Y, Nagai R, Komuro I | title = Tbx5 associates with Nkx2-5 and synergistically promotes cardiomyocyte differentiation | journal = Nature Genetics | volume = 28 | issue = 3 | pages = 276–80 | date = July 2001 | pmid = 11431700 | doi = 10.1038/90123 }}</ref>
NKX 2.5 is a transcription factor that regulates heart development from the Cardiac Crescent of the splanchnic mesoderm in humans.<ref>{{cite book | title = Human Embryology and Developmental Biology | last = Carlson | first = Bruce | name-list-format = vanc | publisher = Saunders | year = 2013 | pages = 104–105; 425 }}</ref> NKX2.5 is dependent upon the JAK-STAT pathway<ref name="pmid7915669">{{cite journal | vauthors = Bodmer R | title = The gene tinman is required for specification of the heart and visceral muscles in Drosophila | journal = [[Development (journal)|Development]] | volume = 118 | issue = 3 | pages = 719–29 | year = 1993 | pmid = 7915669 | doi = | url = http://dev.biologists.org/content/118/3/719}}</ref> 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.<ref name="Winslow">{{cite news | url = https://www.wsj.com/articles/sb109104931954976796 | title =  In 'Tinman' Gene, Scientists See Root Of 2 Heart Defects | last = Winslow | first = R. | name-list-format = vanc | newspaper = Wall Street Journal }}</ref> 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.<ref>{{cite web| url = http://www.muschealth.org/pn/yir-2013/research/tin-man/index.html | title = Developing Genetic Therapies for Congenital Heart Defects | last = Fugate | first = Ethan | name-list-format = vanc | website = www.muschealth.org }}</ref>
NKX 2.5 is a transcription factor that regulates heart development from the Cardiac Crescent of the splanchnic mesoderm in humans.<ref>{{cite book | title = Human Embryology and Developmental Biology | last = Carlson | first = Bruce | name-list-format = vanc | publisher = Saunders | year = 2013 | pages = 104–105; 425 }}</ref> NKX2.5 is dependent upon the JAK-STAT pathway<ref name="pmid7915669">{{cite journal | vauthors = Bodmer R | title = The gene tinman is required for specification of the heart and visceral muscles in Drosophila | journal = Development | volume = 118 | issue = 3 | pages = 719–29 | date = July 1993 | pmid = 7915669 | doi = | url = http://dev.biologists.org/content/118/3/719 }}</ref> 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.<ref name="Winslow">{{cite news | url = https://www.wsj.com/articles/sb109104931954976796 | title =  In 'Tinman' Gene, Scientists See Root Of 2 Heart Defects | last = Winslow | first = R. | name-list-format = vanc | newspaper = Wall Street Journal }}</ref> 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.<ref>{{cite web| url = http://www.muschealth.org/pn/yir-2013/research/tin-man/index.html | title = Developing Genetic Therapies for Congenital Heart Defects | last = Fugate | first = Ethan | name-list-format = vanc | website = www.muschealth.org }}</ref>
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* {{cite journal | vauthors = 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 | title = Homeodomain factor Nkx2-5 in heart development and disease | journal = Cold Spring Harbor Symposia on Quantitative Biology | volume = 67 | issue =  | pages = 107–14 | year = 2003 | pmid = 12858530 | doi = 10.1101/sqb.2002.67.107 }}
* {{cite journal | vauthors = 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 | title = Homeodomain factor Nkx2-5 in heart development and disease | journal = Cold Spring Harbor Symposia on Quantitative Biology | volume = 67 | issue =  | pages = 107–14 | year = 2003 | pmid = 12858530 | doi = 10.1101/sqb.2002.67.107 }}
* {{cite journal | vauthors = Chen CY, Schwartz RJ | title = Recruitment of the tinman homolog Nkx-2.5 by serum response factor activates cardiac alpha-actin gene transcription | journal = Molecular and Cellular Biology | volume = 16 | issue = 11 | pages = 6372–84 | date = Nov 1996 | pmid = 8887666 | pmc = 231639 | doi = 10.1128/mcb.16.11.6372}}
* {{cite journal | vauthors = Chen CY, Schwartz RJ | title = Recruitment of the tinman homolog Nkx-2.5 by serum response factor activates cardiac alpha-actin gene transcription | journal = Molecular and Cellular Biology | volume = 16 | issue = 11 | pages = 6372–84 | date = November 1996 | pmid = 8887666 | pmc = 231639 | doi = 10.1128/mcb.16.11.6372 }}
* {{cite journal | vauthors = Durocher D, Charron F, Warren R, Schwartz RJ, Nemer M | title = The cardiac transcription factors Nkx2-5 and GATA-4 are mutual cofactors | journal = The EMBO Journal | volume = 16 | issue = 18 | pages = 5687–96 | date = Sep 1997 | pmid = 9312027 | pmc = 1170200 | doi = 10.1093/emboj/16.18.5687 }}
* {{cite journal | vauthors = Durocher D, Charron F, Warren R, Schwartz RJ, Nemer M | title = The cardiac transcription factors Nkx2-5 and GATA-4 are mutual cofactors | journal = The EMBO Journal | volume = 16 | issue = 18 | pages = 5687–96 | date = September 1997 | pmid = 9312027 | pmc = 1170200 | doi = 10.1093/emboj/16.18.5687 }}
* {{cite journal | vauthors = Schott JJ, Benson DW, Basson CT, Pease W, Silberbach GM, Moak JP, Maron BJ, Seidman CE, Seidman JG | title = Congenital heart disease caused by mutations in the transcription factor NKX2-5 | journal = Science | volume = 281 | issue = 5373 | pages = 108–11 | date = Jul 1998 | pmid = 9651244 | doi = 10.1126/science.281.5373.108 }}
* {{cite journal | vauthors = Schott JJ, Benson DW, Basson CT, Pease W, Silberbach GM, Moak JP, Maron BJ, Seidman CE, Seidman JG | title = Congenital heart disease caused by mutations in the transcription factor NKX2-5 | journal = Science | volume = 281 | issue = 5373 | pages = 108–11 | date = July 1998 | pmid = 9651244 | doi = 10.1126/science.281.5373.108 }}
* {{cite journal | vauthors = Kim YH, Choi CY, Lee SJ, Conti MA, Kim Y | title = Homeodomain-interacting protein kinases, a novel family of co-repressors for homeodomain transcription factors | journal = The Journal of Biological Chemistry | volume = 273 | issue = 40 | pages = 25875–9 | date = Oct 1998 | pmid = 9748262 | doi = 10.1074/jbc.273.40.25875 }}
* {{cite journal | vauthors = Kim YH, Choi CY, Lee SJ, Conti MA, Kim Y | title = Homeodomain-interacting protein kinases, a novel family of co-repressors for homeodomain transcription factors | journal = The Journal of Biological Chemistry | volume = 273 | issue = 40 | pages = 25875–9 | date = October 1998 | pmid = 9748262 | doi = 10.1074/jbc.273.40.25875 }}
* {{cite journal | vauthors = Kasahara H, Izumo S | title = Identification of the in vivo casein kinase II phosphorylation site within the homeodomain of the cardiac tisue-specifying homeobox gene product Csx/Nkx2.5 | journal = Molecular and Cellular Biology | volume = 19 | issue = 1 | pages = 526–36 | date = Jan 1999 | pmid = 9858576 | pmc = 83910 | doi = 10.1128/mcb.19.1.526}}
* {{cite journal | vauthors = Kasahara H, Izumo S | title = Identification of the in vivo casein kinase II phosphorylation site within the homeodomain of the cardiac tisue-specifying homeobox gene product Csx/Nkx2.5 | journal = Molecular and Cellular Biology | volume = 19 | issue = 1 | pages = 526–36 | date = January 1999 | pmid = 9858576 | pmc = 83910 | doi = 10.1128/mcb.19.1.526 }}
* {{cite journal | vauthors = 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 | title = Mutations in the cardiac transcription factor NKX2.5 affect diverse cardiac developmental pathways | journal = The Journal of Clinical Investigation | volume = 104 | issue = 11 | pages = 1567–73 | date = Dec 1999 | pmid = 10587520 | pmc = 409866 | doi = 10.1172/JCI8154 }}
* {{cite journal | vauthors = 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 | title = Mutations in the cardiac transcription factor NKX2.5 affect diverse cardiac developmental pathways | journal = The Journal of Clinical Investigation | volume = 104 | issue = 11 | pages = 1567–73 | date = December 1999 | pmid = 10587520 | pmc = 409866 | doi = 10.1172/JCI8154 }}
* {{cite journal | vauthors = Kasahara H, Lee B, Schott JJ, Benson DW, Seidman JG, Seidman CE, Izumo S | title = Loss of function and inhibitory effects of human CSX/NKX2.5 homeoprotein mutations associated with congenital heart disease | journal = The Journal of Clinical Investigation | volume = 106 | issue = 2 | pages = 299–308 | date = Jul 2000 | pmid = 10903346 | pmc = 314312 | doi = 10.1172/JCI9860 }}
* {{cite journal | vauthors = Kasahara H, Lee B, Schott JJ, Benson DW, Seidman JG, Seidman CE, Izumo S | title = Loss of function and inhibitory effects of human CSX/NKX2.5 homeoprotein mutations associated with congenital heart disease | journal = The Journal of Clinical Investigation | volume = 106 | issue = 2 | pages = 299–308 | date = July 2000 | pmid = 10903346 | pmc = 314312 | doi = 10.1172/JCI9860 }}
* {{cite journal | vauthors = Zhu W, Shiojima I, Hiroi Y, Zou Y, Akazawa H, Mizukami M, Toko H, Yazaki Y, Nagai R, Komuro I | title = Functional analyses of three Csx/Nkx-2.5 mutations that cause human congenital heart disease | journal = The Journal of Biological Chemistry | volume = 275 | issue = 45 | pages = 35291–6 | date = Nov 2000 | pmid = 10948187 | doi = 10.1074/jbc.M000525200 }}
* {{cite journal | vauthors = Zhu W, Shiojima I, Hiroi Y, Zou Y, Akazawa H, Mizukami M, Toko H, Yazaki Y, Nagai R, Komuro I | title = Functional analyses of three Csx/Nkx-2.5 mutations that cause human congenital heart disease | journal = The Journal of Biological Chemistry | volume = 275 | issue = 45 | pages = 35291–6 | date = November 2000 | pmid = 10948187 | doi = 10.1074/jbc.M000525200 }}
* {{cite journal | vauthors = Hiroi Y, Kudoh S, Monzen K, Ikeda Y, Yazaki Y, Nagai R, Komuro I | title = Tbx5 associates with Nkx2-5 and synergistically promotes cardiomyocyte differentiation | journal = Nature Genetics | volume = 28 | issue = 3 | pages = 276–80 | date = Jul 2001 | pmid = 11431700 | doi = 10.1038/90123 }}
* {{cite journal | vauthors = Hiroi Y, Kudoh S, Monzen K, Ikeda Y, Yazaki Y, Nagai R, Komuro I | title = Tbx5 associates with Nkx2-5 and synergistically promotes cardiomyocyte differentiation | journal = Nature Genetics | volume = 28 | issue = 3 | pages = 276–80 | date = July 2001 | pmid = 11431700 | doi = 10.1038/90123 }}
* {{cite journal | vauthors = Goldmuntz E, Geiger E, Benson DW | title = NKX2.5 mutations in patients with tetralogy of fallot | journal = Circulation | volume = 104 | issue = 21 | pages = 2565–8 | date = Nov 2001 | pmid = 11714651 | doi = 10.1161/hc4601.098427 }}
* {{cite journal | vauthors = Goldmuntz E, Geiger E, Benson DW | title = NKX2.5 mutations in patients with tetralogy of fallot | journal = Circulation | volume = 104 | issue = 21 | pages = 2565–8 | date = November 2001 | pmid = 11714651 | doi = 10.1161/hc4601.098427 }}
* {{cite journal | vauthors = 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 | title = Csx/Nkx2-5 is required for homeostasis and survival of cardiac myocytes in the adult heart | journal = The Journal of Biological Chemistry | volume = 277 | issue = 27 | pages = 24735–43 | date = Jul 2002 | pmid = 11889119 | doi = 10.1074/jbc.M107669200 }}
* {{cite journal | vauthors = 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 | title = Csx/Nkx2-5 is required for homeostasis and survival of cardiac myocytes in the adult heart | journal = The Journal of Biological Chemistry | volume = 277 | issue = 27 | pages = 24735–43 | date = July 2002 | pmid = 11889119 | doi = 10.1074/jbc.M107669200 }}
* {{cite journal | vauthors = Habets PE, Moorman AF, Clout DE, van Roon MA, Lingbeek M, van Lohuizen M, Campione M, Christoffels VM | title = Cooperative action of Tbx2 and Nkx2.5 inhibits ANF expression in the atrioventricular canal: implications for cardiac chamber formation | journal = Genes & Development | volume = 16 | issue = 10 | pages = 1234–46 | date = May 2002 | pmid = 12023302 | pmc = 186286 | doi = 10.1101/gad.222902 }}
* {{cite journal | vauthors = Habets PE, Moorman AF, Clout DE, van Roon MA, Lingbeek M, van Lohuizen M, Campione M, Christoffels VM | title = Cooperative action of Tbx2 and Nkx2.5 inhibits ANF expression in the atrioventricular canal: implications for cardiac chamber formation | journal = Genes & Development | volume = 16 | issue = 10 | pages = 1234–46 | date = May 2002 | pmid = 12023302 | pmc = 186286 | doi = 10.1101/gad.222902 }}
* {{cite journal | vauthors = Ikeda Y, Hiroi Y, Hosoda T, Utsunomiya T, Matsuo S, Ito T, Inoue J, Sumiyoshi T, Takano H, Nagai R, Komuro I | title = Novel point mutation in the cardiac transcription factor CSX/NKX2.5 associated with congenital heart disease | journal = Circulation Journal | volume = 66 | issue = 6 | pages = 561–3 | date = Jun 2002 | pmid = 12074273 | doi = 10.1253/circj.66.561 }}
* {{cite journal | vauthors = Ikeda Y, Hiroi Y, Hosoda T, Utsunomiya T, Matsuo S, Ito T, Inoue J, Sumiyoshi T, Takano H, Nagai R, Komuro I | title = Novel point mutation in the cardiac transcription factor CSX/NKX2.5 associated with congenital heart disease | journal = Circulation Journal | volume = 66 | issue = 6 | pages = 561–3 | date = June 2002 | pmid = 12074273 | doi = 10.1253/circj.66.561 }}
* {{cite journal | vauthors = Shirai M, Osugi T, Koga H, Kaji Y, Takimoto E, Komuro I, Hara J, Miwa T, Yamauchi-Takihara K, Takihara Y | title = The Polycomb-group gene Rae28 sustains Nkx2.5/Csx expression and is essential for cardiac morphogenesis | journal = The Journal of Clinical Investigation | volume = 110 | issue = 2 | pages = 177–84 | date = Jul 2002 | pmid = 12122109 | pmc = 151044 | doi = 10.1172/JCI14839 }}
* {{cite journal | vauthors = Shirai M, Osugi T, Koga H, Kaji Y, Takimoto E, Komuro I, Hara J, Miwa T, Yamauchi-Takihara K, Takihara Y | title = The Polycomb-group gene Rae28 sustains Nkx2.5/Csx expression and is essential for cardiac morphogenesis | journal = The Journal of Clinical Investigation | volume = 110 | issue = 2 | pages = 177–84 | date = July 2002 | pmid = 12122109 | pmc = 151044 | doi = 10.1172/JCI14839 }}
* {{cite journal | vauthors = Watanabe Y, Benson DW, Yano S, Akagi T, Yoshino M, Murray JC | title = Two novel frameshift mutations in NKX2.5 result in novel features including visceral inversus and sinus venosus type ASD | journal = Journal of Medical Genetics | volume = 39 | issue = 11 | pages = 807–11 | date = Nov 2002 | pmid = 12414819 | pmc = 1735007 | doi = 10.1136/jmg.39.11.807 }}
* {{cite journal | vauthors = Watanabe Y, Benson DW, Yano S, Akagi T, Yoshino M, Murray JC | title = Two novel frameshift mutations in NKX2.5 result in novel features including visceral inversus and sinus venosus type ASD | journal = Journal of Medical Genetics | volume = 39 | issue = 11 | pages = 807–11 | date = November 2002 | pmid = 12414819 | pmc = 1735007 | doi = 10.1136/jmg.39.11.807 }}
* {{cite journal | vauthors = Fan C, Liu M, Wang Q | title = Functional analysis of TBX5 missense mutations associated with Holt-Oram syndrome | journal = The Journal of Biological Chemistry | volume = 278 | issue = 10 | pages = 8780–5 | date = Mar 2003 | pmid = 12499378 | pmc = 1579789 | doi = 10.1074/jbc.M208120200 }}
* {{cite journal | vauthors = Fan C, Liu M, Wang Q | title = Functional analysis of TBX5 missense mutations associated with Holt-Oram syndrome | journal = The Journal of Biological Chemistry | volume = 278 | issue = 10 | pages = 8780–5 | date = March 2003 | pmid = 12499378 | pmc = 1579789 | doi = 10.1074/jbc.M208120200 }}
{{refend}}
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{{Transcription factors|g3}}
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[[Category:Transcription factors]]
[[Category:Transcription factors]]
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Latest revision as of 21:57, 16 January 2019

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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RefSeq (mRNA)

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RefSeq (protein)

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Wikidata
View/Edit Human

Homeobox protein Nkx-2.5 is a protein that in humans is encoded by the NKX2.5 gene.[1][2][3]

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.[3] 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.[4]

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.[5][6][7] 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.[8] Nkx-2.5 is expressed in precursor cardiac cells and this expression is necessary in order to lead to proper cardiac development.[9] In Nkx-2.5 gene knock out mice, subjects were found to have induced congenital heart defects by leading to differentially expressed genes.[10] In the case of loss of function of Nkx-2.5, test subjects developed increased heart rate and decreased variability in heart rate.[11] 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.[12]

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[13][14][15][16] and TBX5.[13][17] NKX 2.5 is a transcription factor that regulates heart development from the Cardiac Crescent of the splanchnic mesoderm in humans.[18] NKX2.5 is dependent upon the JAK-STAT pathway[19] 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.[20] 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.[21]

References

  1. ↑ 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.
  2. ↑ 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. PMC 2230031. PMID 8900537.
  3. ↑ 3.0 3.1 "Entrez Gene: NKX2-5 NK2 transcription factor related, locus 5 (Drosophila)".
  4. ↑ 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.
  5. ↑ "NKX2-3 NK2 homeobox 3 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2018-04-13.
  6. ↑ Bartlett, Veenstra, Weeks, Heather, Gert, Daniel (2010). "Examining the Cardiac NK-2 Genes in Early Heart Development". Pediatric cardiology. PMC 2981039.
  7. ↑ "NKX2-1 NK2 homeobox 1 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2018-04-13.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ 13.0 13.1 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. doi:10.1038/nature01827. PMID 12845333.
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ 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. PMID 29568389.
  17. ↑ 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.
  18. ↑ Carlson B (2013). Human Embryology and Developmental Biology. Saunders. pp. 104–105, 425.
  19. ↑ 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.
  20. ↑ Winslow R. "In 'Tinman' Gene, Scientists See Root Of 2 Heart Defects". Wall Street Journal.
  21. ↑ Fugate E. "Developing Genetic Therapies for Congenital Heart Defects". www.muschealth.org.

Further reading

External links

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

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