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Nkx2-5  -  NK2 homeobox 5

Rattus norvegicus

Synonyms: Csx, Homeobox protein NK-2 homolog E, Homeobox protein Nkx-2.5, Nkx-2.5, Nkx2.5, ...
 
 
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Disease relevance of Nkx2-5

  • Interestingly, coincident with NIS expression, Nkx-2.5 mRNA and protein were present in lactating, but not virgin, mammary glands in two human breast cancer samples and in all-trans retinoic acid (tRA)-stimulated MCF-7 breast cancer cells [1].
  • These results show that activation of GATA-4, in cooperation with a factor binding on Nkx-2.5 binding element, is essential for mechanical stretch-induced cardiomyocyte hypertrophy [2].
  • Functional analyses of three Csx/Nkx-2.5 mutations that cause human congenital heart disease [3].
  • Expression of the transcription factor Nkx2.5 increased with hypoxia [4].
 

High impact information on Nkx2-5

  • 5. In coexpression studies, GATA-4 alone was a poor inducer of the hDio2 promoter; however in synergy with Nkx-2.5, it activated D2 reporter gene expression in the human, but not the rat promoter [5].
  • Nkx-2.5 transactivates a 6.5-kb human (h)Dio2-chloramphenicol acetyltransferase construct, with maximal induction reached with a 633-bp proximal promoter region [5].
  • In neonatal rat primary myocardiocytes, most of the hDio2-chloramphenicol acetyltransferase activity was suppressed by mutation of the Nkx-2.5 binding sites [5].
  • RESULTS: In untreated cardiomyocyte cultures, expression of GATA-4 and Nkx2.5 was increased 7- and 4-fold, 72 hr after isolation, but the gene expression of MEF-2c and Oct-1 was reduced to 10% and 70%, at day 3 in culture [6].
  • Sequence scanning identified several potential regulatory elements, including five consensus sequences for the cardiac-specific transcription factor Nkx2.5, an AP-1 site, a cAMP response element, and a hormone response element [7].
 

Biological context of Nkx2-5

  • Lack of a consensus sequence for Nkx2-5 binding within the ECE-1c promoter and mutational analyses of Nkx2-5 consensus sequences identified in the ECE-1a and ECE-1b promoters, respectively, reveal an indirect mechanism of activation that is supported by gel shift assays [8].
  • The cardiac homeobox-containing gene Csx is expressed in the heart and the heart progenitor cells from the very early developmental stage, and targeted disruption of the murine Csx results in embryonic lethality because of the abnormal looping morphogenesis of the primary heart tube [9].
 

Anatomical context of Nkx2-5

  • Members of the transforming growth factor beta1 (TGF-beta) superfamily--namely, TGF-beta and BMP2--applied to undifferentiated murine embryonic stem cells up-regulated mRNA of mesodermal (Brachyury) and cardiac specific transcription factors (Nkx2.5, MEF2C) [10].
 

Other interactions of Nkx2-5

  • Here, we demonstrate for the first time a functional link between Nkx2-5 and ECE-1 [8].
 

Analytical, diagnostic and therapeutic context of Nkx2-5

  • With the use of RNase protection assay, Northern blot, and real-time PCR, the activating effect of Nkx2-5 on mRNA expression of ECE-1 isoforms was confirmed in the chromatin context of H9c2 and endothelial EA.hy926 cells, respectively, by stable Nkx2-5 overexpression [8].
  • Electrophoretic mobility shift assay showed that Csx/Nkx-2.5-binding sequences were bound strongly by WT and C, weakly by B, but not by A [3].
  • Transcript levels of MHCalpha (adult isoform), MHCbeta (fetal isoform), and Nkx2.5, the earliest known marker for cardiogenesis, were measured by real-time quantitative RT-PCR and normalized to levels of 18S rRNA [4].

References

  1. Transcription factor Nkx-2.5 induces sodium/iodide symporter gene expression and participates in retinoic acid- and lactation-induced transcription in mammary cells. Dentice, M., Luongo, C., Elefante, A., Romino, R., Ambrosio, R., Vitale, M., Rossi, G., Fenzi, G., Salvatore, D. Mol. Cell. Biol. (2004) [Pubmed]
  2. GATA-4 is a nuclear mediator of mechanical stretch-activated hypertrophic program. Pikkarainen, S., Tokola, H., Majalahti-Palviainen, T., Kerkela, R., Hautala, N., Bhalla, S.S., Charron, F., Nemer, M., Vuolteenaho, O., Ruskoaho, H. J. Biol. Chem. (2003) [Pubmed]
  3. Functional analyses of three Csx/Nkx-2.5 mutations that cause human congenital heart disease. Zhu, W., Shiojima, I., Hiroi, Y., Zou, Y., Akazawa, H., Mizukami, M., Toko, H., Yazaki, Y., Nagai, R., Komuro, I. J. Biol. Chem. (2000) [Pubmed]
  4. Hypoxia-induced switches of myosin heavy chain iso-gene expression in rat heart. Razeghi, P., Essop, M.F., Huss, J.M., Abbasi, S., Manga, N., Taegtmeyer, H. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  5. The different cardiac expression of the type 2 iodothyronine deiodinase gene between human and rat is related to the differential response of the Dio2 genes to Nkx-2.5 and GATA-4 transcription factors. Dentice, M., Morisco, C., Vitale, M., Rossi, G., Fenzi, G., Salvatore, D. Mol. Endocrinol. (2003) [Pubmed]
  6. Reprogramming of gene expression in cultured cardiomyocytes and in explanted hearts by the myosin ATPase inhibitor butanedione monoxime. Thum, T., Borlak, J. Transplantation (2001) [Pubmed]
  7. Regulation of DHP receptor expression by elements in the 5'-flanking sequence. Liu, L., Fan, Q.I., El-Zaru, M.R., Vanderpool, K., Hines, R.N., Marsh, J.D. Am. J. Physiol. Heart Circ. Physiol. (2000) [Pubmed]
  8. Endothelin-converting enzyme-1 (ECE-1) is a downstream target of the homeobox transcription factor Nkx2-5. Funke-Kaiser, H., Lemmer, J., Langsdorff, C.V., Thomas, A., Kovacevic, S.D., Strasdat, M., Behrouzi, T., Zollmann, F.S., Paul, M., Orzechowski, H.D. FASEB J. (2003) [Pubmed]
  9. Molecular mechanism of cardiac hypertrophy and development. Komuro, I. Jpn. Circ. J. (2001) [Pubmed]
  10. Stem cell differentiation requires a paracrine pathway in the heart. Behfar, A., Zingman, L.V., Hodgson, D.M., Rauzier, J.M., Kane, G.C., Terzic, A., Pucéat, M. FASEB J. (2002) [Pubmed]
 
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