Endothelin-converting enzyme-1 (ECE-1) is a downstream target of the homeobox transcription factor Nkx2-5
| Autor: | H, Funke-Kaiser, J, Lemmer, C V, Langsdorff, A, Thomas, S D, Kovacevic, M, Strasdat, T, Behrouzi, F S, Zollmann, M, Paul, H-D, Orzechowski |
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| Rok vydání: | 2003 |
| Předmět: |
Homeodomain Proteins
Transcriptional Activation Binding Sites Models Genetic Metalloendopeptidases Endothelin-Converting Enzymes Xenopus Proteins Chromatin Cell Line Rats Enzyme Induction Consensus Sequence Homeobox Protein Nkx-2.5 Animals Aspartic Acid Endopeptidases Protein Isoforms Promoter Regions Genetic Myoblasts Cardiac Transcription Factors |
| Zdroj: | FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 17(11) |
| ISSN: | 1530-6860 |
| Popis: | The homeobox transcription factor Nkx2-5 and the zinc metalloprotease endothelin-converting enzyme-1 (ECE-1) are essential for cardiac development. Here, we demonstrate for the first time a functional link between Nkx2-5 and ECE-1. In transiently transfected rat H9c2 cardiomyoblasts, the alternative promoters specific for ECE-1a, ECE-1b, and ECE-1c are activated by Nkx2-5 coexpression. 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. Furthermore, we have evidence of an additional direct activation mechanism of the ECE-1b promoter by 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. The interaction presented in this work provides a possible explanation for distinct phenotypic aspects of patients carrying mutations in the Nkx2-5 gene and may also be of significance for the pathophysiology of heart failure. |
| Databáze: | OpenAIRE |
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