Endothelin-converting enzyme-1 is a downstream target of the homeobox transcription factor Nkx2-5

被引：12

作者：

Funke-Kaiser, H ^{[1
]}

Lemmer, J ^{[1
]}

Langsdorff, CV ^{[1
]}

Thomas, A ^{[1
]}

Kovacevic, SD ^{[1
]}

Strasdat, M ^{[1
]}

Behrouzi, T ^{[1
]}

Zollmann, FS ^{[1
]}

Paul, M ^{[1
]}

Orzechowski, HD ^{[1
]}

机构：

[1] Free Univ Berlin, Benjamin Franklin Med Ctr, Dept Clin Pharmacol, Inst Clin Pharmacol & Toxicol, D-12200 Berlin, Germany

来源：

FASEB JOURNAL | 2003年 / 17卷 / 09期

关键词：

Nkx2-5; ECE-1; heart development; alternative promoters; gene regulation;

D O I：

10.1096/fj.02-0700fje

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 [生物化学与分子生物学]; 081704 [应用化学];

摘要：

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.

引用

页码：1487 / +

页数：26

共 57 条

[1]

Regulation of gene expression by alternative promoters [J].