A ternary complex of transcription factors, Nished and NFATc4, and co-activator p300 bound to an intronic sequence, intronic regulatory element, is pivotal for the up-regulation of myosin light chain-2v gene in cardiac hypertrophy

作者：Mathew S; Mascareno E; Siddiqui MAQ^*

来源：JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279(39): 41018-41027.

DOI：10.1074/jbc.M403578200

Transcriptional up-regulation of the myosin light chain-2 (MLC-2v) gene is an established marker for hypertrophic response in cardiomyocytes. Despite the documentation on the role of several cis-elements in the MLC-2v gene and their cognate proteins in transcription, the mechanism that dictates the preferential increase in MLC-2v gene expression during myocardial hypertrophy has not been delineated. Here we describe the properties of a cardiac specific intronic activator element ( IRE) that shares sequence homology with the repressor element, the cardiac specific sequence, in the chicken MLC-2v gene. The transcription factor, Nished, that recognizes both IRE and the cardiac specific sequence potentiates the transcription of the MLC-2v gene via interaction with another transcription factor, nuclear factor of activated T cells, and the co-activator p300 at the IRE site. Angiotensin II (Ang II), a potent agonist of hypertrophy, causes induction of the MLC-2v gene transcription, which correlates well with the enhanced binding of Nished-nuclear factor of the activated T cells-p300 complex to IRE in the gel mobility shift assay. Losartan, an antagonist of Ang II receptor (AT(1)), abolishes the agonist-dependent stimulation of IRE/protein interaction and the consequent increase in MLC-2v gene transcription. These results together have thus established a transcriptional role of IRE as a direct target sequence of Ang II-mediated signaling that appears to be pivotal in the mechanism underlying the up-regulation of the MLC-2v gene during cardiac hypertrophy.

• 出版日期2004-9-24