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J. Biol. Chem., Vol. 279, Issue 39, 41018-41027, September 24, 2004

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A Ternary Complex of Transcription Factors, Nishéd 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^*

Sumy Mathew, Eduardo Mascareno, and M. A. Q. Siddiqui

From the Department of Anatomy and Cell Biology, Center for Cardiovascular and Muscle Research, State University of New York Downstate Medical Center, Brooklyn, New York 11203

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, Nishéd, 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 Nishéd-nuclear factor of the activated T cells-p300 complex to IRE in the gel mobility shift assay. Losartan, an antagonist of Ang II receptor (AT₁), 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.

Received for publication, March 31, 2004 , and in revised form, June 7, 2004.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

These authors contributed equally to this work.

To whom correspondence should be addressed: Dept. of Anatomy and Cell Biology, Box 5, State University of New York Downstate Medical Center, 450 Clarkson Ave., Brooklyn, NY 11203. Tel.: 718-270-1014; Fax: 718-270-3732; E-mail: maq.siddiqui{at}downstate.edu.

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