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.
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.
Mathew
Sumy
S
Department of Anatomy and Cell Biology, Center for Cardiovascular and Muscle Research, State University of New York Downstate Medical Center, Brooklyn, New York 11203, USA.
Mascareno
Eduardo
E
Siddiqui
M A Q
MA
D000595:Amino Acid Sequence; D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D001667:Binding, Competitive; D015152:Blotting, Northern; D015153:Blotting, Western; D024722:Cardiac Myosins / Q000737:chemistry*; D006332:Cardiomegaly; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D002642:Chick Embryo; D004247:DNA / Q000737:chemistry; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D015723:Gene Library; D017930:Genes, Reporter; D007438:Introns; D008156:Luciferases / Q000378:metabolism; D008957:Models, Genetic; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000378:metabolism; D018994:Myosin Light Chains / Q000737:chemistry*; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins / Q000502:physiology*; D009841:Oligonucleotides / Q000737:chemistry; D011233:Precipitin Tests; D011485:Protein Binding; D012313:RNA / Q000737:chemistry; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism / Q000502:physiology*; D013601:T-Lymphocytes / Q000378:metabolism; D015534:Trans-Activators / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic; D014162:Transfection; D015854:Up-Regulation
D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D018994:Myosin Light Chains; D050778:NFATC Transcription Factors; C107185:Nished protein, Gallus gallus; D009687:Nuclear Proteins; D009841:Oligonucleotides; D012333:RNA, Messenger; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C107184:myosin light chain 2; D000804:Angiotensin II; D012313:RNA; D004247:DNA; D008156:Luciferases; D024722:Cardiac Myosins