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Department of Cell Biology Faculty
M.A.Q. Siddiqui, PH.D.
Professor and Chairman
Department of Cell Biology, Box 5
Tel: (718) 270-1014 • Fax: (718) 270-3732
Signaling Mechanisms and Transcriptional Adaptation in Heart Development and Disease
The research in our laboratory is focused on investigation of the molecular mechanisms underlying the heart development and disease. We have identified a novel regulatory factor called Cardiac Lineage Protein – 1 (CLP-1) that plays a critical role in myogenic development. CLP-1 is expressed very early, prior to cardiac fate assignment, in development and its expression, based on in situ hybridization, coincides remarkably well with the established morphogenetic field of early heart formation. To test the postulate that CLP-1 is a regulator of cardiac gene expression, we ablated the CLP-1 gene in mice. The CLP null mice fetal hearts exhibit a reduced left ventricular chamber with increased myocardial wall thickness. Analysis of contractile and non-contractile protein genes known to be re-expressed during cardiac hypertrophy showed them to have higher expression levels in CLP-1 -/- hearts. The expression of HAND-1 transcription factor, a gene involved in morphogenesis of left ventricular chamber and down-regulated in hypertrophic hearts, was also significantly reduced. CLP-1 and HAND-1 have similar expression patterns in the developing ventricles suggesting that CLP-1 and HAND-1 are part of a genetic program critical to proper heart development, perturbation of which leads to cardiomyopathy.
We further observed that the expression pattern of CLP-1 in developing heart is consistent with its role in controlling RNA transcript elongation by transcriptional elongation factor (p-TEFb). CLP-1 is expressed and co-localized along with the components of p-TEFb complex in developing heart during the period in which the knockout mice lacking the CLP-1 gene develop cardiac hypertrophy. Under conditions of hypertrophy induced by mechanical stretch or agonists treatment CLP-1 dissociates from p-TEFb complex, a finding consistent with the de-repression of p-TEFb kinase activity seen in hypertrophic cardiomyocytes. Blockage of Jak/STAT signaling pathway prevented release of CLP from the p-TEFb despite on going presence of hypertrophic stimulation by mechanical stretch. Our studies suggest that the signaling rendered by the Jak/STAT pathway constitute an essential step in modulation of the transcriptional machinery essential for development of various pathologies associated with hypertrophy. Jak2 kinase plays an important role in left ventricular remodeling during pressure overload hypertrophy. Pharmacological inhibition of Jak2 kinase during pressure overload blocks the development of hypertrophy. We conclude that the dissociation of CLP-1 from p-TEFb complex is responsive to hypertrophic stimuli transduced by cellular signaling transduction pathways which may be a part of the genomic stress response resulting in increased RNA transcript synthesis, the hallmark of hypertrophy in cardiomyocytes.
SELECTED RECENT PUBLICATIONS
Huang, F., Wagner, M., and Siddiqui, M.A.Q. Expression and functional characterization of the mouse CLP-1 gene. Gene 202, 245-259, 2002.
Guo, Y., Mascareno, E. and Siddiqui, M.A.Q. Distinct Components of Jak/Stat Signaling Pathway Mediate the Regulation of Systemic and Tissue-Localized Renin-Angiotensin System. J. Mol. Endocrinol. 18, 2033-2041, 2004.
Huang, F., Wagner, M., and Siddiqui, M.A.Q. Ablation of the CLP-1 Gene Leads to Down-Regulation of the HAND1 Gene and Abnormality of the Left Ventricle of the Heart and Fetal Death. Mech. Develop. 121, 559-572, 2004.
Mathew, S., Mascareno, E., and Siddiqui, M.A.Q. 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. J. Biol. Chem. 279, 41018-41027, 2004.
Mascareno, E., Beckles, D., and Siddiqui, M.A.Q. Janus Kinase-2 signaling mediates apoptosis in rat cardiomyocytes. Vascular Pharm. 43, 327-335, 2005.
Beckles, D., Mascareno, E., and Siddiqui, M.A.Q. Inhibition of Jak2 phosphorylation attenuates pressure-overload cardiac hypertrophy. J. Vascul. Pharm. 45, 350-357, 2006.
Espinoza-Derout, J., Shahmiri, K., Wagner, M., Mascareno, E., Chaqour, B., and Siddiqui, M.A.Q. Pivotal role of cardiac lineage protein-1 (CLP-1) in transcription elongation factor pTEFb complex formation in cardiac hypertrophy. Cardiovas. Res. 75, 129-138, 2007.