Positive Transcription Elongation Factor b Activity in Compensatory Myocardial Hypertrophy is Regulated by Cardiac Lineage Protein-1

Department of Anatomy and Cell Biology, State University of New York Downstate Medical Center, 450 Clarkson Ave, Brooklyn, NY 11203, USA.
Circulation Research (Impact Factor: 11.09). 06/2009; 104(12):1347-54. DOI: 10.1161/CIRCRESAHA.108.191726
Source: PubMed

ABSTRACT Emerging evidence illustrates the importance of the positive transcription elongation factor (P-TEF)b in control of global RNA synthesis, which constitutes a major feature of the compensatory response to diverse hypertrophic stimuli in cardiomyocytes. P-TEFb complex, composed of cyclin T and cdk9, is critical for elongation of nascent RNA chains via phosphorylation of the carboxyl-terminal domain of RNA polymerase (Pol) II. We and others have shown that the activity of P-TEFb is inhibited by its association with cardiac lineage protein (CLP)-1, the mouse homolog of human HEXIM1, in various physiological and pathological conditions. To investigate the mechanism of control of P-TEFb activity by CLP-1 in cardiac hypertrophy, we used a transgenic mouse model of hypertrophy caused by overexpression of calcineurin in the heart. We observed that the level of CLP-1 associated with P-TEFb was reduced markedly in hypertrophic hearts. We also generated bigenic mice (MHC-cyclin T1/CLP-1(+/-)) by crossing MHC-cyclin T1 transgenic mice with CLP-1 heterozygote. The bigenic mice exhibit enhanced susceptibility to hypertrophy that is accompanied with an increase in cdk9 activity via an increase in serine 2 phosphorylation of carboxyl-terminal domain and an increase in GLUT1/GLUT4 ratio. These mice have compensated systolic function without evidence of fibrosis and reduced lifespan. These data suggest that the reduced level of CLP-1 introduced in the background of elevated levels of cyclin T1 elevates derepression of P-TEFb activity and emphasizes the importance of the role of CLP-1 in the mechanism governing compensatory hypertrophy in cardiomyocytes.

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Available from: Eduardo Mascareno, Jun 05, 2014
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    • "HEXIM1 knockout mice exhibited LV hypertrophy during the late stages of fetal development, whereas heart-specific activation of P-TEFb provoked LV hypertrophy in mice [13] [14]. The genetic reduction of HEXIM1 in the background of elevated levels of CycT1 derepresses P-TEFb activity, emphasizing the importance of the role of HEXIM1 in the mechanism governing cardiac hypertrophy [15]. Recently, we also revealed that HEXIM1 suppressed endothelin-1 (ET-1)- induced myocyte growth and RV hypertrophy in hypoxia-induced PH model mice [16]. "
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    ABSTRACT: Pulmonary hypertension (PH) sustains elevation of pulmonary vascular resistance and ultimately leads to right ventricular (RV) hypertrophy and failure and death. Recently, proangiogenic factors hypoxia-inducible factor-1 alpha (HIF-1a) and vascular endothelial growth factor (VEGF) have been known to promote left ventricular myocardial angiogenesis and lead to cardiac hypertrophy, and this would be involved in RV hypertrophy of PH patients. Previously, we revealed that overexpression of HEXIM1 prevents endothelin-1-induced cardiomyocyte hypertrophy and hypertrophic genes expression, and that cardiomyocyte-specific HEXIM1 transgenic mice ameliorates RV hypertrophy in hypoxia-induced PH model. Given these results, here we analyzed the effect of HEXIM1 on the expression of HIF-1α and VEGF and on myocardial angiogenesis of RV in PH. We revealed that overexpression of HEXIM1 prevented hypoxia-induced expression of HIF-1α protein and its target genes including VEGF in the cultured cardiac myocytes and fibroblasts, and that cardiomyocyte-specific HEXIM1 transgenic mice repressed RV myocardial angiogenesis in hypoxia-induced PH model. Thus, we conclude that HEXIM1 could prevent RV hypertrophy, at least in part, via suppression of myocardial angiogenesis through down-regulation of HIF-1α and VEGF in the myocardium under hypoxic condition.
    Biochemical and Biophysical Research Communications 10/2014; 453(3). DOI:10.1016/j.bbrc.2014.09.135 · 2.28 Impact Factor
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    • "larly important to support transcriptional program that meets the heightened needs of energy production in the myocardium. Deregulation of transcriptional elongation has been previously implicated in pathologic cardiac hypertrophy (Anand et al., 2013; Espinoza-Derout et al., 2009; Sano et al., 2002). The link between energy metabolism and NELF raises the distinct possibility that pharmacological agents aimed at enhancing Pol II pausing may overcome stress-triggered metabolic deficiency and cardiac abnormality in humans. "
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    ABSTRACT: Negative elongation factor (NELF) is known to enforce promoter-proximal pausing of RNA polymerase II (Pol II), a pervasive phenomenon observed across multicellular genomes. However, the physiological impact of NELF on tissue homeostasis remains unclear. Here, we show that whole-body conditional deletion of the B subunit of NELF (NELF-B) in adult mice results in cardiomyopathy and impaired response to cardiac stress. Tissue-specific knockout of NELF-B confirms its cell-autonomous function in cardiomyocytes. NELF directly supports transcription of those genes encoding rate-limiting enzymes in fatty acid oxidation (FAO) and the tricarboxylic acid (TCA) cycle. NELF also shares extensively transcriptional target genes with peroxisome proliferator-activated receptor α (PPARα), a master regulator of energy metabolism in the myocardium. Mechanistically, NELF helps stabilize the transcription initiation complex at the metabolism-related genes. Our findings strongly indicate that NELF is part of the PPARα-mediated transcription regulatory network that maintains metabolic homeostasis in cardiomyocytes.
    Cell Reports 03/2014; 7(1). DOI:10.1016/j.celrep.2014.02.028 · 8.36 Impact Factor
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    • "In addition, two other proteins, MePCE and LARP7 are required for the stabilization of the complex by inhibiting degradation of the 7SK RNA (Krueger et al., 2008). Complex formation is fully reversible: its dissociation results in a burst of Cdk9 activity under conditions of stress, UV irradiation, mechanical load, and pharmacological treatments by " hypertrophic agonists " such as endothelin-1, phenylephrine, calcineurin (Nguyen et al., 2001; Sano et al., 2002; Espinoza-Derout et al., 2009). As one additional enzyme was found associated with 7SK complexes (He et al., 2006), one may consider a more general type of regulation by the means of readily reversible inhibition of enzyme activity in complexes with inhibitory proteins mediated by non-coding RNAs. "
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    ABSTRACT: Part of the heterodimeric P-TEF-b element of the Pol II transcription machinery, the cyclin-dependent kinase 9 plays a critical role in gene expression. Phosphorylation of several residues in the polymerase is required for elongation of transcript. It determines the rates of transcription and thus, plays a critical role in several differentiation pathways, best documented in heart development. The synthesis and activity of the protein are tightly regulated in a coordinated manner by at least three non-coding RNAs. First, its kinase activity is reversibly inhibited by formation of a complex with the 334 nt 7SK RNA, from which it is released under conditions of stress. Then, heart development requires a maximal rate of synthesis during cardiomyocyte differentiation, followed by a decrease in the differentiated state. The latter is insured by microRNA-mediated translational inhibition. In a third mode of RNA control, increased levels of transcription are induced by small non-coding RNA molecules with sequences homologous to the transcript. Designated paramutation, this epigenetic variation, stable during development, and hereditarily transmitted in a non-Mendelian manner over several generations, is thought to be a response to the inactivation of one of the two alleles by an abnormal recombination event such as insertion of a transposon.
    Frontiers in Genetics 12/2011; 2:95. DOI:10.3389/fgene.2011.00095
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