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

Abstract

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.

BET Bromodomains Mediate Transcriptional Pause Release in Heart Failure

“…Hyper-activation of P-TEFb and consequent increases in global transcription are considered a hallmark of pathologic cardiac hypertrophy in multiple systems (Espinoza-Derout et al, 2009; Sano et al, 2002; Yoshikawa et al, 2012). Inhibition of CDK9 function in NRVM has been shown to attenuate endothelin-1 mediated hypertrophy in vitro (Sano et al, 2002).…”

Cardiac Lineage Protein-1 (CLP-1) Regulates Cardiac Remodeling via Transcriptional Modulation of Diverse Hypertrophic and Fibrotic Responses and Angiotensin II-transforming Growth Factor β (TGF-β1) Signaling Axis

“…Overexpression of CyclinT1, the Cdk9 kinase partner protein in the P-TEFb complex, has been shown to potentiate cardiac hypertrophy suggesting that CyclinT1 is limiting for activation of P-TEFb activity (15,16). We examined the protein levels of CyclinT1 in Western blot that show an increase in ␣MHC-ANG/CLP-1 ϩ/Ϫ transgene as compared with the wild type hearts without overexpression of ANG ( Fig.…”

Concise synthesis and CDK/GSK inhibitory activity of the missing 9-azapaullones

“…A variant of this synthetic strategy was then used to prepare the hitherto unreported 9-azapaullone (6), in addition to its N-benzyl salt 7a and N-oxide derivative 7b. A study to evaluate the inhibitory activity of these compounds against a range of kinases indentified 7b as a selective inhibitor of CDK9/cyclin T. The potential significance of the function of CDK9/cyclin T in a range of medicinally relevant domains such as cellcycle/transcription regulation, 4,8,30 HIV-1 replication 31 and cardiovascular disease 32 is only beginning to be understood, thus the development of highly selective inhibitors of this complex is a goal of considerable interest. Studies aimed at increasing the potency of 7b and improving its ability to distinguish between CDK9/cyclin T and other kinases are underway.…”