Pivotal role of cardiac lineage protein-1 (CLP-1) in transcriptional elongation factor P-TEFb complex formation in cardiac hypertrophy

Abstract

CLP-1 expression in developing heart and isolated post-natal cardiomyocytes colocalizes with P-TEFb expression and therefore has the potential to regulate RNA transcript elongation by controlling P-TEFb cdk9 kinase activity in heart. We further conclude that the dissociation of CLP-1 from P-TEFb is responsive to hypertrophic stimuli transduced by cellular signal transduction pathways. This process may be part of the genomic stress response resulting in increased RNA transcript synthesis in hypertrophic cardiomyocytes.

BET acetyl-lysine binding proteins control pathological cardiac hypertrophy

“…P-TEFb is a complex containing cyclin-dependent kinase 9 (CDK9) and cyclin T, which is able to phosphorylate the carboxy-terminal domain (CTD) of RNA polymerase II (RNA pol II) and thereby stimulate transcription elongation. P-TEFb and its negative regulators, 7SK RNA and Hexim/CLP-1, have all been shown to regulate cardiac hypertrophy [9–12]. Using the ANF promoter as a prototype, we tested the hypothesis that BRD4 is recruited to target genes and regulates RNA pol II phosphorylation in response to hypertrophic stimuli.…”

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

“…Jak2 is also known to promote ROS production and ECM deposition (26). Although the precise nature of the cross-talk between these signaling events is not known, the regulation of the P-TEFb complex by Jak2 signaling was previously described (14), suggesting perhaps that the modulation of the hypertrophic features observed in ␣MHC-ANG/CLP-1 ϩ/Ϫ hearts is the consequence of enhanced Jak2 function. Precedent also exists for Jak2/Stat3 signaling to undergo functional association with a number of regulatory proteins (27,28).…”

“…CLP-1, the mouse homolog of human hexamethylene bis-acetamide inducible 1 (HEXIM-1), regulates pTEFb activity via its dynamic association/dissociation with pTEFb causing inhibition/activation of Cdk9-mediated serine 2 phosphorylation in the carboxyl-terminal domain of RNA polymerase II. We previously reported that the "on" and "off" association of CLP-1 with pTEFb is Jak2-dependent (14), a phenomenon that is paramount to control of hypertrophic growth (14 -17). More recently, it was reported that the serine kinase activity of Cdk9 not only targets RNA polymerase II but also the conserved serine residues of the polylinker region in Smad3 (18), leading to speculation that CLP-1-mediated changes in pTEFb activity may trigger Cdk9-dependent Smad3 signaling that can modulate collagen expression and fibrosis.…”

7SK RNA, a non-coding RNA regulating P-TEFb, a general transcription factor

“…15 This dissociation is blocked in rat cardiomyocytes by the tyrphostin AG490 tyrosine kinase inhibitor of Jak/Stat activation. 74 7SK RNA, a non-coding RNA regulating P-TEFb www.landesbioscience.com RNA Biologyis one of the first case of RNA/protein couple reported to control eukaryotic transcription. 85 Subsequent discovery that Tat, bound to TAR interacts specifically with P-TEFb through human Cyclin T1 was a landmark to account for HIV transcription regulation.…”