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CDK9 and its repressor LARP7 modulate cardiomyocyte proliferation and response to injury in the zebrafish heart

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    Rights statement: © 2015. Published by The Company of Biologists Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

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Original languageEnglish
Pages (from-to)4560-71
JournalJournal of Cell Science
Volume128
Issue number24
DOIs
Publication statusPublished - 5 Nov 2015

Abstract

Cyclin Dependent Kinase (CDK)9 acts via the Positive Transcription Elongation Factor-b (P-TEFb) complex to activate and expand transcription via RNA polymerase II (RNApol II). It has also been shown to regulate cardiomyocyte hypertrophy with recent evidence linking it to cardiomyocyte proliferation. We hypothesised that modification of CDK9 activity could both impair and enhance the cardiac response to injury by modifying cardiomyocyte proliferation.CDK9 expression and activity were inhibited in the zebrafish (Danio rerio) embryo. We show that dephosphorylation of the Serine2 residue on the Carboxy-Terminal domain of RNApol II (Ser2-RNApol II-CTD) is associated with impaired cardiac structure, function and cardiomyocyte proliferation and also results in impaired functional recovery following cardiac laser injury. In contrast, de-repression of CDK9 activity, by knockdown of La-related protein (LARP7) increases phosphorylation of Ser2-RNApol II-CTD and increases cardiomyocyte proliferation. LARP7 knockdown rescued the structural and functional phenotype associated with knockdown of CDK9.CDK9/LARP7-balance plays a key role in cardiomyocyte proliferation and response to injury. LARP7 represents a potentially novel therapeutic target in promoting cardiomyocyte proliferation and recovery from injury.

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