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

Gianfranco Matrone, Kathryn S Wilson, Sana Maqsood, John J Mullins, Carl S Tucker, Martin A Denvir

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Cyclin dependent kinase (Cdk)9 acts through the positive transcription elongation factor-b (P-TEFb) complex to activate and expand transcription through RNA polymerase 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 residue Ser2 on the C-terminal domain of RNA polymerase II is associated with impaired cardiac structure and function, and cardiomyocyte proliferation and also results in impaired functional recovery following cardiac laser injury. In contrast, de-repression of Cdk9 activity, through knockdown of La-related protein (Larp7) increases phosphorylation of Ser2 in RNA polymerase II and increases cardiomyocyte proliferation. Larp7 knockdown rescued the structural and functional phenotype associated with knockdown of Cdk9. The balance of Cdk9 and Larp7 plays a key role in cardiomyocyte proliferation and response to injury. Larp7 represents a potentially novel therapeutic target to promote cardiomyocyte proliferation and recovery from injury.

Original languageEnglish (US)
Pages (from-to)4560-71
Number of pages12
JournalJournal of Cell Science
Volume128
Issue number24
DOIs
StatePublished - Dec 15 2015

Keywords

  • Animals
  • Cell Proliferation
  • Cyclin-Dependent Kinase 9
  • Heart Injuries
  • Myocytes, Cardiac
  • RNA Polymerase II
  • Ribonucleoproteins
  • Zebrafish
  • Zebrafish Proteins
  • Journal Article
  • Research Support, Non-U.S. Gov't

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