Activation of cardiac Cdk9 represses PGC-1 and confers a predisposition to heart failure.

Abstract

Hypertrophy allows the heart to adapt to workload but culminates in later pump failure; how it is achieved remains uncertain. Previously, we showed that hypertrophy is accompanied by activation of cyclin T/Cdk9, which phosphorylates the C-terminal domain of the large subunit of RNA polymerase II, stimulating transcription elongation and pre-mRNA processing; Cdk9 activity was required for hypertrophy in culture, whereas heart-specific activation of Cdk9 by cyclin T1 provoked hypertrophy in mice. Here, we report that alphaMHC-cyclin T1 mice appear normal at baseline yet suffer fulminant apoptotic cardiomyopathy when challenged by mechanical stress or signaling by the G-protein Gq. At pathophysiological levels, Cdk9 activity suppresses many genes for mitochondrial proteins including master regulators of mitochondrial function (peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1), nuclear respiratory factor-1). In culture, cyclin T1/Cdk9 suppresses PGC-1, decreases mitochondrial membrane potential, and sensitizes cardiomyocytes to apoptosis, effects rescued by exogenous PGC-1. Cyclin T1/Cdk9 inhibits PGC-1 promoter activity and preinitiation complex assembly. Thus, chronic activation of Cdk9 causes not only cardiomyocyte enlargement but also defective mitochondrial function, via diminished PGC-1 transcription, and a resulting susceptibility to apoptotic cardiomyopathy.

• Authors: Motoaki Sano, Sam C Wang, Manabu Shirai, Fernando Scaglia, Min Xie, Satoshi Sakai, Toru Tanaka, Prathit A Kulkarni, Philip M Barger, Keith A Youker, George E Taffet, Yasuo Hamamori, Lloyd H Michael, William J Craigen, Michael D Schneider
• Journal: The EMBO journal (EMBO J) Vol. 23 Issue 17 Pg. 3559-69 (Sep 01 2004) ISSN: 0261-4189 [Print] England
• PMID: 15297879 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• CCNT1 protein, human
• Ccnt1 protein, mouse
• Ccnt1 protein, rat
• Cyclin T
• Cyclins
• DNA-Binding Proteins
• NF-E2-Related Factor 1
• NRF1 protein, human
• Nfe2l1 protein, rat
• Nrf1 protein, mouse
• Nuclear Respiratory Factor 1
• Nuclear Respiratory Factors
• Trans-Activators
• Transcription Factors
• peroxisome-proliferator-activated receptor-gamma coactivator-1
• Cdk9 protein, mouse
• Cyclin-Dependent Kinase 9
• RNA Polymerase II

Topics

• Animals
• Apoptosis
• Cells, Cultured
• Cyclin T
• Cyclin-Dependent Kinase 9 (metabolism)
• Cyclins (metabolism)
• DNA-Binding Proteins (genetics, metabolism)
• Enzyme Activation
• Gene Expression
• Heart Failure (etiology, genetics, metabolism)
• Humans
• Mice
• Myocardium (metabolism)
• Myocytes, Cardiac (metabolism, pathology)
• NF-E2-Related Factor 1
• Nuclear Respiratory Factor 1
• Nuclear Respiratory Factors
• Promoter Regions, Genetic
• RNA Polymerase II (metabolism)
• Rats
• Trans-Activators (genetics, metabolism)
• Transcription Factors (genetics, metabolism)
• Transcription, Genetic