| First Author | Sano M | Year | 2004 |
| Journal | EMBO J | Volume | 23 |
| Issue | 17 | Pages | 3559-69 |
| PubMed ID | 15297879 | Mgi Jnum | J:93118 |
| Mgi Id | MGI:3055997 | Doi | 10.1038/sj.emboj.7600351 |
| Citation | Sano M, et al. (2004) Activation of cardiac Cdk9 represses PGC-1 and confers a predisposition to heart failure. EMBO J 23(17):3559-69 |
| abstractText | 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. |
