RGD Reference Report - Activation of cardiac Cdk9 represses PGC-1 and confers a predisposition to heart failure. - Rat Genome Database

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

Authors: Sano, M  Wang, SC  Shirai, M  Scaglia, F  Xie, M  Sakai, S  Tanaka, T  Kulkarni, PA  Barger, PM  Youker, KA  Taffet, GE  Hamamori, Y  Michael, LH  Craigen, WJ  Schneider, MD 
Citation: Sano M, etal., EMBO J 2004 Sep 1;23(17):3559-69. Epub 2004 Aug 5.
RGD ID: 1556509
Pubmed: PMID:15297879   (View Abstract at PubMed)
PMCID: PMC516624   (View Article at PubMed Central)
DOI: DOI:10.1038/sj.emboj.7600351   (Journal Full-text)

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.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
CCNT1Humancongestive heart failure  ISORGD:1322458 RGD 
CDK9Humancongestive heart failure  ISORGD:1552365protein:increased activity:heart:RGD 
CDK9Humancongestive heart failure  IEP protein:increased activity:ventricle:RGD 
Ccnt1Ratcongestive heart failure  ISORGD:1322458 RGD 
Ccnt1Mousecongestive heart failure  IMP  RGD 
Cdk9Ratcongestive heart failure  ISORGD:1346548protein:increased activity:ventricle:RGD 
Cdk9Ratcongestive heart failure  ISORGD:1552365protein:increased activity:heart:RGD 
Cdk9Mousecongestive heart failure  ISORGD:1346548protein:increased activity:ventricle:RGD 
Cdk9Mousecongestive heart failure  IEP protein:increased activity:heart:RGD 

Objects Annotated

Genes (Rattus norvegicus)
Ccnt1  (cyclin T1)
Cdk9  (cyclin-dependent kinase 9)

Genes (Mus musculus)
Ccnt1  (cyclin T1)
Cdk9  (cyclin dependent kinase 9)

Genes (Homo sapiens)
CCNT1  (cyclin T1)
CDK9  (cyclin dependent kinase 9)


Additional Information