Abstract
The Cdk7/cyclin H/ménage-à-trois 1 (MAT1) heterotrimer has proposed functions in transcription as the kinase component of basal transcription factor TFIIH and is activated in adult hearts by Gq-, calcineurin-, and biomechanical stress-dependent pathways for hypertrophic growth. Using cardiac-specific Cre, we have ablated MAT1 in myocardium. Despite reduced Cdk7 activity, MAT1-deficient hearts grew normally, but fatal heart failure ensued at 6-8 weeks. By microarray profiling, quantitative RT-PCR, and western blotting at 4 weeks, genes for energy metabolism were found to be suppressed selectively, including targets of peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1). Cardiac metabolic defects were substantiated in isolated perfused hearts and isolated mitochondria. In culture, deleting MAT1 with Cre disrupted PGC-1 function: PGC-1alpha failed to activate PGC-1-responsive promoters and nuclear receptors, GAL4-PGC-1alpha was functionally defective, and PGC-1beta was likewise deficient. PGC-1 bound to both MAT1 and Cdk7 in coprecipitation assays. Thus, we demonstrate a requirement for MAT1 in the operation of PGC-1 coactivators that control cell metabolism.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Transport Systems, Neutral / metabolism*
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Animals
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Apoptosis
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Cardiomyopathies / genetics
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Cardiomyopathies / pathology
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Cell Cycle Proteins
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Cell Survival
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Cyclin-Dependent Kinases / metabolism
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Discoidin Domain Receptor 1
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ERRalpha Estrogen-Related Receptor
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Gene Deletion
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Gene Expression Regulation
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Herpes Simplex Virus Protein Vmw65 / metabolism
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Membrane Proteins / metabolism
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Mice
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Mitochondria / metabolism
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Mitochondria / pathology
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Myocardium / enzymology
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Myocardium / pathology
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Phosphorylation
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Protein Binding
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Receptor Protein-Tyrosine Kinases / metabolism
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Receptors, Estrogen / metabolism
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Transcription Factors / genetics*
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Transcription Factors / metabolism
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Transcription, Genetic*
Substances
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Amino Acid Transport Systems, Neutral
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Cell Cycle Proteins
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Herpes Simplex Virus Protein Vmw65
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Membrane Proteins
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Mnat1 protein, mouse
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RNA, Messenger
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Receptors, Estrogen
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Transcription Factors
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peroxisome-proliferator-activated receptor-gamma coactivator-1
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Ddr1 protein, mouse
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Discoidin Domain Receptor 1
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Receptor Protein-Tyrosine Kinases
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Cyclin-Dependent Kinases
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cyclin-dependent kinase 7, mouse