Ménage-à-Trois 1 Is Critical for the Transcriptional Function of PPARγ Coactivator 1
| Autor: | Tomi P. Mäkelä, Michael D. Schneider, Brett H. Graham, Derrick J. Rossi, Motoaki Sano, Min Xie, Fernando Scaglia, Noriaki Shimizu, Katja Helenius, Heinrich Taegtmeyer, Yasukatsu Izumi, Christopher R. Wilson, Lingyun Hu, E. Dale Abel, George E. Taffet, Robia G. Pautler, Sihem Boudina, Masanori Asakura, Anastasia Kralli, Hirotoshi Tanaka |
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| Rok vydání: | 2007 |
| Předmět: |
Cyclin H
Transcription Genetic Cell Survival Physiology HUMDISEASE Apoptosis Cell Cycle Proteins Biology Mice 03 medical and health sciences Discoidin Domain Receptor 1 Coactivator Animals RNA Messenger Phosphorylation Receptor Molecular Biology 030304 developmental biology 0303 health sciences General transcription factor Myocardium 030302 biochemistry & molecular biology Membrane Proteins Receptor Protein-Tyrosine Kinases Herpes Simplex Virus Protein Vmw65 Promoter Cell Biology Molecular biology Cyclin-Dependent Kinases Mitochondria Amino Acid Transport Systems Neutral Gene Expression Regulation Receptors Estrogen Nuclear receptor Transcription factor II H Cyclin-dependent kinase 7 Cardiomyopathies Gene Deletion Protein Binding Transcription Factors |
| Zdroj: | Cell Metabolism. 5:129-142 |
| ISSN: | 1550-4131 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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