| Literature DB >> 17276355 |
Motoaki Sano1, Yasukatsu Izumi, Katja Helenius, Masanori Asakura, Derrick J Rossi, Min Xie, George Taffet, Lingyun Hu, Robia G Pautler, Christopher R Wilson, Sihem Boudina, E Dale Abel, Heinrich Taegtmeyer, Fernando Scaglia, Brett H Graham, Anastasia Kralli, Noriaki Shimizu, Hirotoshi Tanaka, Tomi P Mäkelä, Michael D Schneider.
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.Entities:
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Year: 2007 PMID： 17276355 DOI： 10.1016/j.cmet.2007.01.003
Source DB: PubMed Journal: Cell Metab ISSN： 1550-4131 Impact factor: 27.287