Ménage-à-Trois 1 Is Critical for the Transcriptional Function of PPARγ Coactivator 1

Motoaki Sano, 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

Research output: Contribution to journalArticle

45 Citations (Scopus)

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 γ 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-1α failed to activate PGC-1-responsive promoters and nuclear receptors, GAL4-PGC-1α was functionally defective, and PGC-1β 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.

Original languageEnglish
Pages (from-to)129-142
Number of pages14
JournalCell Metabolism
Volume5
Issue number2
DOIs
Publication statusPublished - 2007 Feb 7
Externally publishedYes

Keywords

  • HUMDISEASE

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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    Sano, M., Izumi, Y., Helenius, K., Asakura, M., Rossi, D. J., Xie, M., Taffet, G., Hu, L., Pautler, R. G., Wilson, C. R., Boudina, S., Abel, E. D., Taegtmeyer, H., Scaglia, F., Graham, B. H., Kralli, A., Shimizu, N., Tanaka, H., Mäkelä, T. P., & Schneider, M. D. (2007). Ménage-à-Trois 1 Is Critical for the Transcriptional Function of PPARγ Coactivator 1. Cell Metabolism, 5(2), 129-142. https://doi.org/10.1016/j.cmet.2007.01.003