TY - JOUR
T1 - Ménage-à-Trois 1 Is Critical for the Transcriptional Function of PPARγ Coactivator 1
AU - Sano, Motoaki
AU - Izumi, Yasukatsu
AU - Helenius, Katja
AU - Asakura, Masanori
AU - Rossi, Derrick J.
AU - Xie, Min
AU - Taffet, George
AU - Hu, Lingyun
AU - Pautler, Robia G.
AU - Wilson, Christopher R.
AU - Boudina, Sihem
AU - Abel, E. Dale
AU - Taegtmeyer, Heinrich
AU - Scaglia, Fernando
AU - Graham, Brett H.
AU - Kralli, Anastasia
AU - Shimizu, Noriaki
AU - Tanaka, Hirotoshi
AU - Mäkelä, Tomi P.
AU - Schneider, Michael D.
N1 - Funding Information:
We thank J. Robbins, F. Graham, R. Capaldi, J. Wong, P. Barger, D. Kelly, and B. Spiegelman for invaluable reagents; S. Wakil, N. Weigel, J. Wong, P. Barger, and T. Westerling for discussions; S. Wang, M. Shirai, M. Ramirez, Q. Xiang, I. Callahan, T. Pham, L. Shirley, and W. Boerwinkle for technical assistance; and the staff of Baylor's Microarray and Integrated Microscopy Core Facilities. This work was supported by NIH grants, the Fondation Leducq Transatlantic Network of Excellence for Cardiovascular Research, and the M.D. Anderson Foundation Professorship (M.D.S.).
PY - 2007/2/7
Y1 - 2007/2/7
N2 - 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.
AB - 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.
KW - HUMDISEASE
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U2 - 10.1016/j.cmet.2007.01.003
DO - 10.1016/j.cmet.2007.01.003
M3 - Article
C2 - 17276355
AN - SCOPUS:33846629472
SN - 1550-4131
VL - 5
SP - 129
EP - 142
JO - Cell Metabolism
JF - Cell Metabolism
IS - 2
ER -