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.
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
UR - http://www.scopus.com/inward/record.url?scp=33846629472&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33846629472&partnerID=8YFLogxK
U2 - 10.1016/j.cmet.2007.01.003
DO - 10.1016/j.cmet.2007.01.003
M3 - Article
C2 - 17276355
AN - SCOPUS:33846629472
VL - 5
SP - 129
EP - 142
JO - Cell Metabolism
JF - Cell Metabolism
SN - 1550-4131
IS - 2
ER -