Ménage-à-trois 1 is critical for the transcriptional function of PPARgamma coactivator 1.
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.
Sano
Motoaki
M
Center for Cardiovascular Development, Baylor College of Medicine, Houston, TX 77030, USA.
Izumi
Yasukatsu
Y
Helenius
Katja
K
Asakura
Masanori
M
Rossi
Derrick J
DJ
Xie
Min
M
Taffet
George
G
Hu
Lingyun
L
Pautler
Robia G
RG
Wilson
Christopher R
CR
Boudina
Sihem
S
Abel
E Dale
ED
Taegtmeyer
Heinrich
H
Scaglia
Fernando
F
Graham
Brett H
BH
Kralli
Anastasia
A
Shimizu
Noriaki
N
Tanaka
Hirotoshi
H
Mäkelä
Tomi P
TP
Schneider
Michael D
MD
D026921:Amino Acid Transport Systems, Neutral / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D009202:Cardiomyopathies / Q000235:genetics / Q000473:pathology; D018797:Cell Cycle Proteins; D002470:Cell Survival; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D000070819:Discoidin Domain Receptor 1; D017353:Gene Deletion; D005786:Gene Expression Regulation; D017405:Herpes Simplex Virus Protein Vmw65 / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D010766:Phosphorylation; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D000097983:ERRalpha Estrogen-Related Receptor
D026921:Amino Acid Transport Systems, Neutral; D018797:Cell Cycle Proteins; D018844:Cyclin-Dependent Kinases; D000070819:Discoidin Domain Receptor 1; D017405:Herpes Simplex Virus Protein Vmw65; D008565:Membrane Proteins; D012333:RNA, Messenger; D020794:Receptor Protein-Tyrosine Kinases; D011960:Receptors, Estrogen; D014157:Transcription Factors; D000097983:ERRalpha Estrogen-Related Receptor; C432410:Mnat1 protein, mouse; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; C083249:Ddr1 protein, mouse; C090586:Cdk7 protein, mouse