Ménage-à-trois 1 is critical for the transcriptional function of PPARgamma coactivator 1

Cell Metab. 2007 Feb;5(2):129-42. doi: 10.1016/j.cmet.2007.01.003.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Transport Systems, Neutral / metabolism*
  • Animals
  • Apoptosis
  • Cardiomyopathies / genetics
  • Cardiomyopathies / pathology
  • Cell Survival
  • Cyclin-Dependent Kinases / metabolism
  • Discoidin Domain Receptor 1
  • Gene Deletion
  • Gene Expression Regulation
  • Herpes Simplex Virus Protein Vmw65 / metabolism
  • Membrane Proteins / metabolism
  • Mice
  • Mitochondria / metabolism
  • Mitochondria / pathology
  • Myocardium / enzymology
  • Myocardium / pathology
  • Phosphorylation
  • Protein Binding
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Receptors, Estrogen / metabolism
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Transcription, Genetic*

Substances

  • Amino Acid Transport Systems, Neutral
  • ERRalpha estrogen-related receptor
  • Herpes Simplex Virus Protein Vmw65
  • Membrane Proteins
  • Mnat1 protein, mouse
  • RNA, Messenger
  • Receptors, Estrogen
  • Transcription Factors
  • peroxisome-proliferator-activated receptor-gamma coactivator-1
  • Ddr1 protein, mouse
  • Discoidin Domain Receptor 1
  • Receptor Protein-Tyrosine Kinases
  • Cyclin-Dependent Kinases
  • cyclin-dependent kinase 7, mouse

Associated data

  • OMIM/GSE6662