Transcription coactivator TRAP220 is required for PPARγ2-stimulated adipogenesis

Abstract

The TRAP (thyroid hormone receptor-associated proteins) transcription coactivator complex (also known as Mediator) was first isolated as a group of proteins that facilitate the function of the thyroid hormone receptor. This complex interacts physically with several nuclear receptors through the TRAP220 subunit, and with diverse activators through other subunits. TRAP220 has been reported to show ligand-enhanced interaction with peroxisome proliferator-activated receptor gamma(2) (PPAR gamma(2)), a nuclear receptor essential for adipogenesis. Here we show that Trap220(-/-) fibroblasts are refractory to PPAR gamma(2)-stimulated adipogenesis, but not to MyoD-stimulated myogenesis, and do not express adipogenesis markers or PPAR gamma(2) target genes. These defects can be restored by expression of exogenous TRAP220. Further indicative of a direct role for TRAP220 in PPAR gamma(2) function via the TRAP complex, TRAP functions directly as a transcriptional coactivator for PPAR gamma(2) in a purified in vitro system and interacts with PPAR gamma(2) in a ligand- and TRAP220-dependent manner. These data indicate that TRAP220 acts, via the TRAP complex, as a PPAR gamma(2)-selective coactivator and, accordingly, that it is specific for one fibroblast differentiation pathway (adipogenesis) relative to another (myogenesis).

A Mediator subunit, MDT-15, integrates regulation of fatty acid metabolism by NHR-49-dependent and -independent pathways inC. elegans

“…The selectivity of MDT-15 action is reminiscent of the reported effects on gene expression by Mediator subunits MED6 in yeast, MDT-1.1/SOP-3 and MDT-13/LET-19 in C. elegans, and MED23/SUR2 and MED1 in mammals (Zhang and Emmons 2001;Ge et al 2002;Wang et al 2004Yoda et al 2005). However, these studies…”

“…For example, in response to short-term fasting, PGC-1␣ coactivates PPAR␣ and HNF4␣ to induce gluconeogenesis and ␤-oxidation in liver, adipose, and heart (Yoon et al 2001;Rhee et al 2003). Similarly, MED1 is required for ligand-stimulated PPAR␣-dependent gene expression in the liver (Jia et al 2004), and for PPAR␥-dependent adipocyte differentiation (Ge et al 2002). Thus, these two coregulators govern metabolic and cell fate decisions by integrating hormonal signals and nutrient state.…”

“…In addition, med1 −/− mouse embryonic fibroblasts fail to properly express many PPAR␥ target genes, and are incapable of undergoing proper adipocyte differentiation, a PPAR␥-dependent cell fate decision (Ge et al 2002). Similarly, PGC-1 proteins stimulate mitochondrial proliferation, oxidative phosphorylation, adaptive thermogenesis, and the fasting response in the liver Lin et al 2005).…”

The Nuclear Hormone Receptor Coactivator NRC Is a Pleiotropic Modulator Affecting Growth, Development, Apoptosis, Reproduction, and Wound Repair

“…TRAP220 ϩ/Ϫ mice are viable but exhibit pituitary hypothyroidism. Null TRAP220 mouse embryonic fibroblasts (MEFs) in culture also fail to undergo adipocyte differentiation, implicating TRAP220 in regulating PPAR␥ activity (17). SRC-1 Ϫ/Ϫ mice are viable and reproduce normally, but show partial resistance to E2, progesterone, androgen, and T3 (65).…”

Transcription coactivator peroxisome proliferator-activated receptor-binding protein/mediator 1 deficiency abrogates acetaminophen hepatotoxicity

“…[ 35 S]Methionine-labeled proteins were synthesized by in vitro translation using the TnT-coupled transcription-translation system (Promega). Immobilized GST fusion protein and 35 S-labeled proteins were used in GST pull-down assays in the presence or absence of TCPOBOP (4,24). Bound proteins were resolved on SDS͞PAGE.…”