1. Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, 1230 York Avenue, New York, New York 10021, USA
2. Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA
3. Present address: Bristol-Myers Squibb, Wilmington, Delaware 19803, USA.

Correspondence to: Robert G. Roeder¹ Correspondence and requests for materials should be addressed to R.G.R. (e-mail: Email: roeder@mail.rockefeller.edu).

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 receptor¹. This complex interacts physically with several nuclear receptors through the TRAP220 subunit, and with diverse activators through other subunits². TRAP220 has been reported to show ligand-enhanced interaction with peroxisome proliferator-activated receptor 2 (PPAR2)^{3, 4}, a nuclear receptor essential for adipogenesis^{5, 6, 7, 8}. Here we show that Trap220^-/- fibroblasts are refractory to PPAR2-stimulated adipogenesis, but not to MyoD-stimulated myogenesis, and do not express adipogenesis markers or PPAR2 target genes. These defects can be restored by expression of exogenous TRAP220. Further indicative of a direct role for TRAP220 in PPAR2 function via the TRAP complex, TRAP functions directly as a transcriptional coactivator for PPAR2 in a purified in vitro system and interacts with PPAR2 in a ligand- and TRAP220-dependent manner. These data indicate that TRAP220 acts, via the TRAP complex, as a PPAR2-selective coactivator and, accordingly, that it is specific for one fibroblast differentiation pathway (adipogenesis) relative to another (myogenesis).