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Transcription coactivator TRAP220 is required for PPARγ2-stimulated adipogenesis

Nature volume 417, pages 563–567 (2002)Cite this article

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 γ2 (PPARγ2)3,4, a nuclear receptor essential for adipogenesis5,6,7,8. Here we show that Trap220-/- fibroblasts are refractory to PPARγ2-stimulated adipogenesis, but not to MyoD-stimulated myogenesis, and do not express adipogenesis markers or PPARγ2 target genes. These defects can be restored by expression of exogenous TRAP220. Further indicative of a direct role for TRAP220 in PPARγ2 function via the TRAP complex, TRAP functions directly as a transcriptional coactivator for PPARγ2 in a purified in vitro system and interacts with PPARγ2 in a ligand- and TRAP220-dependent manner. These data indicate that TRAP220 acts, via the TRAP complex, as a PPARγ2-selective coactivator and, accordingly, that it is specific for one fibroblast differentiation pathway (adipogenesis) relative to another (myogenesis).

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Figure 1: Trap220-/- MEFs have defects in PPARγ2-stimulated adipogenesis.
Figure 2: The adipogenesis defects in Trap220-/- MEFs can be rescued by ectopic expression of TRAP220.
Figure 3: TRAP220 is essential for C/EBPβ-stimulated adipogenesis but not for MyoD-stimulated myogenesis.
Figure 4: TRAP complex interacts directly with PPARγ2, via TRAP220, and is required for optimal PPARγ2 function.

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Acknowledgements

We thank S.O. Freytag for C/EBPβ cDNA and pWZLhygro plasmid; A.B. Lassar for pBabe-MyoD plasmid, anti-myogenin, anti-MyoD and anti-MHC antibodies; T.M. Wilson and S.A. Kliewer for rosiglitazone; G.P. Nolan for Phoenix retrovirus packaging cell lines; J. Zhang, S. Malik, U. Kim, X. Ren and other members of the laboratory for critical reading of the manuscript and discussion. This work was supported by the NIH. K.G. was supported by a postdoctoral fellowship from Charles H. Revson Foundation. A.E.W. was supported by the Swedish Cancer Society.

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  1. Chao-Xing Yuan

    Present address: Bristol-Myers Squibb, Wilmington, Delaware, 19803, USA

Authors and Affiliations

  1. Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, 1230 York Avenue, New York, 10021, USA

    Kai Ge, Mohamed Guermah, Chao-Xing Yuan, Mitsuhiro Ito, Annika E. Wallberg & Robert G. Roeder

  2. Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts, 02115, USA

    Bruce M. Spiegelman

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Correspondence to Robert G. Roeder.

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Ge, K., Guermah, M., Yuan, CX. et al. Transcription coactivator TRAP220 is required for PPARγ2-stimulated adipogenesis. Nature 417, 563–567 (2002). https://doi.org/10.1038/417563a

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