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Transcriptional Intermediary Factor 1 Mediates Physical Interaction and Functional Synergy between the Coactivator-Associated Arginine Methyltransferase 1 and Glucocorticoid Receptor-Interacting Protein 1 Nuclear Receptor Coactivators

Department of Biochemistry and Molecular Biology (C.T., C.-Y.O., M.R.S.), University of Southern California, Los Angeles, California 90089; and Institut de Génétique et de Biologie Moléculaire et Cellulaire (K.K., R.L.), Centre National de la Recherche Scientifique/Institut National de la Santé et de la Recherche Médicale/Université Louis Pasteur/Collège de France, 67404 Illkirch-Cedex, France

Address all correspondence and requests for reprints to: Michael R. Stallcup, Department of Biochemistry and Molecular Biology, University of Southern California, 1333 San Pablo Avenue, MCA 51A, Los Angeles, California 90089-9151. E-mail: stallcup{at}usc.edu.

In previous studies transcriptional intermediary factor 1 (TIF1) was identified as a direct binding partner and potential transcriptional coactivator for nuclear receptors (NRs) but its overexpression inhibited, rather than enhanced, transcriptional activation by NRs. Here we show that TIF1 bound to and enhanced the function of the C-terminal activation domain (AD) of coactivator associated arginine methyltransferase 1 (CARM1) and the N-terminal AD of glucocorticoid receptor-interacting protein 1 (GRIP1). Furthermore, although TIF1 had little or no NR coactivator activity by itself, it cooperated synergistically with GRIP1 and CARM1 to enhance NR-mediated transcription. Inhibition of endogenous TIF1 expression reduced transcriptional activation by the GRIP1 N-terminal domain but not by the CARM1 C-terminal domain, suggesting that TIF1 may be more important for mediating the activity of the former than the latter. Reduction of endogenous TIF1 levels also compromised the androgen-dependent induction of an endogenous target gene of the androgen receptor. Finally, TIF1 formed a ternary complex with the GRIP1 N-terminal and CARM1 C-terminal domains. Thus, we conclude that TIF1 cooperates with NR coactivators GRIP1 and CARM1 by forming a stable ternary complex with them and enhancing the AD function of one or both of them.

NURSA Molecule Pages Link:

Nuclear Receptors:   TRβ  |  ERα  |  GR  |  AR

Coregulators:   TIF1α  |  TIF1β  |  CARM1  |  GRIP1

Ligands:   Dexamethasone  |  17β-Estradiol  |  Dihydrotestosterone  |  Thyroid hormone

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