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The Interaction of TRß1-N Terminus with Steroid Receptor Coactivator-1 (SRC-1) Serves a Full Transcriptional Activation Function of SRC-1

Department of Integrative Physiology (T.I., W.M., N.K.), Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan; Core Research for Evolutional Science and Technology (CREST) (T.I., W.M., N.K.), Japan Science and Technology Corporation (J.S.T.), Kawaguchi, Saitama 332-0012, Japan; Brigham and Women’s Hospital and Harvard Medical School (T.I., A.T., W.W.C., N.K.), Boston, Massachusetts 02115; and Division of Endocrinology and Metabolism (A.T.), Toranomon Hospital, Okinaka Memorial Institute for Medical Research, Tokyo 105-8470, Japan

Address all correspondence and requests for reprints to: Toshiharu Iwasaki, M.D., Ph.D., Department of Integrative Physiology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi 371-8511, Gunma, Japan. E-mail: tiwasaki{at}med.gunma-u.ac.jp.

Steroid receptor coactivator-1 (SRC-1) plays a crucial role in nuclear receptor-mediated transcription including thyroid hormone receptor (TR)-dependent gene expression. Interaction of the TR-ligand binding domain and SRC-1 through LXXLL motifs is required for this action. However, potential interactions between the TRß1-N terminus (N) and SRC-1 have not been explored and thus are examined in this manuscript. Far-Western studies showed that protein construct containing TRß1-N + DNA binding domain (DBD) bound to nuclear receptor binding domain (NBD)-1 (amino acid residue, aa 595–780) of SRC-1 without ligand. Mammalian two-hybrid studies showed that NBD-1, as well as SRC-1 (aa 595-1440), bound to TRß1-N+DBD in the absence of ligand in CV-1 cells. However, NBD-2 (aa 1237–1440) did not bind to this protein. Glutathione-S-transferase pull-down studies showed that TRß1-N (aa 1–105) bound to the broad region of SRC-1-C terminus. Expression vectors encoding a series of truncations and/or point mutations of TRß1 were used in transient transfection-based reporter assays in CV-1 cells. N-terminal truncated TRß1 (N-TRß1) showed lower activity than that of wild-type in both artificial F2-thyroid hormone response element and native malic enzyme response element. These results suggest that there is the interaction between N terminus of TRß1 and SRC-1, which may serve a full activation of SRC-1, together with activation function-2 on TRß1-mediated transcription.

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