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J. Biol. Chem., Vol. 282, Issue 37, 26897-26907, September 14, 2007

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Coactivators PGC-1 and SRC-1 Interact Functionally to Promote the Agonist Activity of the Selective Estrogen Receptor Modulator Tamoxifen^*

Dieter Kressler¹, M. Benjamin Hock, and Anastasia Kralli²

From the Division of Biochemistry, Biozentrum of the University of Basel, Klingelbergstrasse 70, CH-4056 Basel, Switzerland and the Department of Cell Biology, The Scripps Research Institute, La Jolla, California 92037

PGC-1 is a transcriptional coactivator that enhances strongly and in a hormone-dependent manner the activity of the estrogen receptor (ER) while having only weak effects on similar steroid hormone receptors, such as ER or the glucocorticoid receptor. Notably, PGC-1 enhances ER transcriptional activity not only in response to agonist ligands, such as estradiol, but also to selective ER modulators, such as tamoxifen. Here, we dissect the molecular mechanisms underlying the ability of PGC-1 to act selectively on ER and to promote the agonist activity of tamoxifen. We show that receptor selectivity is achieved by PGC-1 interactions with not just the ligand binding domain (LBD), which is highly conserved among nuclear receptors, but also the N-terminal domain and the hinge/AF-2a region of ER, which are less well conserved. PGC-1 interacts directly with the hinge/AF-2a and LBD regions but indirectly and via the coactivator SRC-1 with the N-terminal domain. The three ER surfaces and SRC-1 collectively enable efficient coactivation by PGC-1. Similar ER surfaces and interactions enable PGC-1 to coactivate transcription by tamoxifen-bound ER. Surprisingly, PGC-1 coactivation of tamoxifen-bound ER depends partially on one of the LXXLL motifs of PGC-1 and on Lys³⁶² of the ER LBD (i.e. surfaces implicated in agonist-dependent interactions). Our findings suggest that tamoxifen-induced changes in the ER LBD promote interactions with the coactivator PGC-1, which then cooperates with SRC-1 to enable tamoxifen agonism.

Received for publication, July 9, 2007

^* This work was supported by the Swiss National Science Foundation, the University of Basel, the Swiss Cancer League, the Max Cloëtta Foundation, and National Institute of Health Grant DK064951 (to A. K.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.

¹ Present address: Biochemie-Zentrum der Universität Heidelberg, Im Neuenheimer Feld 328, D-69120 Heidelberg, Germany.

² To whom correspondence should be addressed: Dept. of Cell Biology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037. Tel.: 858-784-7287; Fax: 858-784-9132; E-mail: kralli{at}scripps.edu.

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				D. J Kojetin, T. P Burris, E. V Jensen, and S. A Khan Implications of the binding of tamoxifen to the coactivator recognition site of the estrogen receptor Endocr. Relat. Cancer, December 1, 2008; 15(4): 851 - 870. [Abstract] [Full Text] [PDF]