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Originally published In Press as doi:10.1074/jbc.M007435200 on September 13, 2000

J. Biol. Chem., Vol. 275, Issue 48, 37552-37558, December 1, 2000
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An Antiestrogen-responsive Estrogen Receptor-alpha Mutant (D351Y) Shows Weak AF-2 Activity in the Presence of Tamoxifen*

Paul WebbDagger , Phuong Nguyen, Cathleen Valentine, Ross V. Weatherman§, Thomas S. Scanlan§, and Peter J. Kushner

From the Metabolic Research Unit, University of California, San Francisco and the § Departments of Pharmaceutical Chemistry and Cellular and Molecular Pharmacology, University of California, San Francisco, California 94143-0540

Antiestrogens, including tamoxifen and raloxifene, block estrogen receptor (ER) action by blocking the interactions of an estrogen-dependent activation function (AF-2) with p160 coactivators. Although tamoxifen does show some agonist activity in the presence of ERalpha , this stems from a distinct constitutive activation function (AF-1) that lies within the ERalpha N terminus. Previous studies identified a naturally occurring mutation (D351Y) that allows ERalpha to perceive tamoxifen and raloxifene as estrogens. Here, we examine the contributions of ERalpha activation functions to the D351Y phenotype. We find that the AF-2 function of ERalpha D351Y lacks detectable tamoxifen-dependent activity when tested in isolation but does synergize with AF-1 to allow enhanced tamoxifen response. Weak tamoxifen-dependent interactions between the ERalpha D351Y AF-2 function and GRIP1, a representative p160, can be detected in glutathione S-transferase binding assays and mammalian two-hybrid assays. Furthermore, tamoxifen-dependent AF-2 activity can be detected in the presence of ERalpha D351Y and high levels of overexpressed GRIP1. We therefore propose that the D351Y mutation allows weak tamoxifen-dependent AF-2 activity but that this activity is only detectable when AF-1 is strong, and AF-1 and AF-2 synergize, or when p160s are overexpressed. We discuss the possible structural basis of this effect.

* This work was supported in part by National Institutes of Health Grants DK51083 (to P. J. K.) and Grant DK57574 (to T. S. S.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed. Tel.: 415-476-6789; Fax: 415-476-1660; E-mail: webbp@itsa.ucsf.edu.

Supported by a fellowship from the American Cancer Society of California.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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