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Originally published In Press as doi:10.1074/jbc.M202824200 on June 14, 2002

J. Biol. Chem., Vol. 277, Issue 39, 36499-36508, September 27, 2002
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Mutations in the Helix 3 Region of the Androgen Receptor Abrogate ARA70 Promotion of 17beta -Estradiol-induced Androgen Receptor Transactivation*

Tin Htwe ThinDagger , Eungseok KimDagger , Shuyuan YehDagger , Erik R. Sampson, Yei-Tsung Chen, Loretta L. Collins, Ravi Basavappa§, and Chawnshang Chang

From the George Whipple Laboratory for Cancer Research, Departments of Pathology, Urology, and Radiation Oncology and the Cancer Center, University of Rochester, Rochester, New York 14642

The influence of estrogen on the development of the male reproductive system may be interrupted in a subset of partial androgen insensitivity syndrome (PAIS) patients. PAIS describes a wide range of male undermasculinization resulting from mutations in the androgen receptor (AR) or steroid metabolism enzymes that perturb androgen-AR regulation of male sex organ development. In this study, we are interested in determining if PAIS-derived AR mutants that respond normally to androgen have altered responses to estrogen in the presence of ARA70, a coregulator previously shown to enhance 17beta -estradiol E2-induced AR transactivation. The wild-type AR (wtAR) and two PAIS AR mutants, AR(S703G) and AR(E709K), all bind to androgen and E2 and subsequently translocate to the nucleus. Whereas ARA70 functionally interacts with the wtAR and the PAIS AR mutants in response to androgen, E2 only promotes the functional interaction between ARA70 and the wtAR but not the PAIS AR mutants. ARA70 increases E2 competitive binding to the wtAR in the presence of low level androgen and also retards E2 dissociation from the wtAR. ARA70 is present in both the cytoplasm and the nucleus of various mouse testicular cells during early embryogenesis day 16, at postpartum day 0 during estradiol synthesis and in the Leydig cells at postpartum day 49. ARA70 may be unable to modulate the PAIS AR mutants-E2 binding, diminishing the effect of E2 via AR during male reproductive system development in patients with such mutations. Therefore, the presence of ARA70 in the testosterone and E2-producing Leydig cells may enhance the overall activity of AR during critical stages of male sex organ development.

* This work was supported by the George Whipple Professorship Endowment and National Institutes of Health Grant DK60905, and DAMD17-01-10386.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 These authors contributed equally to this work.

§ Research Scholar of the Leukemia and Lymphoma Society of America.

To whom correspondence should be addressed. Tel.: 585-273-4500; Fax: 585-756-4133; E-mail: chang@URMC.rochester.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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