HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 278, Issue 9, 7699-7708, February 28, 2003

This Article Full Text Full Text (PDF) All Versions of this Article: 278/9/7699    most recent M206172200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Thin, T. H. Articles by Chang, C. Search for Related Content PubMed PubMed Citation Articles by Thin, T. H. Articles by Chang, C. Social Bookmarking                      What's this?

Isolation and Characterization of Androgen Receptor Mutant, AR(M749L), with Hypersensitivity to 17- Estradiol Treatment^*

Tin Htwe Thin, Liang Wang, Eungseok Kim, 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

Estrogens, primarily 17-estradiol (E₂), may play important roles in male physiology via the androgen receptor (AR). It has already been shown that E₂ modulates AR function in LNCaP prostate cancer cells and xenograft CWR22 prostate cancer tissues. Using a molecular model of E₂ bound-AR-ligand binding domain (LBD) and employing site-directed mutagenesis strategies, we screened several AR mutants that were mutated at E₂-AR contact sites. We found a mutation at amino acid 749, AR(M749L), which confers AR hypersensitivity to E₂. The reporter assays demonstrate that E₂ can function, like androgen, to induce AR(M749L) transactivation. This E₂-induced AR mutant transactivation is a direct effect of the AR(M749L), because the transactivation was blocked by antiandrogens. The hypersensitivity of AR(M749L) to E₂ is not due to increased affinity of AR(M749L) for E₂, rather it may be due to the existence of the proper conformation necessary to maintain E₂ binding to the AR-LBD long enough to result in E₂-induced transactivation. AR(M749L) transactivation can be further enhanced in the presence of AR coregulators, such as ARA70 and SRC-1. Therefore, amino acid 749 may represent an important site within the AR-LBD that is involved in interaction with E₂ that, when mutated, allows E₂ induction of AR transactivation.

CiteULike

Complore

Connotea

Del.icio.us

Digg

Reddit

Technorati

This article has been cited by other articles:

				L. Wang, C.-L. Hsu, J. Ni, P.-H. Wang, S. Yeh, P. Keng, and C. Chang Human Checkpoint Protein hRad9 Functions as a Negative Coregulator To Repress Androgen Receptor Transactivation in Prostate Cancer Cells Mol. Cell. Biol., March 1, 2004; 24(5): 2202 - 2213. [Abstract] [Full Text] [PDF]