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J. Biol. Chem., Vol. 279, Issue 2, 1310-1322, January 9, 2004

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Identification of Genetic Pathways Activated by the Androgen Receptor during the Induction of Proliferation in the Ventral Prostate Gland^*

Pascale V. Nantermet, Jian Xu¶, Yuanjiang Yu, Paul Hodor||, Daniel Holder**, Sharon Adamski, Michael A. Gentile, Donald B. Kimmel, Shun-ichi Harada, David Gerhold¶, Leonard P. Freedman, and William J. Ray

From the Department of Molecular Endocrinology and Bone Biology, the ^¶Department of Laboratory Science and Investigative Toxicology, the ^||Department of Molecular Profiling, and the ^**Department of Biometrics Research, Merck Research Laboratories, West Point, Pennsylvania 19486

The androgen receptor (AR), when complexed with 5-dihydrotestosterone (DHT), supports the survival and proliferation of prostate cells, a process critical for normal development, benign prostatic hypertrophy, and tumorigenesis. However, the androgen-responsive genetic pathways that control prostate cell division and differentiation are largely unknown. To identify such pathways, we examined gene expression in the ventral prostate 6 and 24 h after DHT administration to androgen-depleted rats. 234 transcripts were expressed significantly differently from controls (p < 0.05) at both time points and were subjected to extensive data mining. Functional clustering of the data reveals that the majority of these genes can be classified as participating in induction of secretory activity, metabolic activation, and intracellular signaling/signal transduction, indicating that AR rapidly modulates the expression of genes involved in proliferation and differentiation in the prostate. Notably AR represses the expression of several key cell cycle inhibitors, while modulating members of the wnt and notch signaling pathways, multiple growth factors, and peptide hormone signaling systems, and genes involved in MAP kinase and calcium signaling. Analysis of these data also suggested that p53 activity is negatively regulated by AR activation even though p53 RNA was unchanged. Experiments in LNCaP prostate cancer cells reveal that AR inhibits p53 protein accumulation in the nucleus, providing a post-transcriptional mechanism by which androgens control prostate cell growth and survival. In summary these data provide a comprehensive view of the earliest events in AR-mediated prostate cell proliferation in vivo, and suggest that nuclear exclusion of p53 is a critical step in prostate growth.

Received for publication, September 15, 2003 , and in revised form, October 22, 2003.

^* 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 Table I and II.

Both authors contributed equally to this article.

To whom correspondence should be addressed: Merck Research Laboratories, P.O. Box 4, WP26A1000, West Point, PA 19486. Tel.: 215-862-2548; Fax: 215-862-4328; E-mail: james_ray{at}merck.com.

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