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Submitted on March 4, 2005
Accepted on October 20, 2005
Department of Biochemistry & Molecular Biology, University of Miami Miller School of Medicine, 1580 NW 10 Avenue, Miami, FL 33136, Department of Pharmacology, Creighton University, 2500 California Plaza, Omaha, Nebraska 68178 and Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267
* To whom correspondence should be addressed. E-mail: znawaz{at}med.miami.edu.
In this study we report that deletion of E6-associated protein (E6-AP) in mice results in smaller prostate gland compared with normal wild-type animals. To investigate the mechanism(s) by which E6-AP affects prostate gland growth and development, we carried out both in vitro and in vivo experiments. Here, we show that E6-AP interacts with androgen receptor (AR) in a hormone-dependent manner and enhances the transactivation function of AR. Our in vivo data from E6-AP null prostate glands shows that the level of AR protein is elevated while the level of the AR target protein, probasin is decreased. On the other hand the level of AR protein is decreased and its target protein is increased in E6-AP overexpressing stable cell line, suggesting that E6-AP modulates both the protein level and activity of AR. In addition, we show that the levels of phosphatidylinositol 3-kinase (PI3K), total Akt, and phosphorylated Akt are decreased in E6-AP null prostate, suggesting that E6-AP deletion downregulates the signaling of the PI3K-Akt pathway. Here, we also showed that RhoA negatively regulates AR function and RhoA levels are increased in E6-AP null prostate. Furthermore, expression levels of p53, Bax, active caspases and apoptotic index are increased in E6-AP null prostate. Collectively, our data suggest that E6-AP deletion attenuates the growth and development of the prostate gland by interfering with AR function as well as by stimulating p53-mediated apoptosis.
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