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Multifunction Steroid Receptor Coactivator, E6-Associated Protein, Is Involved in Development of the Prostate Gland

Department of Biochemistry and Molecular Biology (O.Y.K., G.F., A.I., S.S., Z.N.), University of Miami Miller School of Medicine, Miami, Florida 33136; Department of Pharmacology (X.C., Y.T.), Creighton University, Omaha, Nebraska 68178; and Department of Pathology and Laboratory Medicine (S.L.), University of Cincinnati College of Medicine, Cincinnati, Ohio 45267

Address all correspondence and requests for reprints to: Dr. Zafar Nawaz, Department of Biochemistry and Molecular Biology, Braman Breast Cancer Institute (M-877), University of Miami Miller School of Medicine, Batchelor’s Building, Room 416, 1580 Northwest 10 Avenue, Miami, Florida 33136. E-mail: znawaz{at}med.miami.edu.

In this study we report that deletion of E6-associated protein (E6-AP) in mice results in a smaller prostate gland compared with that in 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. In this study 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 show that the level of AR protein is elevated while the level of the AR target protein, probasin, is decreased. In contrast, the level of AR protein is decreased, and its target protein is increased in an E6-AP-overexpressing stable cell line, suggesting that E6-AP modulates both the protein level and the activity of AR. In addition, we show that the levels of phosphatidylinositol 3-kinase, total Akt, and phosphorylated Akt are decreased in E6-AP-null prostate, suggesting that E6-AP deletion down-regulates the signaling of the phosphatidylinositol 3-kinase-Akt pathway. We also show 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.

NURSA Molecule Pages Link:

Nuclear Receptors:   AR

Coregulators:   E6AP  |  AIB1

Ligands:   R1881

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