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PMEPA1, an Androgen-regulated NEDD4-binding Protein, Exhibits Cell Growth Inhibitory Function and Decreased Expression during Prostate Cancer Progression¹

Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814-4799 [L. L. X., Y. S., G. P., C. S., M. M., W. Z., D. G. M., J. W. M., S. S.], and Urology Service, Walter Reed Army Medical Center [D. G. M., J. W. M.] and Department of Genitourinary Pathology, Armed Forces Institute of Pathology [I. A. S.], Washington, DC 20307

PMEPA1 was originally identified as a highly androgen-induced gene by serial analysis of gene expression in androgen-treated LNCaP prostate cancer (CaP) cells. PMEPA1 expression is prostate abundant and restricted to prostatic epithelial cells. PMEPA1-encoded protein shows high sequence homology to a mouse N4wbp4-encoded protein that binds to Nedd4 protein, an E3 ubiquitin–protein ligase involved in ubiquitin-dependent, proteasome-mediated protein degradation. Studies from our and other laboratories have suggested the role of PMEPA1 in cell growth regulation as noted by androgen induction of PMEPA1 expression, elevated PMEPA1 expression in nontumorigenic revertants of tumor cell lines after chromosome 8p transfer, and PMEPA1 expression alterations (up- or down-regulation) in human tumors. Here, we demonstrate that PMEPA1 protein through its PY motifs interacts with WW domains of the human NEDD4 protein. Exogenous expression of PMEPA1, in widely used CaP cell lines DU145, PC3, LNCaP, and LNCaP sublines (C4, C4-2, and C4-2B), conferred cell growth inhibition, and at least one of the PY motifs of PMEPA1 may be involved in its cell growth inhibitory functions. Quantitative expression analysis of PMEPA1 in paired normal and tumor cells of 62 patients with primary CaP revealed tumor cells associated decreased expression in 40 of 62 patients that were significantly associated with higher pathologic stage and serum prostate-specific antigen. Taken together, PMEPA1 negatively regulates growth of androgen responsive or refractory CaP cells, and these functions may be mediated through the interaction of PMEPA1 with the NEDD4 protein involved in the ubiquitin–proteasome pathway. Loss or reduced PMEPA1 expression in CaP further suggests for its role in prostate tumorigenesis.

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