The long-term objective is to elucidate the androgen pathway, a cascade of molecular and cellular events triggered by androgen manipulation leading to cell proliferation, differentiation, and/or apoptosis in the prostate. U19/Eaf2 (U19), initially identified as a novel androgen-induced gene, is a key molecule in the androgen pathway. U19 overexpression induces apoptosis of prostate cancer cells in culture and in xenografts. U19 down-regulation and loss-of-heterozygosity were detected in >80% of human advanced prostate cancer specimens. We have generated U19 knockout (KO) mice, which developed lymphoma, nepatocellular carcinoma, and poorly differentiated lung adenocarcinoma. This demonstrated that U19 is a tumor suppressor. The U19 KO prostate exhibited epithelial hyperplasia and dysplasia, suggesting that U19 contributes to the suppression of prostate tumors. Interestingly, U19 KO increased the size of prostate epithelial cells, indicating that U19 is essential in cell size control. U19 was independently identified and termed ELL-associated factor (Eaf2), based on its association with ELL, a fusion partner of MLL in acute myeloid leukemia. Preliminary studies showed that the ELL-binding region of U19 is critical for apoptosis induction. The above observations support our hypothesis that U19 regulates androgen-dependent prostate epithelial homeostasis and that ELL is required for U19 action.
Three specific aims will elucidate the role and mechanisms of U19 action in the prostate in vivo. 1. Test the hypothesis that loss of U19 disrupts homeostasis of full-grown prostate in the presence of androgens but does not affect undeveloped prostate naive to androgens. Markers for differentiation, apoptosis, and proliferation will be examined in U19 KO and wild-type prostate in the absence and in the presence of androgens. 2. Test the hypothesis that U19 and Pten. Two commonly inactivated/down-regulated genes in human prostate cancer, functionally cooperate in suppression of prostate tumors in mice. The effect of U19 deletion or overexpression on Pten KO prostate will be determined. 3. Determine the role of ELL, a U19 binding partner, in U19 action in the prostate. Prostate-specific ELL KO mice will be generated and cross-bred with the U19 KO or transgenic mice to examine the role of ELL and the importance of U19-ELL interaction in vivo. Androgens play important roles in the pathogenesis of prostate cancer and benign prostatic hyperplasia (BPH), two major diseases in American men at old age. Elucidating the androgen pathway in the prostate will provide insights into the mechanisms by which androgens influence BPH and prostate cancer, leading to more effective prevention and treatment of the diseases.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Method to Extend Research in Time (MERIT) Award (R37)
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Urologic and Kidney Development and Genitourinary Diseases Study Section (UKGD)
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Mullins, Christopher V
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University of Pittsburgh
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O'Malley, Katherine J; Eisermann, Kurtis; Pascal, Laura E et al. (2014) Proteomic analysis of patient tissue reveals PSA protein in the stroma of benign prostatic hyperplasia. Prostate 74:892-900
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