The overall goal of the research plan is the elucidation of the molecular mechanisms by which neonatal estrogen initially imprint or transform the prostate gland in a rat animal model. The overall objective of the doctor dissertation is to determine the molecular mechanisms which cause the reduction of androgen receptor (AR) protei expression in prostatic cells following neonatal exposure to estrogens. Previous data from our laboratory provide strong evidence that estrogen down-regulation of AR expression in the developing prostate is mediated at translational or post- translational level since AR protein is markedly decreased following neonatal estradiol benzoate (neoEB) treatment while AR mRNA levels are unaltered. Regulatory mechanisms may include altered rates of A protein degradation, sequestration of AR message, and/or changes in translation efficiency. To evaluate these, the following specific aims are proposed: 1 )To determine if the degradation rate of AR protein is altered, the half-life protein will be measured in control and neoEB-treated rats. 2) To evaluate nuclear sequestration of AR message quantitate AR mRNA levels in the nucleus and cytosol. 3) To determine whether AR translational efficiency regulated, the polysome distribution of AR message will be evaluated in control and treated tissues. 4) Determine whether in vitro translation of AR is affected by cytoplasmic extracts from estrogenized prostates. 5) Determine whether specific trans-acting cytosolic factors are present in estrogenized prostates which associate with 5'-UTR sites on AR transcripts and block full initiation/elongation. 6) Further characterize putative proteins which may b involved in translational regulation of AR mRNA.
| Prins, Gail S; Putz, Oliver (2008) Molecular signaling pathways that regulate prostate gland development. Differentiation 76:641-59 |
| Woodham, Carl; Birch, Lynn; Prins, Gail S (2003) Neonatal estrogen down-regulates prostatic androgen receptor through a proteosome-mediated protein degradation pathway. Endocrinology 144:4841-50 |
| Chang, W Y; Birch, L; Woodham, C et al. (1999) Neonatal estrogen exposure alters the transforming growth factor-beta signaling system in the developing rat prostate and blocks the transient p21(cip1/waf1) expression associated with epithelial differentiation. Endocrinology 140:2801-13 |
| Prins, G S; Marmer, M; Woodham, C et al. (1998) Estrogen receptor-beta messenger ribonucleic acid ontogeny in the prostate of normal and neonatally estrogenized rats. Endocrinology 139:874-83 |
