CONTROL OF PROSTATE-SPECIFIC GENE EXPRESSION

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With the approach of adulthood, the prostate undergoes a developmental change that results in the maturation of that gland at puberty. At this stage, the prostate becomes a differentiated gland which produces proteins fundamental for reproduction and survival of the species. Two recent population trends place the understanding of these processes at the forefront. A decline in male fertility requires a better understanding of normal, reproductive development and an increasing aging population demands a better understanding of the further stages of prostatic growth that often leads to benign prostatic hyperplasia and/or prostate cancer. Androgen plays a key role in the normal development of the prostate however, little is known about the other basic molecular events that are required for organ determination and cell differentiation of the prostate. We have shown that an extremely small probasin promoter fragment contains the necessary regulatory information to target both developmental and prostatic epithelial-specific gene expression to the prostate of transgenic mice. Our hypothesis is that these PB DNA sequences can be used to identify the critical gene regulatory proteins that govern prostatic epithelial cell-specific gene expression. We believe that identifying these critical regulatory proteins which control prostate-specific gene expression will elucidate the mechanisms that control both cell determination and cell differentiation of the prostate. To decipher the information within this PB DNA fragment, the following specific Aims are planned: 1) to characterize the ontogeny of prostate-specific probasin gene expression in the developing mouse UGS; 2) to identify the PB promoter sequences that dictate prostate-specific gene expression; 3) to clone the regulatory factors that interact with the prostate-specific sequences; and 4) to determine the patterns of expression of these prostate-specific factors in the developing mouse. The ultimate goal is to provide a basic understanding of prostatic epithelial cell gene expression that will lead to insight in male infertility and the mechanism that lead to prostatic disease.