The prostate gland is one of the numerous targets for prolactin action. Prolactin influences both the growth and function of the prostate, which are effects of prolactin that are independent of androgens. The production, accumulation and secretion of extraordinarily high levels of citrate are among the normal physiological functions of the prostate. These functions are specialized, differentiated activities of the prostate epithelium and are regulated by prolactin. Citrate production by the prostate epithelium involves specialized metabolic pathways that result in citrate synthesis and limited citrate oxidation and utilization. Prolactin regulates citrate metabolism by regulating the expression of the enzymes that play a central role in the pathways of citrate metabolism in the prostate. Alterations in the differentiated function of citrate related metabolism are among the earliest changes associated with the development of prostate neoplasm and benign prostate hyperplasia. The long-term objectives of this project are to understand the factors and regulatory mechanisms involved in this unique major function of the secretory epithelial cells of the prostate gland, and the possible implications in prostatic neoplasms. An important aspect of these objectives is the elucidation of the role and mechanism of prolactin regulation of prostate metabolic genes and ultimately prostate citrate production. The hypothesis of this project is that prolactin regulates the expression of specific """"""""metabolic"""""""" genes in the prostate through a signaling mechanism that requires PKC dependent activation of the AP1 transcription factor. In addition, the signaling mechanism involves prolactin receptor activation of PKC and does not involve the JAK/STAT cytokine signaling pathway.
Four specific aims are proposed to test this hypothesis: 1) to demonstrate that phospholipase C couples the prolactin receptor to activation of PKC epsilon; 2) to establish that prolactin activation of PKC leads to JNK activation and AP1 transcriptional activity; 3) to demonstrate that AP1 interaction with the TPA-response element is responsible for prolactin regulation of metabolic gene expression; and 4) to demonstrate that the PKC-mediated prolactin regulation of the metabolic genes does not require the involvement of Jak2/STAT signaling. If successful, these studies will identify a novel mechanism of prolactin regulation of metabolic gene expression in the prostate and indicate novel targets for the treatment of prostatic disease. ? ? ?
