Prolactin receptor signaling of prolactin metabolic effects in the prostate

描述(申请人提供)：前列腺是催乳素作用的众多靶点之一。催乳素影响前列腺的生长和功能，这是催乳素的作用，它不依赖于雄激素。产生、积累和分泌超高水平的柠檬酸盐是前列腺的正常生理功能之一。这些功能是前列腺上皮的特殊的、差异化的活动，由催乳素调节。由前列腺上皮产生的柠檬酸涉及特殊的代谢途径，导致柠檬酸的合成和有限的柠檬酸氧化和利用。催乳素通过调节在前列腺中柠檬酸代谢途径中起核心作用的酶的表达来调节柠檬酸代谢。柠檬酸相关代谢分化功能的改变是与前列腺癌和良性前列腺增生症发展相关的最早的变化之一。这个项目的长期目标是了解前列腺分泌上皮细胞这一独特的主要功能所涉及的因素和调节机制，以及在前列腺癌中的可能意义。这些目标的一个重要方面是阐明催乳素调节前列腺代谢基因的作用和机制，最终调节前列腺柠檬酸的产生。该项目的假设是，催乳素通过一种需要依赖PKC激活AP1转录因子的信号机制来调节前列腺中特定的“代谢”基因的表达。此外，该信号转导机制涉及催乳素受体激活PKC，而不涉及JAK/STAT细胞因子信号转导途径。为了验证这一假说，提出了四个特定的目标：1)证明磷脂酶C将催乳素受体偶联到PKC epsilon的激活；2)证实PKC的催乳素激活导致JNK激活和AP1转录活性；3)AP1与TPA反应元件的相互作用负责催乳素对代谢基因表达的调节；4)证明PKC介导的催乳素对代谢基因的调节不需要JAK2/STAT信号的参与。如果成功，这些研究将确定催乳素调节前列腺代谢基因表达的新机制，并为前列腺癌的治疗指明新的靶点。

DESCRIPTION (provided by applicant): 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.