Prolactin receptor signaling of prolactin metabolic effects in the prostate

描述（由申请人提供）：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，这是催乳素独立于雄激素的作用。非常高水平的柠檬酸盐的产生、积累和分泌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化、分化活动，并受催乳素调节。前列腺上皮的柠檬酸盐产生涉及导致柠檬酸盐合成和有限的柠檬酸盐氧化和利用的专门代谢途径。催乳素通过调节在前列腺柠檬酸盐代谢途径中起核心作用的酶的表达来调节柠檬酸盐代谢。柠檬酸盐相关代谢的分化功能改变是与前列腺肿瘤和良性前列腺增生发生相关的最早变化之一。本项目的长期目标是了解参与前列腺分泌上皮细胞这一独特主要功能的因素和调节机制，以及前列腺肿瘤的可能影响。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和最终前列腺柠檬酸盐产生的作用和机制。该项目的假设是，催乳素通过需要PKC依赖性激活AP 1转录因子的信号传导机制调节前列腺中特定“代谢”基因的表达。此外，信号传导机制涉及PKC的催乳素受体激活，而不涉及JAK/STAT细胞因子信号传导途径。本论文的主要目的是验证这一假说：1）证明磷脂酶C与催乳素受体偶联激活PKC β，2）证明催乳素激活PKC导致JNK激活和AP 1转录活性，3）证明AP 1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AP 1与TPA反应元件的相互作用导致代谢基因表达的调节。和4）证明PKC介导的催乳素对代谢基因的调节不需要Jak 2/STAT信号转导的参与。如果成功，这些研究将确定一种新的机制，催乳素调节代谢基因表达的前列腺，并指出新的目标，前列腺疾病的治疗。

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.