Functional characterization of PrLZ in prostate cancer

描述(申请人提供)：我的实验室的研究重点是识别新的前列腺特异性基因，定义它们的调节和功能，并利用这些知识来预防和治疗前列腺疾病。我们使用谱系相关的人类前列腺癌(PCA)细胞系LNCaP和C4-2作为前列腺癌进展模型，以揭示在前列腺癌进展过程中表达增加的基因。在这项拟议的研究中，我们将阐明PrLZ(前列腺亮氨酸拉链)的功能，这是一种由我的实验室分离的前列腺特异性和雄激素反应的新基因。PrLZ基因定位于染色体8q21.1，在人类前列腺癌中扩增频率最高。这是在8q21扩增子中发现的唯一前列腺特异性基因。我们的数据表明PrLZ的表达与前列腺上皮的增殖活性有关，而其异常增强的表达是前列腺癌的早期标志。PrLZ的过表达促进了PCa细胞株的体外生长和体内肿瘤的生长，并增强了肿瘤发生过程中重要的生长因子Midkine的表达。PrLZ可能与某些14-3-3蛋白相互作用，这种相互作用可能调节PrLZ的功能。PrLZ具有这些特点，有望成为PCa诊断的新标记物和潜在的治疗靶点。这项建议的具体目标是： 目的1.应用LNCaP PCA进展模型确定PrLZ表达与PCa进展之间的因果关系。由于PrLZ可能导致PCa生长和转移的增加，我们将改变PrLZ在PCA进展模型中的表达水平，以证实PrLZ的致癌功能。 目的2.鉴定PrLZ亚型及其与14-3-3蛋白的相互作用。由于某些14-3-3亚型可能调节PrLZ的致癌功能，我们将首先鉴定该亚型，然后再确定该亚型的抑瘤特性。 目的3.将Midkine定义为PrLZ下游靶基因。PrLZ可能通过增强中期因子的表达促进细胞增殖。我们将建立一个可诱导的系统来确定PrLZ和中期因子表达之间的关系。

DESCRIPTION (provided by applicant): The research in my laboratory is focused on identifying novel prostate-specific genes, defining their regulation and function, and utilizing the knowledge to prevent and treat prostate diseases. We employed the lineage-related human prostate cancer (PCa) cell lines, LNCaP and C4-2, as a PCa progression model to uncover genes with increased representation during PCa progression. In this proposed study, we will elucidate the function of PrLZ (Prostate Leucine Zipper), a novel, prostate-specific, and androgen-responsive gene, isolated by my laboratory. The PrLZ gene is localized at chromosome 8q21.1, within a locus most frequently amplified in human PCa. It is the only prostate-specific gene identified in the 8q21 amplicon. Our data demonstrated that the expression of PrLZ correlated to proliferative activity of the prostate epithelium, while its abnormally enhanced expression was an early marker for PCa. Over-expression of PrLZ promoted growth of the PCa cell lines in vitro and tumors in vivo, and enhanced the expression of midkine, an important growth factor in tumorigenesis. PrLZ may interact with certain 14-3-3 proteins and the interaction may modulate the PrLZ function. With these characteristics, PrLZ appears to be a novel marker for PCa diagnosis and a potential therapeutic target for PCa. Specific aims of this proposal are: Aim 1. To determine the causal relationship between PrLZ expression and PCa progression using the LNCaP PCa progression model. Since PrLZ may confer increased PCa growth and metastasis, we will change the level of PrLZ expression in the PCa progression model to confirm the oncogenic function of the PrLZ. Aim 2. To characterize PrLZ isoforms and to determine their interaction with 14-3-3 proteins. Because certain 14-3-3 isoform may modulate the oncogenic function of the PrLZ, we will first identify the isoform, and then determine the tumor suppressive property of this isoform. Aim 3. To define midkine as a downstream target gene of the PrLZ. PrLZ may promote proliferation by enhancing midkine expression. We will develop an inducible system to determine the relationship between PrLZ and midkine expression.