Functional characterization of PrLZ in prostate cancer

描述（申请人提供）：我实验室的研究重点是发现新的前列腺特异性基因，确定其调控和功能，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PCa进展模型，以发现在PCa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，这是一种新的，前列腺特异性的，雄激素应答基因，由我的实验室分离出来。PrLZ基因定位于染色体8q21.1，在人类PCa中最常扩增的位点内。它是唯一在8q21扩增子中发现的前列腺特异性基因。我们的数据表明，PrLZ的表达与前列腺上皮的增殖活性相关，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细胞系体外和体内肿瘤的生长，并增强了肿瘤发生过程中重要生长因子midkine的表达。PrLZ可能与某些14-3-3蛋白相互作用，相互作用可调节PrLZ的功能。具有这些特征，PrLZ似乎是前列腺癌诊断的新标志物和潜在的治疗靶点。这项建议的具体目标是：

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.