A new regulator for Wnt/beta-catenin signaling and prostate tumorigenesis

描述（由申请人提供）：累积的证据表明Wnt/？-发挥着重要作用连环蛋白通路在前列腺发育和肿瘤发生中的作用。细胞质和细胞核的失调？-连环蛋白已被证明是肿瘤发生中的关键事件。因此，意义？人类肿瘤中的连环蛋白被两种基因突变的发现所证实。连环蛋白和肿瘤细胞中的破坏复合物成分。超过80%的结直肠癌在肿瘤抑制因子APC中具有失活突变。在肝细胞癌中也发现了轴蛋白的突变。此外，在GSK 32靶位点的四个丝氨酸/苏氨酸残基内发现了点突变，连环蛋白在多种人类恶性肿瘤中的作用。有趣的是，突变？连环蛋白、APC和破坏复合物的其它组分在前列腺癌样品中非常罕见。然而，增加核？在疾病进展期间，在晚期前列腺癌中经常观察到连环蛋白。因此，其他途径/机制可能在Wnt/β-淀粉样蛋白的调节中起主导作用。catenin信号通路在前列腺癌发生和发展过程中的作用。 在过去，我们发现LAPSER 1，也被称为LZTS 2（亮氨酸拉链推定肿瘤抑制因子2），是一个新的？连环蛋白相互作用蛋白。人类LZTS 2基因位于染色体10q24.3上。该区域已被证明在各种人类肿瘤中经常丢失，包括前列腺癌。LZTS 2蛋白的过表达影响？连环蛋白，抑制转录活性？连环蛋白，并抑制细胞生长。有趣的是，在LZTS 2的C-末端内鉴定了功能性HIV Rev样富含亮氨酸的CRM 1/exportin调节的核输出信号（内斯）。通过这个内斯场址，LZTS 2可以加强？连环蛋白和减少核水平？细胞中的连环蛋白使用免疫组织化学方法，我们进一步证明了LZTS 2在前列腺的管腔上皮细胞的细胞质中表达，并且其表达在人前列腺肿瘤样品中显著降低。这些数据阐明了LZTS 2作为Wnt/β-半乳糖苷酶新调节因子的重要作用。连环蛋白介导的转录、细胞生长和肿瘤发生。 尽管Wnt/？？-连环蛋白信号通路在前列腺肿瘤发生中已被确立，其确切的通路/机制是连环蛋白信号通路调节异常的基础。连环蛋白在前列腺癌细胞中的作用仍不清楚。我们最近的发现LZTS 2是一个？-连环蛋白相互作用蛋白，并调节活性和细胞定位的？连环蛋白指向LZTS 2作为Wnt/β-因此，我们提出了一系列的实验，在这个修订的RO 1应用，以解决我们的中心假设，LZTS 2负调控Wnt/β-连环蛋白信号通路。catenin信号通路及其失调将激活Wnt/β-catenin信号通路。catenin信号通路，并有助于肿瘤的发生。提出了三个具体的目标如下：1）使用基因敲除小鼠模型表征LZTS 2的生物学作用，2）检测LZTS 2在人前列腺癌中的表达，3）研究Wnt/β？LZTS 2介导的连环蛋白信号在前列腺肿瘤发生中的作用上述具体目标阐明了LZTS 2在肿瘤发生中的重要性，并确定了Wnt/β 2-受体调节异常的新机制。连环蛋白信号在肿瘤发生中的作用。对前列腺癌和其他肿瘤的新诊断标志物、治疗靶点和方法的深入了解是值得期待的。

DESCRIPTION (provided by applicant): Accumulated evidence has shown a significant role for the Wnt/?-catenin pathway in prostate development and tumorigenesis. Dysregulation of cytoplasmic and nuclear ?-catenin has been demonstrated to be a key event in tumorigenesis. Thus, the significance of ?-catenin in human tumors was corroborated by discoveries of mutations in both ?-catenin and the destruction complex components in tumor cells. More than 80% of colorectal cancers possess inactive mutations in the tumor suppressor, APC. Mutations in axin were also found in hepatocellular carcinomas. Moreover, point mutations within the four serine/threonine residues in the target sites of GSK32 were found in ?-catenin in a wide variety of human malignancies. Intriguingly, mutations in ?-catenin, APC, and other components of the destruction complex are very rare in prostate cancer samples. However, increased nuclear ?-catenin has been frequently observed in advanced prostate cancers during the disease progression. Therefore, other pathways/mechanisms may play a dominant role in the regulation of the Wnt/??-catenin signaling pathway during the course of prostate cancer initiation and progression. In the past, we identified that LAPSER1, also named LZTS2 (leucine zipper putative tumor suppressor 2), is a novel ?-catenin interacting protein. The human LZTS2 gene is located on chromosome 10q24.3. This region has been shown to be frequently lost in a variety of human tumors, including prostate cancer. Over- expression of LZTS2 protein affects the subcellular localization of ?-catenin, represses the transcriptional activity of ?-catenin, and inhibits cell growth. Intriguingly, a functional HIV Rev-like leucine rich, CRM1/exportin regulated nuclear export signal (NES) was identified within the C-terminus of LZTS2. Through this NES site, LZTS2 can enhance the nuclear export of ?-catenin and reduce the level of nuclear ?-catenin in cells. Using immunohistochemistry approaches, we further demonstrated that LZTS2 is expressed in the cytoplasm of luminal epithelial cells of prostate glands, and its expression is significantly reduced in human prostate tumor samples. These data elucidate an important role for LZTS2 as a novel regulator in Wnt/??-catenin-mediated transcription, cell growth, and tumorigenesis. Although a critical role for the Wnt/??-catenin signaling pathway has been established in prostate tumorigenesis, the precise pathways/mechanisms underlying the dysregulation of??-catenin in prostate cancer cells still remain unclear. Our recent findings that LZTS2 is a ?-catenin interacting protein and modulates the activity and cellular localization of ?-catenin point to LZTS2 as a novel regulator for the Wnt/??-catenin signaling pathway Therefore, we propose a series of experiments in this revised RO1 application to address our central hypothesis that LZTS2 negatively regulates the Wnt/??-catenin signaling pathway and its dysregulation will activate the Wnt/??-catenin signaling pathway and contribute to tumorigenesis. Three specific aims are proposed as follows: 1) characterizing the biological role of LZTS2 using knockout mouse models, 2) examining LZTS2 expression in human prostate cancers, and 3) investigating the dysregulation of Wnt/??-catenin signaling by LZTS2 in prostate tumorigenesis. The above specific aims address the significance of LZTS2 in tumorigenesis and identify the novel mechanisms for dysregulation of Wnt/??-catenin signaling in tumorigenesis. Insights into new diagnostic markers, therapeutic targets and approaches for prostate cancer and other tumors are expected.