PROJECT 3:CONNEXIN AND CADHERIN CROSSTALK IN PROSTATE CANCER PROGRESSION

项目 3：连接蛋白和钙粘蛋白在前列腺癌进展中的相互作用

• 批准号: 8360443
• 负责人: Parmender Paul Mehta
• 金额: $ 1.42万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360443
• 关键词: Cadherins; Cell-Cell Adhesion; Cells; Chimera organism; Connexin 43; Connexins; E-Cadherin; E-Cadherin Staining Method; Endocytosis; Epithelial Cells; Extracellular Domain; Funding; Gap Junctions; Grant; Growth; In Vitro; Malignant neoplasm of prostate; Mediating; Molecular; N-Cadherin; National Center for Research Resources; Nebraska; PC3 cell line; Pathogenesis; Principal Investigator; Prostatic Neoplasms; Protein Family; Research; Research Infrastructure; Resources; Role; Signal Transduction; Source; Testing; United States National Institutes of Health; cancer cell; cell motility; cost; in vivo; knock-down; molecular mass; prevent; small molecule; tumor progression

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Gap junctions are conglomerations of cell-cell channels that are formed by a family of proteins, called connexins, which are designated according to molecular mass. They permit the direct passage of small molecules between adjoining cells. Our studies have shown that in invasive prostate tumors connexin32 and connexin43 remain intracellular whereas in well differentiated prostate tumors both connexins are assembled into gap junctions. Moreover, forced expression of both connexins in prostate cancer cells induces differentiation and inhibits growth in vitro and in vivo. Our studies have also shown that expression of anti-metastatic E-cadherin facilitates gap junction assembly, whereas expression of pro-invasive N-cadherin disrupts assembly. Our central hypothesis is that bidirectional signaling between cadherins and connexins is required to maintain the polarized and the differentiated state of epithelial cells and that gap junction assembly is the downstream target of signaling initiated by cadherins, with E-cadherin facilitating the assembly and N-cadherin promoting the disassembly. The proposed studies in aim 1 will determine how E-cadherin mediated cell-cell adhesion controls the assembly of connexins into gap junctions in prostate cancer cells. The hypothesis to be tested is that cadherin mediated cell-cell adhesion induces a signaling cascade, which modulates gap junction assembly. Wild type and extracellular domain deleted cadherins that are unable to induce cell-cell adhesion will be used. The proposed studies in aim 2 will determine the molecular mechanisms by which E-cadherin and N-cadherin modulate gap junction assembly differentially. This aim tests the hypothesis that E-cadherin facilitates gap junction assembly by preventing the endocytosis of connexins whereas N-cadherin promotes disassembly by inducing endocytosis. E-cadherin and N-cadherin will be knocked down in various prostate cancer cell lines in which connexins are either assembled into gap junctions or remain intracellular. Alternatively, wild type N-cadherin, and its chimeras that modulate cell motility differentially, will be expressed in Ecadherin expressing prostate cancer cell lines. These studies will enhance our understanding about the role of cadherins and connexins in the pathogenesis of prostate cancer.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 间隙连接是由蛋白质家族形成的细胞细胞通道的集合，称为 连接蛋白，根据分子质量指定。他们允许直接通过 相邻细胞之间的小分子。我们的研究表明，在侵入性前列腺肿瘤中 connexin32和connexin43保持细胞内，而在分化良好的前列腺肿瘤中都保持 连接素组装成间隙连接。此外，在 前列腺癌细胞诱导分化并抑制体外和体内的生长。我们的研究有 还表明，抗中转移E-钙粘着蛋白的表达有助于间隙连接组件，而 促侵入性N-钙粘蛋白的表达破坏了组装。我们的中心假设是双向 需要钙粘着蛋白和连接素之间的信号传导才能维持极化和 上皮细胞的分化状态，而间隙连接组件是 钙粘蛋白发起的信号传导，E-钙粘蛋白促进组装和N-钙粘蛋白促进 拆卸。 AIM 1中提出的研究将确定e-钙粘蛋白介导的细胞细胞如何 粘附控制连接素的组装到前列腺癌细胞中的间隙连接处。这 要测试的假设是钙粘蛋白介导的细胞 - 细胞粘附诱导信号级联， 调节间隙连接组件。野生型和细胞外结构域删除了钙粘蛋白 将无法诱导细胞细胞粘附。 AIM 2中提出的研究将确定 E-钙粘蛋白和N-钙粘蛋白调节间隙连接组件的分子机制 差异。这个目的检验了以下假设：电子钙粘蛋白通过 防止连接蛋白的内吞作用 内吞作用。 E-钙粘蛋白和N-钙粘蛋白将在各种前列腺癌细胞系中被击倒 连接素要么组装成间隙连接，要么保持细胞内。或者，野性 N-钙粘蛋白及其调节细胞运动的嵌合体将在Ecadherin中表达 表达前列腺癌细胞系。这些研究将增强我们对 钙粘蛋白和连接素在前列腺癌发病机理中的作用。