Cell-cell adhesion and signal transduction

描述(由申请人提供)：细胞-细胞黏附对于组织结构的发展和维持是必不可少的。除了在机械黏附中的作用外，细胞间连接还为细胞提供关于它们在组织中的位置的信息，这些信息后来被转化为关于细胞增殖、分化或细胞死亡的重要决定。这些沟通渠道在癌症中被打断或受到干扰。当正常的上皮细胞在培养中受到接触抑制并在达到融合时停止增殖时，癌细胞不是接触抑制的，而是在融合后继续生长。细胞间黏附结构与细胞增殖调控之间的分子机制尚不清楚。虽然细胞使用不同类型的细胞-细胞黏附结构，但在人类癌症中，黏附连接似乎经常受到干扰。粘附性连接蛋白E-钙粘素、α-连环素和β-连环素在肿瘤细胞中经常发生突变，E-钙粘附素或α-连环素的缺失与肿瘤的侵袭性和不良的临床预后有关。我们之前使用了条件性基因敲除方法，发现z-catenin负向调节小鼠角质形成细胞的增殖，是执行接触抑制程序所必需的。在这一应用中，我们建议使用α-连环蛋白基因敲除角质形成细胞作为模型系统，以揭示α-连环蛋白介导的细胞增殖控制的分子机制。为此，我们将发现并研究α-连环蛋白下游的信号中间产物的功能，并介导其在接触抑制中的作用。我们最近确定Erk1/2和Wnt通路在α-连环蛋白缺失的角质形成细胞中上调。由于这些信号转导通路对调节小鼠角质形成细胞的增殖至关重要，我们将确定(-catenin)介导的Erk1/2和Wnt信号的调节机制和意义。这些研究将有助于扩展我们对细胞间黏附介导的细胞增殖控制的知识，并为α-连环蛋白的信号作用提供新的见解。这一信息将有助于未来有效的抗癌治疗的发展。

DESCRIPTION (provided by applicant): Cell-cell adhesion is essential for development and maintenance of tissue architecture. In addition to their role in mechanical adhesion, intercellular junctions provide cells with information concerning their position within the tissue that is later translated into important cell decisions concerning proliferation, differentiation or cell death. These lines of communication are broken or perturbed in cancer. While normal epithelial cells in culture are contact-inhibited and stop proliferating upon reaching the confluence, the cancer cells are not contact-inhibited and continue to grow past confluence. The molecular mechanisms connecting intercellular adhesion structures with regulation of cell proliferation are poorly understood. While cells use different types of cell-cell adhesion structures, the Adherens Junctions appear to be often perturbed in human cancers. The Adherens Junction proteins E-cadherin, alpha-, and beta-catenins are often mutated in tumor cells, and loss of E-cadherin or alpha-catenin correlates with tumor aggressiveness and poor clinical outcome. We have previously used a conditional gene knockout approach and found that (z-catenin negatively regulates proliferation of mouse keratinocytes and is required for execution of contact inhibition program. In this application we propose to use alpha-catenin-knockout keratinocytes as a model system to reveal the molecular mechanisms responsible for alpha-catenin-mediated control of cell proliferation. For this purpose, we will discover and investigate the function of signaling intermediates that act downstream from alpha-catenin and mediate its role in contact inhibition. We have recently determined that Erkl/2 and Wnt pathways are upregulated in the alpha-catenin-null keratinocytes. Since these signal transduction pathways are critical for regulation of cell proliferation of mouse keratinocytes, we will determine the mechanisms and significance of (-catenin-mediated regulation of Erkl/2 and Wnt signaling. These studies will help to extend our knowledge of cell-cell adhesion-mediated control of cell proliferation and provide new insights about the signaling role of alpha-catenin. This information will be useful for the future development of efficient anticancer therapies.