Cadherin-regulated apoptosis and survival signaling in epithelial cells

描述（由申请人提供）：我们的目的是了解极化上皮细胞中细胞-细胞接触介导的信号传导调节上皮结构和肿瘤发生的机制。E-钙粘蛋白是一种细胞间粘附分子，对极化上皮器官的发育和功能至关重要。引人注目的是，E-钙粘蛋白也是一种主要的肿瘤抑制因子。E-cadherin表达的缺失发生在家族性癌症综合征和散发性癌症中，肾细胞癌是两者的突出例子。E-钙粘蛋白的肿瘤抑制作用以前被归因于抑制细胞运动和对Wnt信号传导的影响。在这里，我们试图定义一个新的肿瘤抑制功能的E-钙粘蛋白。我们已经确定，失巢凋亡（“无家可归”），这表示细胞-基质相互作用的剥夺引起的凋亡，是由钙粘蛋白介导的。抗失巢凋亡是转移能力的标志。我们已经确定了？PIX是Cdc 42和Rac GTP酶的激活剂，在肾上皮细胞中赋予针对钙粘蛋白介导的凋亡的保护。? PIX直接与Scrib结合，Scrib是一种促进E-钙粘蛋白介导的细胞-细胞粘附的肿瘤抑制因子。这项建议测试的假设，？PIX-Scrib复合物调节上皮细胞中钙粘蛋白介导的存活信号此外，它解决了假定的促凋亡功能的E-钙粘蛋白的背景下，透明细胞肾细胞癌（CC-RCC）。VHL是一种调节E-钙粘蛋白表达的抑癌基因，在CC-RCC中起主要作用。本提案的目标将在三个方面实现。目标1建立的功能域的要求？PIX对抗钙粘蛋白介导的细胞凋亡。目标2定义了抄写员的角色-？钙粘蛋白结合诱导的细胞凋亡中的PIX复合物。目的3确定CC-RCC中VHL的缺失是否赋予对E-钙粘蛋白介导的凋亡的保护。总的来说，拟议的研究将阐明一个新的功能，上皮细胞形态发生和肿瘤抑制的关键重要性的E-钙粘蛋白。 公共卫生相关性：上皮细胞-细胞粘附对于内部器官的发育和功能以及通过尚不清楚的机制预防肿瘤形成是必不可少的。我们已经发现上皮细胞-细胞粘附调节程序性细胞死亡，并且已经鉴定了在正常上皮细胞中防止这种死亡的机制的组分。阐明这些机制对于我们理解上皮癌非常重要，上皮癌占所有癌症死亡率的80%以上。

DESCRIPTION (provided by applicant): Our objective is to understand the mechanisms by which cell-cell contact-mediated signaling in polarized epithelial cells regulates epithelial architecture and oncogenesis. E-cadherin is a cell-cell adhesion molecule that is essential to development and function of polarized epithelial organs. Strikingly, E-cadherin is also a major tumor suppressor. Loss of E-cadherin expression occurs in familial cancer syndromes and sporadic cancer, with renal cell carcinoma serving a prominent example of both. The tumor suppressive role of E-cadherin has previously been ascribed to inhibition of cell motility and effects on Wnt signaling. Here we seek to define a novel tumor suppressor function for E- cadherin. We have determined that anoikis ("homelessness"), which denotes apoptosis elicited by deprivation of cell-matrix interaction, is mediated by cadherin-engagement. Resistance to anoikis is a hallmark of metastatic capacity. We have established that ?PIX, an activator of the Cdc42 and Rac GTPases, confers protection against cadherin- mediated apoptosis in kidney epithelial cells. ?PIX binds directly to Scrib, a tumor suppressor that promotes E-cadherin-mediated cell-cell adhesion. This proposal tests the hypothesis that the ?PIX-Scrib complex modulates cadherin-mediated survival signaling in epithelial cells. It moreover addresses the putative pro-apoptotic function of E-cadherin in the context of clear cell renal cell carcinoma (CC-RCC). The von Hippel- Lindau tumor suppressor gene VHL, a regulator of E-cadherin expression, plays a major causal role in CC-RCC. The goals of this proposal will be accomplished in three aims. Aim 1 establishes the requirement for functional domains in ?PIX to counteract cadherin- mediated apoptosis. Aim 2 defines the role of the Scrib-?PIX complex in apoptosis elicited by cadherin-engagement. Aim 3 determines whether loss of VHL in CC-RCC confers protection against E-cadherin-mediated apoptosis. Collectively, the proposed studies will elucidate a novel function of E-cadherin of pivotal importance to epithelial morphogenesis and tumor suppression. PUBLIC HEALTH RELEVANCE: Epithelial cell-cell adhesion is essential to development and function of internal organs, as well as in prevention of tumor formation by mechanisms that are not well understood. We have discovered that epithelial cell-cell adhesion regulates programmed cell death, and have identified components of the machinery that prevents this death in normal epithelial cells. Elucidation of these mechanisms is important to our understanding of epithelial cancers, which account for more that 80% of all cancer fatalities.