Cadherin-regulated apoptosis and survival signaling in epithelial cells

描述（由申请人提供）：我们的目标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-细胞黏附分子，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 -钙粘蛋白表达缺失发生在家族性癌症综合征和散发性癌症中，肾细胞癌是这两种情况的突出例子。E-cadherin的肿瘤抑制作用以前被认为是通过抑制细胞运动和影响Wnt信号传导来实现的。在这里，我们试图为E-钙粘蛋白定义一种新的肿瘤抑制功能。我们已经确定，由于细胞-基质相互作用被剥夺而引起的细胞凋亡是由钙粘蛋白参与介导的。对anoikis的抵抗是转移能力的标志。我们已经确定了吗？PIX是Cdc42和Rac gtpase的激活剂，对钙粘蛋白介导的肾上皮细胞凋亡具有保护作用。？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。这个提议验证了？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，该研究还探讨了在透明细胞肾细胞癌（CC-RCC）中E-cadherin的促凋亡功能。von Hippel- Lindau肿瘤抑制基因VHL是E-cadherin表达的调节因子，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建立了对？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。钙粘蛋白参与引起的细胞凋亡中的PIX复合体。目的3确定在CC-RCC中VHL的丧失是否对e -钙粘蛋白介导的细胞凋亡具有保护作用。总的来说，拟议的研究将阐明e -钙粘蛋白在上皮形态发生和肿瘤抑制中具有关键作用的新功能。

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.