Cadherin-regulated apoptosis and survival signaling in epithelial cells

钙粘蛋白调节上皮细胞凋亡和生存信号

• 批准号: 8444356
• 负责人: STEEN HENNING HANSEN
• 金额: $ 33.94万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8444356
• 关键词: Accounting; Address; Adherens Junction; Adhesives; Anoikis; Apoptosis; Apoptotic; Architecture; Binding; Cadherins; Cell Adhesion Molecules; Cell Death; Cell Line; Cell-Cell Adhesion; Cells; Cessation of life; Clear Cell; Complex; Data; Development; Down-Regulation; E-Cadherin; Epithelial; Epithelial Cells; Etiology; GIT1 gene; GIT2 gene; Goals; Guanine Nucleotide Exchange Factors; Guanosine Triphosphate Phosphohydrolases; Hereditary Malignant Neoplasm; Homelessness; Hypoxia; Hypoxia Inducible Factor; Link; Loss of E-cadherin Expression; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Methods; Morbidity - disease rate; Morphogenesis; Neoplasm Metastasis; Organ; Oxygen; PAK-1 kinase; Patients; Play; Prevention; Property; Proteins; Receptor Protein-Tyrosine Kinases; Recruitment Activity; Regulation; Renal Cell Carcinoma; Repression; Research; Resistance; Role; Signal Transduction; Small GTPase Activators; Syndrome; Testing; Tumor Suppression; Tumor Suppressor Genes; Tumor Suppressor Proteins; VHL protein; Von Hippel-Lindau Syndrome; Von Hippel-Lindau Tumor Suppressor Protein; Work; base; cell motility; cell transformation; deprivation; kidney epithelial cell; monolayer; mutant; novel; prevent; public health relevance; reconstitution; scaffold; small hairpin RNA; transcription factor; tumor; tumorigenesis; ubiquitin-protein ligase

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.

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。