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: 8233310
• 负责人: STEEN HENNING HANSEN
• 金额: $ 36.11万
• 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/8233310
• 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. 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.

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，对于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，肾细胞癌是这两种癌症的一个突出例子。 E-钙粘蛋白的肿瘤抑制作用先前被归因于细胞运动的抑制和对 Wnt 信号传导的影响。在这里，我们试图定义 E-钙粘蛋白的一种新的肿瘤抑制功能。我们已经确定，失巢凋亡（“无家可归”）是由钙粘蛋白接合介导的，失巢凋亡是指因细胞与基质相互作用的剥夺而引发的细胞凋亡。对失巢凋亡的抵抗是转移能力的标志。我们已经确定，?PIX（Cdc42 和 Rac GTPases 的激活剂）可针对肾上皮细胞中钙粘蛋白介导的细胞凋亡提供保护。 ?PIX 直接与 Scrib 结合，Scrib 是一种肿瘤抑制因子，可促进 E-钙粘蛋白介导的细胞间粘附。该提案测试了以下假设：?PIX-Scrib 复合物调节上皮细胞中钙粘蛋白介导的生存信号传导。此外，它还解决了透明细胞肾细胞癌 (CC-RCC) 中 E-钙粘蛋白的推定促凋亡功能。 von Hippel-Lindau 抑癌基因 VHL 是 E-钙粘蛋白表达的调节因子，在 CC-RCC 中发挥着重要的因果作用。该提案的目标将通过三个目标来实现。目标 1 确定了 ?PIX 中功能域对抗钙粘蛋白介导的细胞凋亡的要求。目标 2 定义了 Scrib-?PIX 复合物在钙粘蛋白结合引发的细胞凋亡中的作用。目标 3 确定 CC-RCC 中 VHL 的缺失是否能提供针对 E-钙粘蛋白介导的细胞凋亡的保护。总的来说，拟议的研究将阐明 E-钙粘蛋白的新功能，其对上皮形态发生和肿瘤抑制至关重要。 公共健康相关性：上皮细胞间粘附对于内脏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至关重要。我们发现上皮细胞间粘附调节程序性细胞死亡，并确定了防止正常上皮细胞死亡的机制的组成部分。阐明这些机制对于我们了解上皮癌非常重要，上皮癌占所有癌症死亡人数的 80% 以上。