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

基本信息

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
项目类别：
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

项目摘要

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-钙粘着蛋白是一种细胞 - 细胞粘附分子，对于偏振上皮器官的发展和功能至关重要。令人惊讶的是，电子钙粘蛋白也是主要的肿瘤抑制剂。 e-钙粘蛋白表达的丧失发生在家族性癌症综合征和零星癌中，肾细胞癌是两者的突出例子。 E-钙粘着蛋白的肿瘤抑制作用先前已归因于细胞运动性和对WNT信号的影响。在这里，我们试图为e-钙蛋白定义一种新型的肿瘤抑制功能。我们已经确定Anoikis（“无家可归”）是通过钙粘蛋白 - 参与度介导的，它表示通过剥夺细胞 - 矩阵相互作用引起的凋亡。对Anoikis的抵抗是转移能力的标志。我们已经确定了CDC42和RAC GTPases的激活剂PIX赋予肾上皮细胞中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粘附的肿瘤抑制剂。该提案检验了以下假设：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，它解决了在透明细胞肾细胞癌（CC-RCC）的背景下，E-钙粘着蛋白的推定促凋亡功能。 von Hippel-Lindau肿瘤抑制基因VHL是E-钙粘蛋白表达的调节剂，在CC-RCC中起主要因果作用。该提案的目标将以三个目标来实现。 AIM 1确定了对pix中功能域的要求，以抵消钙粘蛋白介导的凋亡。 AIM 2定义了crib- pix复合物在通过钙粘蛋白 - 参与引起的凋亡中的作用。 AIM 3确定CC-RCC中VHL的损失是否赋予对电子钙粘蛋白介导的细胞凋亡的保护。总的来说，拟议的研究将阐明电子钙粘着蛋白对上皮形态发生和抑制肿瘤的重要性的新功能。