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:8233310
- 负责人:
- 金额:$ 36.11万
- 依托单位:
- 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:
- 关键词:AccountingAddressAdherens JunctionAdhesivesAnoikisApoptosisApoptoticArchitectureBindingCadherinsCell Adhesion MoleculesCell DeathCell LineCell-Cell AdhesionCellsCessation of lifeClear CellComplexDataDevelopmentDown-RegulationE-CadherinEpithelialEpithelial CellsEtiologyGIT1 geneGIT2 geneGoalsGuanine Nucleotide Exchange FactorsGuanosine Triphosphate PhosphohydrolasesHereditary Malignant NeoplasmHomelessnessHypoxiaHypoxia Inducible FactorLinkLoss of E-cadherin ExpressionMalignant Epithelial CellMalignant NeoplasmsMediatingMethodsMorbidity - disease rateMorphogenesisNeoplasm MetastasisOrganOxygenPAK-1 kinasePatientsPlayPreventionPropertyProteinsReceptor Protein-Tyrosine KinasesRecruitment ActivityRegulationRenal Cell CarcinomaRepressionResearchResistanceRoleSignal TransductionSmall GTPase ActivatorsSyndromeTestingTumor SuppressionTumor Suppressor GenesTumor Suppressor ProteinsVHL proteinVon Hippel-Lindau SyndromeVon Hippel-Lindau Tumor Suppressor ProteinWorkbasecell motilitycell transformationdeprivationkidney epithelial cellmonolayermutantnovelpreventpublic health relevancereconstitutionscaffoldsmall hairpin RNAtranscription factortumortumorigenesisubiquitin-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.
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。
公共卫生相关性:上皮细胞 - 细胞粘附对于内部器官的发展和功能以及预防肿瘤形成的机制至关重要。我们发现上皮细胞 - 细胞粘附可调节编程的细胞死亡,并确定了阻止正常上皮细胞中这种死亡的机械组件。阐明这些机制对于我们对上皮癌的理解很重要,这占所有癌症死亡的80%。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
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STEEN HENNING HANSEN其他文献
STEEN HENNING HANSEN的其他文献
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