Role of Desmosomal Adhesion in Carcinogenesis

桥粒粘附在癌发生中的作用

基本信息

批准号：
8197909
负责人：
My Georgia Mahoney
金额：
$ 33.37万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-12-01 至 2014-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8197909
关键词：
1-Phosphatidylinositol 3-Kinase Adherens Junction Adhesions Adhesives Affect Architecture Arrhythmogenic Right Ventricular Dysplasia Autoimmune Process Basal Cell Basal cell carcinoma Binding Cadherins Cardiomyopathies Caveolae Cell Adhesion Molecules Cell Differentiation process Cell Proliferation Cell Survival Cell membrane Cell-Cell Adhesion Cells Cellular biology Chemicals Complex Data Desmosomes Development Disease Embryonic Development Endocytosis Epidermis Epithelial Epithelial Cell Proliferation Epithelial Cells Event Gene Mutation Genes Goals Growth Growth and Development function Hair Hair follicle structure Health Heart Human Human Development Human Genetics In Vitro Inherited Intercellular Junctions Intracellular Transport Investigation Knock-out Knockout Mice Laboratories MAP Kinase Gene MEKs Malignant - descriptor Malignant Neoplasms Mediating Membrane Microdomains Molecular Mus Mutation Oncogenic Papilloma Pathology Pathway interactions Play Population Premalignant Process Proteins Proteolytic Processing Proto-Oncogene Proteins c-akt Role Signal Pathway Signal Transduction Signal Transduction Pathway Site Skin Skin Cancer Skin Neoplasms Squamous cell carcinoma Stem cells Structure Testing Therapeutic Tissues Transgenic Mice Tumor-Derived Work cancer therapy carcinogenesis caveolin 1 cell growth design desmoglein desmoglein 1 desmoglein 2 in vivo innovation involucrin keratinocyte mouse model new therapeutic target novel overexpression progenitor promoter public health relevance tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): Desmosomes are intercellular adhesive junctions that play pivotal roles in maintaining tissue architecture, integrity and function. Desmogleins (Dsg) 1-4 are the transmembrane components of desmosomes and are the target molecules in several human autoimmune, infectious and heritable diseases highlighting their roles in cell-cell adhesion, skin barrier function, and hair follicle development. However, whether these desmogleins can mediate cell signaling under normal and diseased conditions is still poorly understood. In human, genetic mutations in the DSG2 gene results in inherited arrhythmogenic right ventricular dysplasia/cardiomyopathy. Studies of the Dsg2 null mice attest to the importance of Dsg2 during embryonic development and in stem cell growth and survival. Furthermore, Dsg2 is over-expressed in certain epithelial malignancies suggesting a role in cell proliferation and differentiation that favor of tumor development. We recently provide strong evidence that overexpression of Dsg2 in epidermal keratinocytes deregulates multiple signaling pathways associated with increased growth rate, anchorage-independent cell survival, and the development of skin tumors in vivo. These compelling results call for an in-depth investigation of novel roles of desmosomal cadherins in epithelial cell biology and skin tumor development. The long-term goal of our laboratory is to elucidate desmosome-mediated signaling at the molecular and cellular level; particularly, the differences between normal and pathogenic signaling during skin development. Our central hypothesis is that desmogleins can activate signaling events that are independent of desmosomal structure and adhesive function. We argue that the function of desmogleins strictly within the context of the desmosome is not sufficient to explain their diverse biologic effects. Thus the overall goal for this proposal is to elucidate the cellular and molecular mechanisms activated by Dsg2 that impact epithelial cell growth, survival and malignant transformation. This goal will be pursued in three Specific Aims designed to: 1) Assess the effects of Dsg2 on signaling and malignant transformation when expressed in different cell populations specifically progenitor and differentiating epithelial cells; 2) Assess the role of proteolytic processing of Dsg2 in epithelial cell growth and survival; and 3) Determine the role of caveolin-1 in Dsg2-mediated signaling and malignant transformation. The proposed work is innovative because it capitalizes on our recent discovered "oncogenic" role of Dsg2 and preliminary data showing complex proteolytic processing of Dsg2 and localization of Dsg2 with caveolin-1 to the caveolae, specialized lipid rafts that are involved in many key growth and survival signaling pathways. The results obtained here will enhance our understanding of desmosomal cadherins and the pathology of desmosome-associated diseases and will help identify new directions for therapeutic treatments of acquired and inherited diseases resulting from impaired desmosome function. PUBLIC HEALTH RELEVANCE: This application will help define the roles of desmosomal cadherins in modulating, not only epithelial cell-cell adhesion, but also cell growth and survival. In particular, we will focus on desmoglein 2, which is up regulated in several skin cancers. Determining the molecular mechanisms by which desmoglein 2 affects tumor growth and development has the potential of identifying new targets for therapeutic cancer treatments.

描述（由申请人提供）：脱糖体是细胞间的粘合剂连接，它们在维持组织结构，完整性和功能方面起着关键作用。脱木蛋白（DSG）1-4是脱粒体的跨膜成分，是几种人类自身免疫性，传染性和可遗传疾病中的靶分子，突出了它们在细胞细胞粘附，皮肤屏障功能和毛囊发育中的作用。但是，在正常和患病状况下，这些脱木蛋白是否可以介导细胞信号传导仍然很少了解。在人类中，DSG2基因中的遗传突变导致遗传心律失常右心室发育不良/心肌病。 DSG2无效小鼠的研究证明了DSG2在胚胎发育过程中的重要性以及干细胞生长和生存。此外，DSG2在某些上皮恶性肿瘤中表现出了过度表达，这表明在细胞增殖和分化中起作用，这有利于肿瘤发育。最近，我们提供了有力的证据表明，表皮角质形成细胞中DSG2的过表达取消了与生长速率增加，独立的细胞存活以及体内皮肤肿瘤的发育相关的多种信号通路。这些引人入胜的结果呼吁深入研究脱乳小蛋白在上皮细胞生物学和皮肤肿瘤发育中的新作用。我们实验室的长期目标是阐明分子和细胞水平上的脱骨介导的信号传导。特别是，皮肤发育过程中正常信号和致病信号之间的差异。我们的中心假设是，去蛋白可以激活独立于脱蓝色结构和粘合功能的信号事件。我们认为，在脱糖体的背景下，脱木蛋白的功能不足以解释其多种生物学作用。因此，该提案的总体目标是阐明由DSG2激活的细胞和分子机制，影响上皮细胞的生长，生存和恶性转化。该目标将在以下三个特定目标中实现：1）评估DSG2在不同细胞群体中表达的特异性祖细胞和区分上皮细胞时对信号传导和恶性转化的影响； 2）评估DSG2蛋白水解加工在上皮细胞生长和存活中的作用； 3）确定小窝蛋白-1在DSG2介导的信号传导和恶性转化中的作用。拟议的工作具有创新性，因为它利用了我们最近发现的DSG2的“致癌”作用和初步数据，显示了DSG2的复杂蛋白水解处理以及DSG2与Caveolin-1在小窝中的定位，对小窝，专门的脂质筏涉及许多关键的生长和生存信号通道。此处获得的结果将增强我们对脱发核蛋白的理解和脱骨相关疾病的病理学，并将有助于确定因乳胶功能受损而导致的获得和遗传性疾病的治疗方法的新方向。公共卫生相关性：此应用将有助于定义脱骨钙蛋白在调节中的作用，不仅是上皮细胞 - 细胞粘附，而且还可以细胞生长和生存。特别是，我们将专注于Desmoglein 2，该2在几种皮肤癌中受到调节。确定Desmoglein 2影响肿瘤生长和发育的分子机制具有鉴定治疗性癌症治疗的新靶标。