Role of Desmosomal Adhesion in Carcinogenesis

桥粒粘附在癌发生中的作用

• 批准号: 8386930
• 负责人: My Georgia Mahoney
• 金额: $ 31.7万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 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/8386930
• 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

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.

描述（由申请人提供）：桥粒是细胞间粘附连接，在维持组织结构、完整性和功能方面发挥着关键作用。桥粒糖蛋白 (Dsg) 1-4 是桥粒的跨膜成分，是多种人类自身免疫性疾病、传染性疾病和遗传性疾病的靶分子，突出了它们在细胞间粘附、皮肤屏障功能和毛囊发育中的作用。然而，这些桥芯糖蛋白是否可以在正常和患病条件下介导细胞信号传导仍知之甚少。在人类中，DSG2 基因的基因突变会导致遗传性致心律失常性右心室发育不良/心肌病。对 Dsg2 缺失小鼠的研究证明了 Dsg2 在胚胎发育以及干细胞生长和存活过程中的重要性。此外，Dsg2 在某些上皮恶性肿瘤中过度表达，表明其在有利于肿瘤发展的细胞增殖和分化中发挥作用。我们最近提供了强有力的证据，表明表皮角质形成细胞中 Dsg2 的过度表达会解除与生长速率增加、贴壁依赖性细胞存活和体内皮肤肿瘤发展相关的多个信号通路的调节。这些令人信服的结果需要深入研究桥粒钙粘蛋白在上皮细胞生物学和皮肤肿瘤发展中的新作用。我们实验室的长期目标是在分子和细胞水平上阐明桥粒介导的信号传导；特别是皮肤发育过程中正常信号和致病信号之间的差异。我们的中心假设是桥粒芯糖蛋白可以激活独立于桥粒结构和粘附功能的信号事件。我们认为桥粒芯糖蛋白严格在桥粒范围内的功能不足以解释它们不同的生物学作用。因此，该提案的总体目标是阐明 Dsg2 激活的影响上皮细胞生长、存活和恶性转化的细胞和分子机制。该目标将通过三个具体目标来实现，旨在： 1) 评估 Dsg2 在不同细胞群（特别是祖细胞和分化上皮细胞）中表达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caveolin-1在Dsg2介导的信号传导和恶性转化中的作用。这项工作具有创新性，因为它利用了我们最近发现的 Dsg2 的“致癌”作用，以及显示 Dsg2 复杂蛋白水解加工和 Dsg2 与 Caveolin-1 一起定位到小凹（参与许多关键生长和生存信号通路的特殊脂筏）的初步数据。这里获得的结果将增强我们对桥粒钙粘蛋白和桥粒相关疾病的病理学的理解，并将有助于确定桥粒功能受损引起的获得性和遗传性疾病的治疗新方向。