Desmosomal components and epithelial cell fate decision

描述（由申请人提供）：桥粒是细胞间粘附连接，在维持组织结构和功能方面发挥关键作用，如当它们受损时发生几种皮肤脆性和毛发异常状况所示。 桥粒芯糖蛋白（Dsg）是桥粒的Ca 2+依赖性粘附组分，Dsg 1、3和4是多种人类自身免疫性、感染性和遗传性疾病的靶分子。 因此，这些蛋白质在细胞-细胞粘附、皮肤屏障功能和毛囊发育中的作用已被充分确立。 然而，这些桥粒芯糖蛋白是否可以介导细胞内信号转导途径知之甚少。 对Dsg 2缺失小鼠的研究证明了Dsg 2在胚胎发育以及干细胞生长和存活过程中的重要性。 此外，Dsg 2在某些上皮恶性肿瘤（包括鳞状细胞癌（SCC））中过表达，表明其在有利于肿瘤发展的细胞增殖和分化中的作用。 然而，目前尚不清楚Dsg 2是否-以及如果是的话-如何促成SCC的恶性表型。 因此，我们建立了在表皮中过表达Dsg 2的体内转基因小鼠模型。 初步结果表明，Dsg 2的异位表达诱导过度增殖的表皮表型，增加角质形成细胞的凋亡抗性，并增强乳头状瘤的发展。 与这些观察结果一致，Dsg 2过表达也与表皮信号转导失调和肿瘤相关基因（包括转移相关蛋白）上调相关。 这些信号传导组分先前已经涉及上皮细胞和组织的过度增殖和/或恶性转化。 基于这一强有力的初步证据，我们建议从分子上定义Dsg 2调节上皮细胞命运的途径。 该目标将在两个具体目标中追求：1）确定Dsg 2表达支持上皮细胞存活和增殖的分子机制，和2）确定Dsg 2 Tg小鼠体内对皮肤肿瘤发生的易感性增加的分子机制。 总体而言，拟议的研究将阐明Dsg 2的新型细胞内信号传导作用，因为它们与皮肤结构，功能和致癌作用有关。 项目叙述/与公共卫生的相关性：该应用将有助于定义桥粒钙粘蛋白在调节上皮细胞-细胞粘附以及细胞生长和存活中的作用。 特别是，我们将集中在桥粒芯糖蛋白2，这是上调几种上皮来源的癌症。 确定桥粒芯糖蛋白2影响肿瘤生长和发育的分子机制具有确定治疗性癌症治疗的新靶点的潜力。

DESCRIPTION (provided by applicant): Desmosomes are intercellular adhesive junctions that play pivotal roles in maintaining tissue architecture and function as illustrated by the development of several skin fragility and hair abnormality conditions when they are impaired. Desmogleins (Dsg) are the Ca2+dependent adhesion components of desmosomes and Dsg1, 3, and 4 are the target molecules in several human autoimmune, infectious, and inherited diseases. Thus, the roles of these proteins in cell-cell adhesion, skin barrier function, and hair follicle development are well established. However, whether these desmogleins can mediate intracellular signal transduction pathways is poorly understood. Studies of Dsg2 null mice attest to the importance of Dsg2 during embryonic development and in stem cell growth and survival. Furthermore, Dsg2 is overexpressed in certain epithelial malignancies including squamous cell carcinomas (SCC) suggesting its role in cell proliferation and differentiation that favor of tumor development. However, it is unknown whether - and if so how - Dsg2 contributes to the malignant phenotype of SCC. Consequently we established an in vivo transgenic mouse model overexpressing Dsg2 in the epidermis. Preliminary results demonstrate that ectopic expression of Dsg2 induced a hyperproliferative epidermal phenotype, increased apoptosis resistance of keratinocytes, and enhanced development of papillomas. Consistent with these observations, Dsg2 overexpression was also associated with deregulated epidermal signal transduction and upregulation of tumor-associated genes including the metastasis-associated proteins. These signaling components have previously been implicated in hyperproliferation and/or malignant transformation of epithelial cells and tissues. Based on this strong preliminary evidence we propose to molecularly define the pathways by which Dsg2 modulates epithelial cell fate. This goal will be pursued in two specific aims to: 1) determine the molecular mechanisms by which Dsg2 expression supports epithelial cell survival and proliferation, and 2) determine molecular mechanisms underlying increased susceptibility of Dsg2 Tg mice to skin tumorigenesis in vivo. Overall, the proposed studies will elucidate novel intracellular signaling roles of Dsg2 as they relate to skin structure, function, and carcinogenesis. Project Narrative/Relevance to Public Health: 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 epithelia-derived 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.