Desmosomal components and epithelial cell fate decision

描述(申请人提供)：桥粒是细胞间的粘连连接，在维持组织结构和功能方面发挥关键作用，当它们受损时，几种皮肤脆性和头发异常情况的发展就证明了这一点。桥粒蛋白(Desmogleins，DSG)是桥粒的钙离子依赖性黏附成分，DSG1、DSG3和DSG4是多种自身免疫性、感染性和遗传性疾病的靶分子。因此，这些蛋白质在细胞-细胞黏附、皮肤屏障功能和毛囊发育中的作用已经得到了很好的证实。然而，这些桥粒蛋白是否能介导细胞内的信号转导通路还知之甚少。对Dsg2缺失小鼠的研究证实了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在包括鳞状细胞癌(SCC)在内的某些上皮性恶性肿瘤中过表达，提示其在细胞增殖和分化中的作用，有利于肿瘤的发展。然而，目前尚不清楚Dsg2是否--如果是--与鳞癌的恶性表型有关。因此，我们建立了一种体内转基因小鼠模型，该模型在表皮中高表达Dsg2。初步结果表明，Dsg2的异位表达诱导了表皮细胞的过度增殖，增加了角质形成细胞的抗凋亡能力，并促进了乳头状瘤的发展。与这些观察结果一致的是，Dsg2的过度表达也与表皮信号转导的失控和包括转移相关蛋白在内的肿瘤相关基因的上调有关。这些信号成分以前被认为与上皮细胞和组织的过度增殖和/或恶性转化有关。基于这一强有力的初步证据，我们建议从分子上定义Dsg2调控上皮细胞命运的途径。这一目标将通过两个具体目标来实现：1)确定Dsg2表达支持上皮细胞存活和增殖的分子机制；2)确定Dsg2转基因小鼠体内皮肤肿瘤易感性增加的分子机制。总体而言，拟议的研究将阐明Dsg2与皮肤结构、功能和癌症发生有关的新的细胞内信号作用。 项目叙述/与公共卫生的相关性：这一应用将有助于确定桥粒钙粘附素在调节上皮细胞-细胞黏附以及细胞生长和存活方面的作用。特别是，我们将重点研究桥粒芯糖蛋白2，它在几种上皮源性癌症中表达上调。确定桥粒芯糖蛋白2影响肿瘤生长和发展的分子机制有可能确定癌症治疗的新靶点。

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.