COBRE: UNE MED CTR: P1: ROLE OF DESMOSOMES IN ORAL SQUAMOUS CELL CARCINOMA

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。桥粒是层状鳞状上皮组织中突出的细胞-细胞连接，其组成因组织不同层的细胞而异。目前尚不清楚为什么细胞利用不同的成分在同一组织内组装桥粒。然而，可能是由不同分子成分组成的桥粒发挥不同的功能，导致粘连特性的改变。在鳞状细胞癌中，桥粒体蛋白的表达普遍降低；然而，这些蛋白对肿瘤发生的作用在很大程度上是未知的。我们的长期目标是了解桥粒在维持鳞状上皮组织正常表型中的作用，并确定它们在肿瘤发生过程中的改变是否影响细胞行为。我们的假设是桥粒组成的改变导致了不同的粘附和/或细胞-细胞信号的改变。我们的实验室在细胞粘附和细胞运动的功能分析方面有丰富的经验，我们的定位是在我们理解桥粒的功能和这种细胞结构在鳞状细胞癌的发展中所起的作用方面做出重大贡献。具体目的是：1)确定桥粒的组成是否影响细胞的粘附、增殖和运动；2)进一步了解plakophilin-1在桥粒和细胞核中的功能。Plakophilin-1是一种桥粒蛋白，存在于细胞核和质膜中，这使我们提出Plakophilin-1参与可能与桥粒粘连有关的核信号传导。我们将通过结构/功能研究来探讨嗜血小板蛋白-1的核-胞质转运机制；使用独特的“活化”形式的plakophilin-1来研究这种蛋白在粘附和细胞信号传导中的作用；并研究与白细胞介素- 1相关的核蛋白。总的来说，本文提出的研究将定义桥粒组分对细胞运动、侵袭性和信号传导的贡献。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Desmosomes are prominent cell-cell junctions in stratified squamous epithelial tissues, whose composition varies among cells of the different layers of the tissue. It is not known why cells utilize different components to assemble desmosomes within the same tissue. However, it is likely that desmosomes comprised of different molecular components perform diverse functions and lead to altered adhesive characteristics. Desmosomal protein expression is generally reduced in squamous cell carcinomas; however, the contribution of these proteins to tumorigenesis is largely unknown. Our long-term goals are to understand the role desmosomes play in maintaining the normal phenotype of squamous epithelial tissues and to determine if their alteration during tumorigenesis influences cellular behavior. Our hypothesis is that changes in desmosomal composition result in differential adhesion and/or altered cell-cell signaling. Our laboratory has extensive experience in functional analysis of cell-cell adhesion and cell motility, and we are positioned to make significant contributions to our understanding of desmosome function and the role this cellular structure plays in the development of squamous cell carcinomas. The specific aims are: 1) To determine if the composition of desmosomes influences cell adhesion, proliferation and motility; and 2) To further understand the function of plakophilin-1 in the desmosome and in the nucleus. Plakophilin-1 is a desmosomal protein that is found in the nucleus as well as in the plasma membrane, which led us to propose that plakophilin-1 participates in nuclear signaling that may be linked to desmosomal adhesion. We will use structure/function studies to investigate the mechanism of nucleo-cytoplasmic transport of plakophilin-1 ; use a unique "activatible" form of plakophilin-1 to investigate the role of this protein in adhesion and in cellular signaling; and investigate nuclear proteins that associate with plakophilin-l. Collectively, the studies proposed herein will define the contribution of desmosomal components to cellular motility, invasiveness and signaling.