Role of Plakophilin-1 in HNSCC

Plakophilin-1 在 HNSCC 中的作用

• 批准号: 7146371
• 负责人: JAMES K WAHL
• 金额: $ 36.75万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7146371
• 关键词: cell adhesion; gene expression; gene targeting; head; intercellular connection; play; proteins; role

DESCRIPTION (provided by applicant): Understanding molecular changes in progression of head and neck squamous cell carcinoma (HNSCC) is essential for predicting clinical outcome and for developing effective therapies for treating the disease. Plakophilin-1 is a member of the Armadillo (Arm) protein family that is a structural component of the cell-cell adhesion junction known as the desmosome. In addition, plakophilin-1 is found in the nucleus, where its function is unknown. A well-studied member of the Arm family, beta-catenin, normally associates at the plasma membrane with the adherens cell-cell adhesion complex but also is found in the nucleus where it is a transcriptional regulator in the Wnt signaling pathway and plays a critical role in colon cancer. Data presented in this proposal show that not only is plakophilin-1 protein expression reduced in HNSCC, reducing plakophilin-1 expression in cell lines leads to increased cell motility in vitro. The central hypothesis for this project is that plakophilin-1, similar to beta-catenin, plays roles in both cell-cell adhesion and gene expression and that a shift in these cellular events plays a critical role in the malignant progression of HNSCC. The goal for the proposed work is to define the nuclear role for plakophilin-1 in HNSCC by showing that loss of plakophilin-1 expression alters the expression of genes relevant to tumor progression. The specific aims are (1) to determine the mechanisms of plakophilin-1 translocation to the nucleus, (2) to determine the nuclear function of the plakophilin-1/TLS complex, and (3) to determine the role of plakophilin-1 target genes in HNSCC progression. This work will be greatly aided by 2 tools already developed for the project: a highly specific monoclonal antibody to plakophilin-1 and an activatable form of plakophilin-1 that can be exogenously expressed in cells. Defining the nuclear function of plakophilin-1 will lay the ground work for identifying new prognostic markers for HNSCC and also potential targets for novel therapeutic strategies for treating the disease.

描述（由申请人提供）：了解头部和颈部鳞状细胞癌（HNSCC）进展的分子变化对于预测临床结果和开发治疗疾病的有效疗法至关重要。 plakophilin-1是Armadillo（ARM）蛋白质家族的成员，它是细胞细胞粘附连接的结构成分，称为脱粒体。另外，在核中发现了plakophilin-1，其中其功能尚不清楚。一个经过良好研究的ARM家族β-catenin的成员通常在质膜上与粘附细胞细胞粘附复合物相关联，但在核中也发现了它是Wnt信号传导途径中的转录调节剂，并且在结肠癌中起关键作用。该提案中提出的数据表明，HNSCC中的plakophilin-1蛋白表达不仅降低了plakophilin-1蛋白的表达，从而降低了细胞系中plakophilin-1的表达，从而导致体外细胞运动增加。该项目的中心假设是，与β-catenin相似的plakophilin-1在细胞 - 细胞粘附和基因表达中都起着作用，并且这些细胞事件的变化在HNSCC的恶性进展中起关键作用。拟议的工作的目的是通过表明plakophilin-1表达的丧失改变与肿瘤进展相关的基因的表达来定义plakophilin-1在HNSCC中的核作用。具体目的是（1）确定plakophilin-1易位到核的机制，（2）确定plakophilin-1/tls复合物的核功能，以及（3）确定plakophilin-1靶基因在HNSCC进展中的作用。已经为该项目开发的2种工具将极大地帮助这项工作：一种高度特异性的单克隆抗体，可激活的plakophilin-1形式，可以在细胞中外源表达。 定义plakophilin-1的核功能将为识别HNSCC的新预后标记以及用于治疗该疾病的新型治疗策略的潜在目标。