REGULATION OF CYCLIN D1 EXPRESSION IN THE INTESTINE

肠道中细胞周期蛋白 D1 表达的调节

• 批准号: 6690370
• 负责人: JENNIFER D. BLACK
• 金额: $ 26万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-15 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6690370
• 关键词: carcinogenesis; cell growth regulation; cell line; cyclins; enzyme activity; flow cytometry; gastrointestinal epithelium; green fluorescent proteins; intestine neoplasm; isozymes; laboratory mouse; mitogen activated protein kinase; neoplastic growth; nuclear runoff assay; posttranslational modifications; protein kinase C; protein protein interaction; tissue /cell culture

DESCRIPTION (provided by applicant): Cyclin D1 is a tightly regulated cell cycle control molecule that functions as a key determinant of progression through G1 phase and as a major sensor of extracellular growth stimulatory and inhibitory signals. Aberrant expression of cyclin D1 is one of the most frequent abnormalities in human cancer, and is believed to play a causative role in tumorigenesis. Understanding of the mechanisms underlying control of cyclin D1 accumulation under normal and pathological conditions is, therefore, of key importance. Based on preliminary data obtained using the intestinal epithelium as a model system, strategies are proposed to test the hypothesis that PKC signaling plays a critical role in regulating the expression of cyclin D1 in intestinal epithelial cells and that disruption of PKC-mediated cyclin D1 control contributes to intestinal neoplasia. The following findings provide the foundation for this hypothesis: (a) PKC activation in intestinal epithelial cells leads to rapid downregulation of cyclin D1, via a novel glycogen synthase kinase-3B independent and MAPK-dependent mechanism; (b) inhibition of PKC isozyme activity/expression in intestinal cells is associated with marked hyperinduction of cyclin D1 and increased cell growth; and (c) intestinal adenomas and adenocarcinomas are frequently characterized by reduced/abrogated PKC an expression and elevated levels of cyclin D1. To explore further the link between PKC signaling and control of cyclin D1 accumulation in intestinal cells, the following Specific Aims will be addressed: (1) Determine the mechanisms underlying PKC-induced downregulation of cyclin D1; (2) understand the mechanisms involved in cyclin D1 hyperinduction associated with loss of PKC signaling; (3) identify the specific member(s) of the PKC family involved in regulating cyclin D1 accumulation; (4) examine the signaling pathways involved in PKC-related downmodulation and hyperinduction of cyclin D1; and (5) examine the relationship between PKC a regulation of cyclin D1 expression and tumorigenicity of intestinal cells.

描述（由申请人提供）：细胞周期蛋白D1是一个严格调节的细胞 循环控制分子作为进展的关键决定因素 通过G1阶段，作为细胞外生长刺激性的主要传感器和 抑制信号。 Cyclin D1的异常表达是最多的表达 人类癌症经常异常，据信是一种因果关系 在肿瘤发生中的作用。了解对 因此，在正常和病理条件下的细胞周期蛋白D1积累是 关键的重要性。基于使用肠道获得的初步数据 上皮作为模型系统，提出了检验假设的策略 PKC信号在调节细胞周期蛋白的表达中起着关键作用 肠上皮细胞中的D1和PKC介导的细胞周期蛋白D1的破坏 控制有助于肠道肿瘤。以下发现提供了 该假设的基础：（a）肠上皮中的PKC激活 细胞通过一种新型的糖原合酶导致细胞周期蛋白D1的快速下调 激酶-3b独立和MAPK依赖性机制； （b）抑制PKC 肠细胞中的同工酶活性/表达与标记有关 细胞周期蛋白D1的过度诱导和细胞生长增加； （c）肠道 腺瘤和腺癌经常以减少/废除的特征 PKC A表达和细胞周期蛋白D1的水平升高。进一步探索链接 PKC信号传导与肠道中细胞周期蛋白D1积累的控制之间 单元格，将解决以下特定目标：（1）确定 PKC诱导的细胞周期蛋白D1下调的机制； （2）理解 与PKC丢失有关的细胞周期蛋白D1高诱导的机制 信号传导； （3）确定参与PKC家族的特定成员 调节细胞周期蛋白D1积累； （4）检查涉及的信号通路 在PKC相关的下调和细胞周期蛋白D1的过度诱导中； （5）检查 PKC A调节细胞周期蛋白D1表达与 肠细胞的肿瘤性。