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: 6620564
• 负责人: JENNIFER D. BLACK
• 金额: $ 25.68万
• 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/6620564
• 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）：Cyclin D1 是一种严格调控的细胞 作为进展关键决定因素的周期控制分子 通过 G1 期并作为细胞外生长刺激和的主要传感器 抑制信号。细胞周期蛋白 D1 的异常表达是最常见的表达异常之一 人类癌症中常见的异常现象，并被认为是其致病原因 在肿瘤发生中的作用。了解控制的潜在机制 因此，正常和病理条件下细胞周期蛋白 D1 的积累是： 至关重要。根据使用肠道获得的初步数据 上皮细胞作为模型系统，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 以及 PKC 介导的细胞周期蛋白 D1 的破坏 控制有助于肠道肿瘤的发生。以下发现提供了 该假设的基础：(a) 肠上皮中的 PKC 激活 细胞通过一种新型糖原合酶导致细胞周期蛋白 D1 快速下调 激酶 3B 独立且 MAPK 依赖的机制； (b) PKC的抑制 肠细胞中的同工酶活性/表达与显着相关 细胞周期蛋白 D1 的过度诱导和细胞生长的增加； (c) 肠道 腺瘤和腺癌的特征通常是减少/消除 PKC 表达且细胞周期蛋白 D1 水平升高。进一步探索链接 PKC 信号传导与肠道内细胞周期蛋白 D1 积累的控制之间的关系 细胞，将解决以下具体目标：（1）确定 PKC 诱导细胞周期蛋白 D1 下调的机制； (2)了解 与 PKC 丢失相关的细胞周期蛋白 D1 过度诱导的机制 信号发送； (3) 确定参与其中的 PKC 家族的具体成员 调节细胞周期蛋白 D1 积累； (4)检查涉及的信号通路 参与 PKC 相关的细胞周期蛋白 D1 下调和过度诱导； (5) 检查 PKC对细胞周期蛋白D1表达的调节与 肠细胞的致瘤性。