REGULATION OF CYCLIN D1 EXPRESSION IN THE INTESTINE

描述（由申请人提供）：细胞周期蛋白D1是一种严格调控的细胞 一种周期控制分子，作为疾病进展的关键决定因素 通过G1期，并作为细胞外生长刺激的主要传感器， 抑制信号细胞周期蛋白D1的异常表达是细胞周期中 在人类癌症中经常出现异常，并被认为是导致癌症的原因。 在肿瘤发生中的作用。了解控制疾病的基本机制 因此，在正常和病理条件下细胞周期蛋白D1的积累， 关键的重要性。根据使用肠道获得的初步数据， 上皮作为一个模型系统，提出了策略来检验假设 PKC信号在调节细胞周期蛋白的表达中起关键作用， D1在肠上皮细胞中的表达及PKC介导的cyclin D1的破坏 控制有助于肠肿瘤形成。以下调查结果提供了 这一假设的基础：（a）PKC激活在肠上皮细胞 细胞导致细胞周期蛋白D1的快速下调，通过一种新的糖原合酶 激酶-3 B非依赖性和MAPK依赖性机制;（B）PKC抑制 肠细胞中的同工酶活性/表达与显著的 细胞周期蛋白D1的过度诱导和增加的细胞生长;和（c）肠 腺瘤和腺癌的特征通常是减少/消除 PKC表达和细胞周期蛋白D1水平升高。为了进一步探讨 PKC信号传导与细胞周期蛋白D1在肠上皮细胞中的积聚 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缺失相关的细胞周期蛋白D1过度诱导的机制 （3）识别参与信号传导的PKC家族的特定成员， 调节细胞周期蛋白D1的积累;（4）检查参与的信号通路 PKC相关下调和细胞周期蛋白D1的过度诱导;和（5）检查 蛋白激酶C α对细胞周期蛋白D1表达调控与细胞凋亡的关系 肠细胞的致瘤性。

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.