REGULATION OF CYCLIN D1 EXPRESSION IN THE INTESTINE

描述(申请人提供)：细胞周期蛋白D1是一种受严格调控的细胞 作为进程的关键决定因素的周期控制分子 通过G1期，作为细胞外刺激生长的主要感受器 抑制信号。细胞周期蛋白D1的异常表达是最常见的 人类癌症中频繁的异常，被认为是导致癌症的原因 在肿瘤发生中的作用。对潜在控制机制的理解 因此，在正常和病理条件下，细胞周期蛋白D1的积聚是 具有关键的重要性。基于使用肠道获得的初步数据 以上皮细胞为模型系统，提出了检验该假说的策略 PKC信号在细胞周期蛋白表达调控中的关键作用 肠上皮细胞中细胞周期蛋白D_1及PKC介导的细胞周期蛋白D_1的破坏 对照有助于肠道肿瘤的发生。以下调查结果提供了 这一假说的基础：(A)肠上皮细胞中PKC的激活 细胞通过一种新的糖原合成酶导致细胞周期蛋白D1的快速下调 K3B非依赖和MAPK依赖的机制；(B)抑制PKC 肠道细胞的同工酶活性/表达与显著的 细胞周期蛋白D1的过度诱导和细胞生长增加；以及(C)肠道 腺瘤和腺癌的特征通常是减少/消失。 PKCα表达和细胞周期蛋白D1水平升高。要进一步探索这一联系 PKC信号转导与细胞周期蛋白D1在肠道蓄积的调控 将解决以下具体目标：(1)确定 蛋白激酶C诱导细胞周期蛋白D1下调的机制；(2)了解 细胞周期蛋白D1过度诱导与蛋白激酶C丢失相关的机制 (3)确定参与PKC家族的特定成员(S)。 调节细胞周期蛋白D1的积聚；(4)检测信号转导途径 在PKC相关的细胞周期蛋白D1的下调和过度诱导中；以及(5)检测 调控细胞周期蛋白D1表达的蛋白激酶C与细胞周期蛋白的关系 肠道细胞的致瘤性。

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.