Regulation of cyclin D1 expression in the intestine

描述（来自申请人）：Cyclin D1 是一种严格调控的细胞周期控制分子，其功能是细胞外生长刺激和抑制信号的关键传感器以及 G1 期进展的关键决定因素。 cyclin D1 的异常表达是人类癌症中最常见的异常之一，并且被认为在肿瘤发生中发挥重要作用。因此，了解正常和病理条件下细胞周期蛋白 D1 积累的控制机制至关重要。我们的研究已确定蛋白激酶 C a (PKCa) 是肠上皮细胞中细胞周期蛋白 D1 表达的新型调节因子。 PKCa 在肠道中表现出生长抑制和肿瘤抑制特性，并且其表达在肠道肿瘤发展的早期就消失了。基于大量新数据，提出了解决问题的策略 该假设认为 PKCa 信号传导在调节肠细胞中细胞周期蛋白 D1 的表达中起着关键作用，并且 PKCa 介导的细胞周期蛋白 D1 控制的破坏会导致肠肿瘤。以下主要发现为这一假设提供了基础： (a) PKCa 活性通过两种机制抑制未转化肠细胞中的细胞周期蛋白 D1 积累：抑制帽依赖性翻译起始和阻断细胞周期蛋白 D1 mRNA 积累； (b) PKCa 对细胞周期蛋白 D1 翻译的抑制作用涉及翻译抑制子 4E-BP1 的激活； (c) PKCa 信号传导的丧失与细胞周期蛋白 D1 mRNA 和蛋白的过度诱导以及细胞增殖增加有关，(c) 结肠癌细胞中 PKCa 的恢复会抑制细胞周期蛋白 D1 mRNA 和蛋白并抑制锚定依赖性生长。为了进一步探索 PKCa 信号传导与肠细胞中细胞周期蛋白 D1 积累的控制之间的联系，将解决以下具体目标：（1）确定 PKCa 信号传导调节 PP2A 活性和 4E-BP1 的机制 (2) 探讨 Id1 抑制在正常和肿瘤性肠细胞中 PKCa 诱导的细胞周期蛋白 D1 下调中的作用，(3) 研究与肠上皮细胞中 PKCa 信号传导缺失相关的细胞周期蛋白 D1 mRNA 过度诱导的机制，以及 (4) 探讨 PKCa 信号传导在调节细胞周期蛋白 D1 水平和维持肠道稳态中的作用体内。该项目的长期目标是了解协调肠上皮更新过程的机制 在正常条件下，确定肠道细胞如何克服这些控制而产生肿瘤，并确定预防和治疗肠道肿瘤的新靶点。 癌症。

DESCRIPTION (from the applicant): Cyclin D1 is a tightly regulated cell cycle control molecule that functions as a critical sensor of extracellular growth stimulatory and inhibitory signals and a key determinant of progression through G1 phase. Aberrant expression of cyclin D1 is one of the most frequent abnormalities in human cancer, and is believed to play an important role in tumorigenesis. Understanding of the mechanisms underlying control of cyclin D1 accumulation under normal and pathological conditions is, therefore, of key importance. Our studies have identified protein kinase C a (PKCa) as a novel regulator of cyclin D1 expression in intestinal epithelial cells. PKCa exhibits growth inhibitory and tumor suppressor properties in the intestine, and its expression is lost early during intestinal tumor development. Based on extensive new data, strategies are proposed to address the hypothesis that PKCa signaling plays a critical role in regulating the expression of cyclin D1 in intestinal cells, and that disruption of PKCa-mediated cyclin D1 control contributes to intestinal neoplasia. The following key findings provide the foundation for this hypothesis: (a) PKCa activity represses cyclin D1 accumulation in non-transformed intestinal cells by two mechanisms: inhibition of cap-dependent translation initiation and blockade of cyclin D1 mRNA accumulation; (b) inhibitory effects of PKCa on cyclin D1 translation involve activation of the translational repressor 4E-BP1; (c) loss of PKCa signaling is associated with hyperinduction of cyclin D1 mRNA and protein and increased cell proliferation, and (c) restoration of PKCa in colon cancer cells represses cyclin D1 mRNA and protein and inhibits anchorage-independent growth. To explore further the link between PKCa signaling and control of cyclin D1 accumulation in intestinal cells, the following Specific Aims will be addressed: (1) To determine the mechanisms by which PKCa signaling modulates PP2A activity and 4E-BP1 hypophosphorylation/activation to effect cyclin D1 loss in intestinal cells, (2) To explore the role of Id1 suppression in PKCa-induced downregulation of cyclin D1 in normal and neoplastic intestinal cells, (3) To investigate the mechanisms involved in cyclin D1 mRNA hyperinduction associated with loss of PKCa signaling in intestinal epithelial cells, and (4) To explore the role of PKCa signaling in regulation of cyclin D1 levels and maintenance of intestinal homeostasis in vivo. The long-term goals of this project are to understand the mechanisms that orchestrate the process of intestinal epithelial renewal under normal conditions, to determine how intestinal cells overcome these controls to produce tumors, and to identify novel targets for prevention and therapy of intestinal cancer.