Regulation of cyclin D1 expression in the intestine

描述（来自申请人）：细胞周期蛋白D1是一种严格调控的细胞周期控制分子，作为细胞外生长刺激和抑制信号的关键传感器和G1期进展的关键决定因素。细胞周期蛋白D1的异常表达是人类肿瘤中最常见的异常之一，被认为在肿瘤的发生中起重要作用。因此，了解在正常和病理条件下细胞周期蛋白D1积累的潜在控制机制至关重要。我们的研究已经确定蛋白激酶C α（PKCa）作为一种新的调节细胞周期蛋白D1在肠上皮细胞的表达。PKCa在肠中表现出生长抑制和肿瘤抑制特性，并且其表达在肠肿瘤发展的早期丧失。根据广泛的新数据，提出了解决 假设PKCa信号在调节肠细胞中细胞周期蛋白D1的表达中起关键作用，并且PKCa介导的细胞周期蛋白D1控制的破坏有助于肠肿瘤形成。以下关键发现为这一假说提供了基础：（a）PKC α活性通过两种机制抑制非转化肠细胞中cyclin D1的积累：抑制帽依赖性翻译起始和阻断cyclin D1 mRNA的积累：（B）PKC α对cyclin D1翻译的抑制作用涉及翻译抑制子4 E-BP 1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增加的细胞增殖相关，以及（c）结肠癌细胞中PKCa的恢复抑制细胞周期蛋白D1 mRNA和蛋白并抑制锚定非依赖性生长。为了进一步探讨PKCa信号通路与细胞周期蛋白D1（cyclinD 1）在肠细胞中的表达之间的关系，本研究的主要目的是：（1）研究PKCa信号通路调控PP 2A活性和4 E-BP 1的机制 （2）探讨Id 1抑制在正常和肿瘤肠细胞中PKC α诱导的cyclin D1下调中的作用;（3）探讨肠上皮细胞中cyclin D1 mRNA过度诱导与PKC α信号丢失相关的机制，（4）探讨PKCa信号通路在体内调控cyclin D1水平及维持肠道内环境稳定中的作用。这个项目的长期目标是了解肠上皮更新过程的机制 在正常情况下，确定肠道细胞如何克服这些控制产生肿瘤，并确定预防和治疗肠道肿瘤的新靶点。 癌

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.