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: 8020046
• 负责人: JENNIFER D. BLACK
• 金额: $ 32.23万
• 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 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8020046
• 关键词: Address; Adenocarcinoma Cell; Agonist; Anchorage-Independent Growth; Biochemical; CCND1 gene; Cell Cycle; Cell Cycle Regulation; Cell Proliferation; Cell Survival; Cells; Characteristics; Colon Adenocarcinoma; Colon Carcinoma; Cyclin D1; Data; Development; Down-Regulation; Enzymes; Epithelial; Epithelial Cell Proliferation; Epithelial Cells; Event; Exhibits; Family; Foundations; Funding; G1 Phase; Genetic; Genetic Transcription; Goals; Growth; Homeostasis; Human; Intestinal Cancer; Intestinal Neoplasms; Intestines; Link; MAP Kinase Gene; Maintenance; Malignant Neoplasms; Mediating; Messenger RNA; Molecular; Mus; PI3K/AKT; Pathway interactions; Phosphoric Monoester Hydrolases; Play; Prevention; Prevention therapy; Process; Property; Protein Kinase C; Protein Phosphatase 2A Regulatory Subunit PR53; Proteins; Regulation; Research; Role; Signal Transduction; Techniques; Tissue Microarray; Tissues; Transcriptional Regulation; Translation Initiation; Translational Activation; Translations; Tumor Suppression; Tumor Suppressor Proteins; base; cancer cell; cell growth regulation; crypt cell; extracellular; gene repression; genetic regulatory protein; in vivo; intestinal crypt; mRNA Stability; member; mouse model; neoplastic; novel; public health relevance; restoration; sensor; tumor; tumorigenesis

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. PUBLIC HEALTH RELEVANCE: Cyclin D1 plays a critical role in regulation of cell growth and survival. Although increased expression of this molecule is one of the most common abnormalities in human cancer, the mechanisms underlying its aberrant accumulation are poorly understood. We have identified PKCa, which is lost early during intestinal tumorigenesis, as a novel repressor of cyclin D1 levels in intestinal cells. Understanding of the interplay between PKCa and cyclin D1 may identify new leads for prevention and/or therapy of intestinal tumors.

描述（来自申请人）：Cyclin D1是一个严格调控的细胞周期控制分子，它是细胞外生长刺激和抑制信号的关键传感器，并且是通过G1相进展的关键决定因素。细胞周期蛋白D1的异常表达是人类癌症中最常见的异常之一，被认为在肿瘤发生中起着重要作用。因此，了解在正常和病理条件下对细胞周期蛋白D1积累的基础机制的理解至关重要。我们的研究已将蛋白激酶C A（PKCA）确定为肠上皮细胞中细胞周期蛋白D1表达的新调节剂。 PKCA在肠中表现出生长抑制性和肿瘤抑制特性，其表达在肠道肿瘤发育期间早期丧失。基于广泛的新数据，提出了解决的策略来解决 PKCA信号传导在调节肠细胞中Cyclin D1的表达以及PKCA介导的Cyclin D1控制的破坏中起着至关重要的作用的假设，这有助于肠道肿瘤。以下关键发现为该假设提供了基础：（a）PKCA活性通过两种机制抑制了非转化的肠细胞中细胞周期蛋白D1的积累：抑制CAP依赖性翻译起始和Cyclin D1 mRNA积累的阻断； （b）PKCA对细胞周期蛋白D1翻译的抑制作用涉及转化阻遏物4E-BP1的激活； （c）PKCA信号传导的丧失与细胞周期蛋白D1 mRNA和蛋白质的过度诱导有关，并增加细胞增殖，以及（c）结肠癌细胞中PKCA的恢复抑制细胞周期蛋白D1 mRNA和蛋白质，并抑制独立于锚固的生长。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，将解决以下特定目标：（1）确定PKCA信号调节PP2A活性和4E-BP1的机制 （2）探索ID1抑制在PKCA诱导的正常和肿瘤肠细胞中的下调ID1抑制在PKCA诱导的下调，（3）研究与Cyclin D1 MRNA D1 MRNA高诱导中涉及的机制相关的机制，在PKCA诱导的机制中，（3）在肠道细胞中的作用（2）探索ID1抑制在PKCA诱导的下调Cyclin d1 mRNA超诱导中涉及PKCA的损失的机制（3）在调节细胞周期蛋白D1水平的信号传导和体内肠内稳态的维持。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，确定肠细胞如何克服这些对照以产生肿瘤，并确定预防和治疗肠道的新目标 癌症。 公共卫生相关性：Cyclin D1在调节细胞生长和生存中起着至关重要的作用。尽管该分子的表达增加是最常见的异常之一 人类癌症，其异常积累的基础机制很差 理解。我们已经确定了PKCA，该PKCA在肠道肿瘤发生期间早期丢失， 作为肠细胞中细胞周期蛋白D1水平的新型阻遏物。对互动的理解 在PKCA和Cyclin D1之间可以确定预防和/或治疗的新潜在客户 肠道肿瘤。