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: 6690370
• 负责人: JENNIFER D. BLACK
• 金额: $ 26万
• 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 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6690370
• 关键词: carcinogenesis; cell growth regulation; cell line; cyclins; enzyme activity; flow cytometry; gastrointestinal epithelium; green fluorescent proteins; intestine neoplasm; isozymes; laboratory mouse; mitogen activated protein kinase; neoplastic growth; nuclear runoff assay; posttranslational modifications; protein kinase C; protein protein interaction; tissue /cell culture

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.

描述（由申请人提供）：Cyclin D1是一种严格调控的细胞