Transcriptional Control in Hepatocyte Proliferation

肝细胞增殖的转录控制

• 批准号: 6524459
• 负责人: Linda E GREENBAUM
• 金额: $ 24.96万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-21 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6524459
• 关键词: apoptosis; cell cycle; cell proliferation; cyclins; enhancer binding protein; genetic transcription; laboratory mouse; liver cells; liver regeneration; posttranslational modifications; retinoblastoma protein

DESCRIPTION (provided by applicant): The adult liver has a remarkable capacity to restore its mass in response to partial hepatectomy, liver transplantation, or toxic or inflammatory injury. Regeneration after partial hepatectomy is impaired in CCAAT enhancer binding protein beta(C/EBP-beta) -/- mice and is associated with decreased hepatocyte DNA synthesis, prolonged hypoglycemia and reduced expression of growth-associated and cell cycle-associated genes, including cyclin E. Resistance to Fas-mediated apoptotic injury in C/EBP-beta -/- livers also links C/EBP-beta to the regulation of the initial liver injury response. Physiologic associations between C/EBP-alpha and beta and the retinoblastoma protein in other cell types and the finding that pRb phosphorylation is decreased in C/EBP-beta -/- livers after partial hepatectomy link C/EBP-beta with pRb phosphorylation, cyclin E activation and hepatocyte cell cycle progression. Phosphorylation of specific domains in the C/EBP-beta protein overrides the block to cell cycle progression associated with induction of unmodified C/EBP-beta in cell models, suggesting that posttranslational modifications of C/EBP-beta are also necessary for hepatocyte cell cycle progression in the regenerating liver. The Specific Aims of this proposal are (1) To identify the component(s) of the apoptotic pathway that are abnormally regulated in Fas-antibody treated C/EBP-beta -/- livers and to determine if C/EBP-beta is also involved in the regulation of TNF-alpha mediated apoptotic liver injury. (2) To determine whether C/EBP-beta and/or C/EBP-alpha interactions with pRb are important for pRb phosphorylation, cyclin E activation and hepatocyte cell cycle progression. (3) To define the C/EBP-beta functional domains that are required for hepatocyte proliferation. C/EBP-beta proteins modified at residues that correspond to phosphoacceptor sites linked to signaling pathways in the regenerating liver will be introduced into CIEBP-beta -/- primary hepatocytes and assessed for their ability to facilitate hepatocyte cell cycle progression. Together these studies will provide important mechanistic insights regarding the basis for the response of the liver to injury and for hepatocyte proliferation following growth stimulation. This knowledge will be useful for the development of therapeutics to augment the regenerative capacity of the liver in a variety of liver diseases.

描述（由申请人提供）：成年肝脏具有显着的能力，可以恢复其响应部分肝切除术，肝移植的质量， 或有毒或炎症性损伤。部分肝切除术后的再生是 在CCAAT增强剂结合蛋白β（C/EBP-beta）中受损 - / - 鼠标 与肝细胞DNA合成减少，低血糖和 生长相关和细胞周期相关基因的表达降低， 包括Cyclin E. C/EBP-beta中FAS介导的凋亡损伤的抗性 - / - 肝脏还将C/EBP-beta链接到初始肝损伤的调节 回复。 C/EBP-Alpha和Beta之间的生理关联以及 其他细胞类型的视网膜母细胞瘤蛋白质和PRB的发现 部分肝切除术后C/EBP-β-/ - 肝的磷酸化降低 将C/EBP-β与PRB磷酸化，细胞周期蛋白E激活和肝细胞联系起来 细胞周期进程。 C/EBP-beta中特定域的磷酸化 蛋白质超出与诱导相关的细胞周期进程的块 细胞模型中未修饰的C/EBP-beta，表明翻译后 C/EBP-β的修改对于肝细胞周期也是必需的 再生肝脏的进展。该提议的具体目的是 （1）识别异常的凋亡途径的分量 在FAS抗体治疗的C/EBP-β-/ - 肝脏中调节，并确定是否 C/EBP-beta还参与了TNF-α介导的凋亡的调节 肝损伤。 （2）确定C/EBP-beta和/或C/EBP-Alpha是否 与PRB的相互作用对于PRB磷酸化，细胞周期蛋白E很重要 激活和肝细胞细胞周期进程。 （3）定义C/EBP-beta 肝细胞增殖所需的功能域。 c/ebp-beta 在与磷酸acceptor位点相对应的残基修饰的蛋白质 将肝脏中的信号通路引入 Ciebp-beta - / - 初级肝细胞，并评估了其促进的能力 肝细胞细胞周期进程。这些研究将共同​​提供 关于响应的基础的重要机械见解 生长刺激后的肝脏损伤和肝细胞增殖。 这些知识对于开发治疗学以增强很有用 肝脏在多种肝病中的再生能力。