Transcriptional Control in Hepatocyte Proliferation

肝细胞增殖的转录控制

• 批准号: 6614463
• 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 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6614463
• 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）：成人肝脏具有显着的恢复其质量的能力，以响应部分肝切除术、肝移植、 或中毒性或炎性损伤。部分肝切除术后的再生 CCAAT 增强子结合蛋白 β(C/EBP-β) -/- 小鼠中受损，并且 与肝细胞 DNA 合成减少、长期低血糖和 生长相关和细胞周期相关基因的表达减少， C/EBP-β 对 Fas 介导的细胞凋亡损伤的抵抗 -/- 肝脏还将 C/EBP-beta 与初始肝损伤的调节联系起来 回复。 C/EBP-alpha 和 beta 之间的生理关联 其他细胞类型中的视网膜母细胞瘤蛋白以及 pRb 的发现 部分肝切除术后 C/EBP-β -/- 肝脏的磷酸化降低 将 C/EBP-beta 与 pRb 磷酸化、细胞周期蛋白 E 激活和肝细胞联系起来 细胞周期进展。 C/EBP-beta 中特定结构域的磷酸化 蛋白质克服了与诱导相关的细胞周期进程的阻碍 细胞模型中未修饰的 C/EBP-beta 的存在，表明翻译后 C/EBP-β 的修饰对于肝细胞细胞周期也是必要的 肝脏再生过程中的进展。该提案的具体目标是 (1) 鉴定凋亡途径中异常的成分 在 Fas 抗体处理的 C/EBP-beta -/- 肝脏中受到调节，并确定是否 C/EBP-β 还参与 TNF-α 介导的细胞凋亡的调节 肝损伤。 (2) 确定是否是C/EBP-beta和/或C/EBP-alpha 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展。 (3) 定义C/EBP-beta 肝细胞增殖所需的功能域。 C/EBP-β 在对应于所连接的磷酸受体位点的残基处修饰的蛋白质 再生肝脏中的信号通路将被引入 CIEBP-beta -/- 原代肝细胞并评估其促进的能力 肝细胞细胞周期进展。这些研究将共同​​提供 关于响应基础的重要机制见解 肝脏损伤和生长刺激后肝细胞增殖。 这些知识将有助于开发增强疗效的疗法 各种肝脏疾病中肝脏的再生能力。