Transcriptional control in hepatocyte proliferation

肝细胞增殖的转录控制

基本信息

批准号：
7800423
负责人：
Linda E GREENBAUM
金额：
$ 30.73万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-09-21 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7800423
关键词：
A Mouse Adenovirus Vector Amino Acids Applications Grants Binding Binding Sites Biological Assay Bromodeoxyuridine Cell Culture Techniques Cell Cycle Cells Co-Immunoprecipitations Cyclic AMP DNA DNA Replication Factor DNA biosynthesis Data Developmental Biology E2F1 gene EP300 gene Exhibits Fasting Gene Expression Gene Targeting Genes Genetic Transcription Genomics Growth Growth Factor Hepatic Hepatocarcinogenesis Hepatocyte In Vitro Inflammatory Injury Laboratories Licensing Licensing Factor Link Liver Liver Regeneration Measures Mediating Metabolic Metabolism Modeling Modification Molecular Mus Mutate NIH Program Announcements Natural regeneration Nature Partial Hepatectomy Phase Phase Transition Phosphorylation Physiological Primary carcinoma of the liver cells Proteins Recruitment Activity Refractory Regulation Relative (related person)Replication Licensing Research Personnel Role Serum Signal Transduction Site-Directed Mutagenesis Staging Testing Time Transcription Coactivator Transcriptional Activation Transcriptional Regulation base cdc Genes in vivo liver cell proliferation liver transplantation mRNA Expression mutant programs promoter regenerative response therapeutic development

项目摘要

DESCRIPTION (provided by applicant): The ability of the liver to recover from toxic, infectious or inflammatory injury and following liver transplantation is due in large part to the ability of quiescent (GO), metabolically active hepatocytes to reenter the cell cycle en masse. Hepatocyte reentry into the cell cycle and genomic integrity are critically dependent on E2F regulated activation of DNA replication licensing factors. TGF-a induces hepatocyte proliferation in physiologic growth and in the preneoplastic stages of hepatocellular carcinoma. We have identified C/EBP¿ as a key transcriptional activator of E2F-regulated genes that control the licensing of DNA replication during hepatocyte proliferation. We have shown that induction of C/EBP¿-dependent induction of DNA replication factors is both stimulated by TGF-a and dependent on C/EBP¿ in primary hepatocytes. Recent evidence has identified an important link between the metabolic state and activation of cell cycle associated genes including those regulated by E2F factors. We have discovered that the potential coactivator PGC-1a, previously implicated in the response to fasting, is rapidly induced following partial hepatectomy in a C/EBP¿-dependent manner and is bound to the promoters of E2F regulated genes including several C/EBP¿ targets, suggesting that this coactivator is an important link between metabolic signals and hepatocyte proliferation. Based on data from our laboratory and others, we hypothesize that C/EBP¿ is a central integrator of growth factor and metabolic signals to hepatocytes. In Specific Aim 1, we will investigate the contribution of C/EBP¿ phosphorylation and C/EBP¿-E2F interactions for regulation of DNA licensing proteins during hepatocyte proliferation. In Specific Aim 2, we will investigate the mechanism for activation of PGC-1a by C/EBP¿. In Specific Aim 3, we will analyze the functional role of PGC-1a in hepatocyte proliferation in the regenerating liver. This grant application is directly responsive to Program announcement PA-06-231. "Developmental Biology and Regeneration of the Liver." Understanding the mechanisms underlying hepatocyte proliferation will inform the development of therapeutics to augment the regenerative capacity of the liver and will elucidate mechanisms of abnormal hepatocyte proliferation that occur during early stages of hepatocellular carcinogenesis.

描述（由申请人提供）：肝脏从毒性、感染性或炎症性损伤以及肝移植后恢复的能力在很大程度上归因于静止（GO）、代谢活跃的肝细胞重新进入细胞周期的能力。肝细胞重新进入细胞周期和基因组完整性关键取决于 E2F 调节的 DNA 复制许可因子的激活，TGF-a 在生理生长和肿瘤前期阶段诱导肝细胞增殖。我们已经鉴定出 C/EBP¿作为E2F调节基因的关键转录激活剂，控制肝细胞增殖过程中DNA复制的许可，我们已经证明C/EBP的诱导。 - DNA 复制因子的依赖性诱导既受 TGF-a 刺激又依赖于 C/EBP¿最近的证据已经确定了代谢状态和细胞周期相关基因（包括受 E2F 因子调节的基因）激活之间的重要联系，我们发现先前与禁食反应有关的潜在共激活剂 PGC-1a 会迅速发挥作用。在 C/EBP 中部分肝切除术后诱导依赖的方式并与 E2F 调节基因的启动子结合，包括几个 C/EBP¿目标，表明这种共激活因子是代谢信号和肝细胞增殖之间的重要联系。根据我们实验室和其他实验室的数据，我们研究了 C/EBP¿是生长因子和肝细胞代谢信号的中心整合者。在具体目标 1 中，我们将研究 C/EBP 的贡献。磷酸化和 C/EBP¿ -E2F 相互作用在肝细胞增殖过程中调节 DNA 许可蛋白在特定目标 2 中，我们将研究 C/EBP 激活 PGC-1a 的机制。在具体目标 3 中，我们将分析 PGC-1a 在再生肝脏中的肝细胞增殖的功能作用。该资助申请直接响应计划公告“肝脏的发育生物学和再生机制”。潜在的肝细胞增殖将为增强肝脏再生能力的治疗方法的开发提供信息，并将阐明肝细胞癌发生早期阶段发生的异常肝细胞增殖的机制。