Transcriptional control in hepatocyte proliferation

肝细胞增殖的转录控制

基本信息

批准号：
7589776
负责人：
Linda E GREENBAUM
金额：
$ 26.25万
依托单位：
UNIVERSITY OF PENNSYLVANIA
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 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7589776
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（由适用提供）：肝脏从有毒，传染性或炎症性损伤以及肝移植后恢复的能力很大程度上归功于静态（GO）（GO），代谢活性的肝细胞能够重新进入细胞周期。肝细胞重新进入细胞周期，基因组完整性严重取决于E2F调节的DNA复制许可因子的激活。 TGF-A诱导肝细胞增殖在生理生长和肝细胞癌的肿瘤阶段。我们已经确定C/EBP¿是控制肝细胞增殖期间DNA复制许可的E2F调节基因的关键转录激活因子。我们已经表明，c/eBP？依赖于DNA复制因子的诱导既受到TGF -A的刺激，又依赖于原发性肝细胞中的C/EBP。。最近的证据已经确定了代谢状态与细胞周期相关基因激活之间的重要联系，包括受E2F因子调节的基因。 We have discovered that the potential coactivator PGC-1a, previously implicated in the response to fasting, is rapidly induced following partial hepatictomy 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.根据我们的实验室和其他人的数据，我们假设C/EBP课程是生长因子和肝细胞代谢信号的中心集成因子。在特定目标1中，我们将研究C/EBP¿磷酸化和C/EBP¿-E2F相互作用在肝细胞增殖过程中DNA许可蛋白调节的贡献。在特定的目标2中，我们将通过C/EBP€调查激活PGC-1A的机制。在特定目标3中，我们将分析PGC-1A在再生肝脏中肝细胞增殖中的功能作用。该赠款申请直接响应计划公告PA-06-231。 “发育生物学和肝脏的再生。”了解肝细胞增殖的基础机制将为疗法的发展提供信息，以增强肝脏的再生能力，并将阐明在肝细胞癌发生的早期阶段发生的异常肝细胞增殖机制。