Transcriptional control in hepatocyte proliferation

描述(申请人提供)：肝脏从毒性、感染性或炎症性损伤中恢复的能力和肝移植后的能力在很大程度上是由于静止(GO)、代谢活跃的肝细胞集体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依赖于E2F调节的DNA复制许可因子的激活。转化生长因子-α在生理性生长和癌前病变阶段诱导肝细胞增殖。我们已经确定C/EBP是E2F调节基因的关键转录激活因子，该基因控制着肝细胞增殖过程中DNA复制的许可。我们发现，在原代肝细胞中，依赖C/EBP的DNA复制因子的诱导既受转化生长因子-α的刺激，又依赖于C/EBP。最近的证据表明，代谢状态和细胞周期相关基因的激活之间存在着重要的联系，包括那些受E2F因子调控的基因。我们发现，先前参与禁食反应的潜在辅助激活因子PGC-1a在肝部分切除后以C/EBP？依赖的方式被迅速诱导，并与包括几个C/EBP？靶点在内的E2F调节基因的启动子结合，表明该辅助激活因子是代谢信号与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，我们假设C/EBP？是肝细胞生长因子和代谢信号的中心整合因子。在具体目标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对DNA许可蛋白调控的贡献。在具体目标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。“发育生物学和肝脏再生。”了解肝细胞增殖的机制将有助于开发增强肝脏再生能力的治疗方法，并将阐明肝细胞异常增殖的机制，这些机制发生在肝细胞癌变的早期阶段。

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.