C/EBP BETA IN HEPATOCYTE GENE EXPRESSION & PROLIFERATION

肝细胞基因表达中的 C/EBP Beta

• 批准号: 6176261
• 负责人: MARIO CHOJKIER
• 金额: $ 28.88万
• 依托单位: VETERANS MEDICAL RESEARCH FDN/SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6176261
• 关键词: DNA binding protein; albumins; athymic mouse; biological signal transduction; cachexia; cell differentiation; cell growth regulation; cell proliferation; clinical research; enhancer binding protein; fluorescence microscopy; gene expression; genetically modified animals; human subject; immunocytochemistry; in situ hybridization; laboratory mouse; liver cells; nitric oxide; oxidative stress; phosphorylation; site directed mutagenesis; tissue /cell culture; transcription factor; transfection /expression vector; transforming growth factors

DESCRIPTION: This renewal proposal focuses on the signal transduction pathways that modulate hepatocyte gene expression and proliferation through site-specific phosphorylations of C/EBP-beta. Preliminary results show that TGF-alpha and phorbol esters/PKC-alpha mediate their effects on hepatocyte proliferation, at least in part, through the activation of ribosomal S6-kinase and phosphorylation of C/EBP-beta on its activation domain. In addition, cachexia and TNF-alpha inhibit albumin transcription, at least in part, throug an oxidative stress/NO cascade resulting in the activation of stress-activated protein (SAP)- kinase and phosphorylation of C/EBP-beta on its basic domain, which abolishes the binding of C/EBP-beta to the albumin enhancer/promoter DNA sequence. The specific aims are 1) assess the role of phosphorylation on hepatocyte proliferation, 2) examine the modulation of hepatocyte proliferatio in C/EBP-beta mice, 3) examine the regulation of the cell cycle by C/EBP-beta in hepatocytes, 4) assess the role of oxidative stress and NO on C/EBP-beta phosphorylation and inhibition of albumin transcription induced by cachexia an TNF-alpha, 5) examine the modulation of albumin expression in C/EBP-beta transgenic mice, and 6) examine the mechanisms that induce decreased albumin expression in human cachexia.

描述：此更新提案的重点是信号转导 通过调节肝细胞基因表达和增殖的途径 C/EBP-beta的位点特异性磷酸化。 初步结果表明 TGF-Alpha和Phorbol酯/PKC-Alpha介导了它们对肝细胞的影响 至少部分通过核糖体的激活而扩散 C/EBP-beta在其活化域上的S6-激酶和磷酸化。 在 加上Cachexia和TNF-Alpha抑制白蛋白转录，至少在 部分，通过氧化应力/无级联反应导致激活 应力激活蛋白（SAP） - C/EBP-β上的激酶和磷酸化 它的基本领域，废除了C/EBP-Beta对白蛋白的结合 增强子/启动子DNA序列。 具体目的是1）评估 肝细胞增殖上的磷酸化，2）检查调节 C/EBP-β小鼠中的肝细胞增殖，3）检查调节 C/EBP-β在肝细胞中的细胞周期，4）评估氧化的作用 压力，无需C/EBP-β磷酸化和白蛋白的抑制作用 Cachexia an a tnf-alpha诱导的转录，5）检查调节 C/EBP-β转基因小鼠中的白蛋白表达，6）检查 诱导人炎症中白蛋白表达降低的机制。