Greenbaum L E, Li W, Cressman D E, Peng Y, Ciliberto G, Poli V, Taub R
Department of Genetics, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6145, USA.
J Clin Invest. 1998 Sep 1;102(5):996-1007. doi: 10.1172/JCI3135.
After two-thirds hepatectomy, normally quiescent liver cells are stimulated to reenter the cell cycle and proliferate to restore the original liver mass. The level of bZIP transcription factor CCAAT enhancer-binding protein beta (C/EBPbeta) increases in the liver during the period of cell proliferation. The significance of this change in C/EBP expression is not understood. To determine the role of C/EBPbeta in the regenerating liver, we examined the regenerative response after partial hepatectomy in mice that contain a targeted disruption of the C/EBPbeta gene. Posthepatectomy, hepatocyte DNA synthesis was decreased to 25% of normal in C/EBPbeta -/- mice. The reduced regenerative response was associated with a prolonged period of hypoglycemia that was independent of expression of C/EBPalpha protein and gluconeogenic genes. C/EBPbeta -/- livers showed reduced expression of immediate-early growth-control genes including the Egr-1 transcription factor, mitogen-activated protein kinase protein tyrosine phosphatase (MKP-1), and HRS, a delayed-early gene that encodes an mRNA splicing protein. Cyclin B and E gene expression were dramatically reduced in C/EBPbeta -/- livers whereas cyclin D1 expression was normal. The abnormalities in immediate-early gene expression in C/EBPbeta -/- livers were distinct from those seen in IL-6 -/- livers. These data link C/EBPbeta to the activation of metabolic and growth response pathways in the regenerating liver and demonstrate that C/EBPbeta is required for a normal proliferative response.
在进行三分之二肝切除术后，原本静止的肝细胞会被刺激重新进入细胞周期并增殖，以恢复原来的肝脏质量。在细胞增殖期间，肝脏中bZIP转录因子CCAAT增强子结合蛋白β（C/EBPβ）的水平会升高。C/EBP表达的这种变化的意义尚不清楚。为了确定C/EBPβ在肝脏再生中的作用，我们研究了C/EBPβ基因靶向破坏的小鼠在部分肝切除术后的再生反应。肝切除术后，C/EBPβ基因敲除小鼠的肝细胞DNA合成降至正常水平的25%。再生反应减弱与低血糖持续时间延长有关，且这一过程与C/EBPα蛋白和糖异生基因的表达无关。C/EBPβ基因敲除的肝脏中，包括Egr-1转录因子、丝裂原活化蛋白激酶蛋白酪氨酸磷酸酶（MKP-1）和HRS（一种编码mRNA剪接蛋白的延迟早期基因）在内的即时早期生长控制基因的表达降低。C/EBPβ基因敲除的肝脏中细胞周期蛋白B和E的基因表达显著降低，而细胞周期蛋白D1的表达正常。C/EBPβ基因敲除的肝脏中即时早期基因表达的异常与白细胞介素-6基因敲除的肝脏中所见的异常不同。这些数据将C/EBPβ与再生肝脏中代谢和生长反应途径的激活联系起来，并表明C/EBPβ是正常增殖反应所必需的。
