Flodby P, Antonson P, Barlow C, Blanck A, Porsch-Hällström I, Xanthopoulos K G
Center for Biotechnology, Karolinska Institute, NOVUM, Huddinge, Sweden.
Exp Cell Res. 1993 Sep;208(1):248-56. doi: 10.1006/excr.1993.1244.
Regenerating liver provides a system for studying the mechanisms controlling regulated proliferation of differentiated hepatocytes. A set of transcription factors termed hepatocyte nuclear factors (HNF-1, -3, -4) and CCAAT/enhancer binding protein (C/EBP) isoforms are known to regulate several genes predominantly expressed in the liver. To assess whether these factors might be involved in the hepatocyte proliferation program, we have studied the expression of the three C/EBP isoforms C/EBP alpha, C/EBP beta, and C/EBP delta and the two hepatocyte-enriched transcription factors, HNF-1 and HNF-4, in rat liver at various time points after partial hepatectomy and sham operations using transcriptional "run-on" assays and Northern blot and Western blot experiments. We report here that partial hepatectomy in rats leads to dramatic changes in the pattern of expression of some of these genes. The three C/EBP isoforms are differentially regulated in response to partial hepatectomy and are likely to play different roles in determining the proliferation/differentiation state of hepatocytes. In particular, C/EBP alpha expression is rapidly down-regulated, whereas C/EBP delta is induced. C/EBP beta expression is also increased, although an increase is also observed after sham operation. The drastic decrease in C/EBP alpha under these conditions of active DNA synthesis and rapid cell proliferation further supports the concept of a potential incompatibility between high C/EBP alpha protein levels and cell proliferation. The patterns of transcriptional rates of HNF-1 and HNF-4 during the different stages of the regenerative process are similar. However, HNF-1 steady-state mRNA and protein levels are significantly changed while HNF-4 remains virtually unaffected, indicating that post-transcriptional mechanisms are also involved in the regulation of HNF-1 gene expression.
再生肝脏提供了一个用于研究控制分化肝细胞有序增殖机制的系统。已知一组被称为肝细胞核因子（HNF-1、-3、-4）和CCAAT/增强子结合蛋白（C/EBP）异构体的转录因子可调节主要在肝脏中表达的多个基因。为了评估这些因子是否可能参与肝细胞增殖程序，我们使用转录“连续分析”以及Northern印迹和Western印迹实验，研究了大鼠在部分肝切除和假手术后不同时间点，三种C/EBP异构体C/EBPα、C/EBPβ和C/EBPδ以及两种富含肝细胞的转录因子HNF-1和HNF-4的表达情况。我们在此报告，大鼠的部分肝切除导致其中一些基因的表达模式发生显著变化。三种C/EBP异构体对部分肝切除的反应存在差异调节，并且可能在决定肝细胞的增殖/分化状态中发挥不同作用。特别是，C/EBPα的表达迅速下调，而C/EBPδ被诱导。C/EBPβ的表达也增加，尽管在假手术后也观察到增加。在活跃DNA合成和快速细胞增殖的这些条件下，C/EBPα的急剧下降进一步支持了高C/EBPα蛋白水平与细胞增殖之间可能存在不相容性的概念。在再生过程的不同阶段，HNF-1和HNF-4的转录速率模式相似。然而，HNF-1的稳态mRNA和蛋白水平发生了显著变化，而HNF-4实际上保持不变，这表明转录后机制也参与了HNF-1基因表达的调节。
