Schmiedeberg P, Biempica L, Czaja M J
Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461.
J Cell Physiol. 1993 Feb;154(2):294-300. doi: 10.1002/jcp.1041540212.
Hepatic expression of the protooncogenes c-fos and c-myc occurs within 2 h after partial hepatectomy, and these immediate early genes are thought to prime the hepatocytes for subsequent proliferation. To examine whether such gene activation occurred in the setting of hepatocyte proliferation after toxic liver injury, protooncogene expression was examined during the regenerative response following liver injury from carbon tetrachloride (CCl4) or galactosamine (GalN). The pattern of protooncogene expression after CCl4 mirrored that seen after partial hepatectomy, with rises in c-fos and c-myc mRNA content within 2 h, and then a rapid return to baseline levels. In contrast, early c-fos and c-myc expression did not occur after GalN injury. Instead GalN-induced regeneration led to a delayed, and prolonged c-fos and c-myc activation which peaked 24-48 h after injury. Increases in c-jun, jun-B, and jun-D mRNA levels also occurred in both models at times similar to the rises of c-fos and c-myc expression. Although the timing of DNA synthesis was identical after GalN or CCl4 treatment, the proliferative response after GalN injury was significantly less than that of CCl4, and marked by the histologic appearance of oval cells. The coadministration of 2-acetylaminofluorene, an inhibitor of differentiated hepatocyte proliferation, together with CCl4 altered the usual pattern of post-CCl4 protooncogene expression to one resembling that seen after GalN injury. Thus, the timing of protooncogene expression during liver regeneration may vary considerably. These variations may influence the nature of the proliferative response in terms of which cell type(s) proliferates, and the amount of regeneration that ensues.
原癌基因c-fos和c-myc在部分肝切除术后2小时内即出现肝脏表达，这些即刻早期基因被认为可使肝细胞为随后的增殖做好准备。为了研究在中毒性肝损伤后肝细胞增殖情况下是否发生此类基因激活，在四氯化碳（CCl4）或半乳糖胺（GalN）所致肝损伤后的再生反应过程中检测了原癌基因表达。CCl4处理后原癌基因的表达模式与部分肝切除术后相似，c-fos和c-myc mRNA含量在2小时内升高，随后迅速恢复至基线水平。相比之下，GalN损伤后未出现早期c-fos和c-myc表达。相反，GalN诱导的再生导致c-fos和c-myc激活延迟且持续时间延长，在损伤后24 - 48小时达到峰值。在两个模型中，c-jun、jun-B和jun-D mRNA水平的升高也与c-fos和c-myc表达升高的时间相似。尽管GalN或CCl4处理后DNA合成的时间相同，但GalN损伤后的增殖反应明显小于CCl4处理后的反应，且以卵圆细胞的组织学表现为特征。将分化肝细胞增殖抑制剂2-乙酰氨基芴与CCl4共同给药，改变了CCl4处理后原癌基因的通常表达模式，使其类似于GalN损伤后所见的模式。因此，肝再生过程中原癌基因表达的时间可能有很大差异。这些差异可能会影响增殖反应的性质，包括哪种细胞类型增殖以及随后发生的再生量。
