Westwick J K, Weitzel C, Leffert H L, Brenner D A
Department of Medicine, University of North Carolina, Chapel Hill 27599-7038.
J Clin Invest. 1995 Feb;95(2):803-10. doi: 10.1172/JCI117730.
Compensatory hepatic regeneration after partial hepatectomy (PH) is dependent upon the extent of resection. This study analyzes the regulation of the AP-1 transcription factor c-Jun during hepatic regeneration. There is a progressive increase in c-jun mRNA levels after sham operation, one-third PH, and two-thirds PH. A concomitant increase in AP-1 binding activity is also observed. The c-Jun protein is a major constituent of the AP-1 complex in quiescent and early regenerating liver. The activity of c-Jun nuclear kinase (JNK), which phosphorylates the activation domain of the c-Jun protein, is markedly stimulated after one-third PH. JNK1 or an immunologically related kinase is a constituent of this stimulated JNK activity after PH. When primary cultures of adult rat hepatocytes are incubated with epidermal growth factor or transforming growth factor-alpha, AP-1 transcriptional activity is increased and the activation domain of the c-Jun protein is further potentiated. Phosphopeptide mapping of the endogenous c-Jun protein in proliferating cultured hepatocytes demonstrates phosphorylation of the c-Jun activation domain. Combining the results of these in vivo and culture studies, we conclude that the minimal stimulation of one-third PH activates JNK, which phosphorylates the c-Jun activation domain in hepatocytes, resulting in enhanced transcription of AP-1-dependent genes.
部分肝切除术后的代偿性肝再生取决于切除范围。本研究分析了肝再生过程中AP-1转录因子c-Jun的调控情况。在假手术、三分之一肝切除和三分之二肝切除后，c-jun mRNA水平呈渐进性升高。同时也观察到AP-1结合活性增加。c-Jun蛋白是静止和早期再生肝脏中AP-1复合物的主要成分。在三分之一肝切除后，磷酸化c-Jun蛋白激活域的c-Jun核激酶（JNK）活性受到显著刺激。JNK1或一种免疫相关激酶是肝切除后这种受刺激的JNK活性的组成部分。当成年大鼠肝细胞原代培养物与表皮生长因子或转化生长因子-α孵育时，AP-1转录活性增加，c-Jun蛋白的激活域进一步增强。增殖培养肝细胞中内源性c-Jun蛋白的磷酸肽图谱显示c-Jun激活域发生磷酸化。综合这些体内和培养研究结果，我们得出结论，三分之一肝切除的最小刺激激活了JNK，JNK使肝细胞中的c-Jun激活域磷酸化，导致AP-1依赖性基因转录增强。
