Rouquet N, Carlier K, Briand P, Wiels J, Joulin V
INSERM U-380, ICGM, Paris, France.
Biochem Biophys Res Commun. 1996 Dec 4;229(1):27-35. doi: 10.1006/bbrc.1996.1753.
Fas (Apo1/CD95) is a member of the tumour necrosis factor/nerve growth factor receptor superfamily and mediates apoptosis in various cell types (for review sec [1]). Although this apoptotic activity has been clearly related to homeostasis in the immune system and pathological situations in non-lymphoid organs, the Fas signaling pathway remains mostly elusive. We and others previously showed that Fas-induced apoptosis of primary culture hepatocytes requires either an inhibitor of translation or a protein kinase inhibitor, suggesting that two distinct pathways of Fas signaling exist in hepatocytes. We report here that activation of ICE-like and CPP32-like cysteine proteases are required for Fas-mediated apoptosis, but that these pathways involve different subclasses of serine proteases and are selectively modulated by inhibitors of protein tyrosine kinases. These results confirm that distinct pathways can lead to Fas-induced apoptosis in hepatocytes. Further understanding of these pathways could facilitate the rational design of anti-apoptotic drugs in liver diseases associated with massive Fas-mediated hepatocyte apoptosis, including fulminant hepatitis.
Fas（Apo1/CD95）是肿瘤坏死因子/神经生长因子受体超家族的成员，介导多种细胞类型的凋亡（综述见[1]）。尽管这种凋亡活性与免疫系统的稳态以及非淋巴器官的病理状况明显相关，但Fas信号通路仍大多难以捉摸。我们和其他人先前表明，Fas诱导原代培养肝细胞凋亡需要翻译抑制剂或蛋白激酶抑制剂，这表明肝细胞中存在两条不同的Fas信号通路。我们在此报告，Fas介导的凋亡需要ICE样和CPP32样半胱氨酸蛋白酶的激活，但这些通路涉及丝氨酸蛋白酶的不同亚类，并受到蛋白酪氨酸激酶抑制剂的选择性调节。这些结果证实，不同的通路可导致肝细胞中Fas诱导的凋亡。进一步了解这些通路有助于合理设计抗凋亡药物，用于治疗与大量Fas介导的肝细胞凋亡相关的肝脏疾病，包括暴发性肝炎。
