Rouquet N, Allemand I, Molina T, Bennoun M, Briand P, Joulin V
INSERM U-380, ICGM, Paris, France.
Oncogene. 1995 Sep 21;11(6):1061-7.
A transgenic mouse model for hepatocarcinoma has been previously produced by targeting SV40 T-antigen expression to the liver. To evaluate the perturbation of cell death occurring during hepatocarcinogenesis, we examined the Fas-induced apoptosis on hepatocytes expressing T-antigen. Whereas anti-Fas antibody induced apoptosis in primary cultured normal hepatocytes, they imparted a weak cytotoxicity on primary cultured hepatocytes expressing T-antigen. This resistance of hepatic Fas-mediated apoptosis appears to result in an enhancement of a protective mechanism involving the protein kinase C signaling pathway rather than in a down-regulation of Fas-antigen expression. We further demonstrated that anti-Fas antibody does not have as efficient a lethal effect in T-antigen transgenic mice as in wild-type mice. The livers of transgenic mice injected with anti-Fas mAbs showed large intact regions with a few scattered apoptotic bodies: these regions strictly corresponded with carcinoma nodules, expressing high level of T-antigen. Our results describe a novel function for SV40 T-antigen which could contribute to viral pathogenesis by protecting infected cells against the host apoptotic defense mechanism.
先前已通过将SV40 T抗原表达靶向肝脏构建了一种肝癌转基因小鼠模型。为了评估肝癌发生过程中细胞死亡的扰动情况，我们检测了Fas诱导的对表达T抗原的肝细胞的凋亡作用。抗Fas抗体可诱导原代培养的正常肝细胞发生凋亡，但对原代培养的表达T抗原的肝细胞的细胞毒性较弱。肝脏中Fas介导的凋亡抵抗似乎导致了涉及蛋白激酶C信号通路的保护机制增强，而非Fas抗原表达下调。我们进一步证明，抗Fas抗体在T抗原转基因小鼠中的致死作用不如在野生型小鼠中有效。注射抗Fas单克隆抗体的转基因小鼠肝脏显示出大片完整区域，仅有少数散在的凋亡小体：这些区域与癌结节严格对应，且表达高水平的T抗原。我们的结果描述了SV40 T抗原的一种新功能，它可能通过保护受感染细胞免受宿主凋亡防御机制的影响而促进病毒发病机制。
