REPLICATIVE SENESCENCE AND HEPATIC TUMOR DEVELOPMENT

我们先前已经证明，c-myc的过度表达和转化 双转基因小鼠肝脏中生长因子-α的表达 导致严重的DNA损伤，肝脏生长发育异常 与c-myc单发相比，肿瘤的年龄要小得多。 转基因小鼠。我们现在报告双转基因转化生长因子-α/c-myc 肝细胞在有丝分裂时迅速失去增殖能力 肝部分切除(PH)后的刺激。在四周大的时候， PH后BrdU掺入的总体比率与 C-myc和转化生长因子-α/c-myc肝脏，并超过野生型 (WT)小鼠。然而，在10周龄时，c-myc单一转基因 肝细胞表现出比WT细胞更强的增殖优势 而转化生长因子-α/c-myc双转基因肝细胞 在有丝分裂刺激下增殖的能力。这一数字减少了 增殖性反应伴随着总量的减少。 增殖中的肝细胞的分数以及 诱导Cyclin A、Cyclin B和cdc2基因表达。这些数据 显示c-myc和转化生长因子-α的结构性共表达加速 PH后再生电位的年龄相关性损失及建议 分化的肝细胞的早期复制衰老可能具有 在为启动细胞提供选择性生长优势方面的作用 该模型中的种群。

We have previously shown that overexpression of c-myc and transforming growth factor-alpha (TGF-alpha) in the liver of double transgenic mice results in severe DNA damage, aberrant hepatic growth and development of tumors at a much younger age than that observed in c-myc single transgenic mice. We now report that double transgenic TGF-alpha/c-myc hepatocytes rapidly lose their ability to proliferate upon mitogenic stimulation following partial hepatectomy (PH). At four weeks of age, the overall rate of BrdU-incorporation following PH was comparable in c-myc and TGF-alpha/c-myc livers and exceeded that seen in wild type (WT) mice. However, by 10 weeks of age c-myc single transgenic hepatocytes demonstrated proliferative advantages over the WT cells whereas TGF-alpha/c-myc double transgenic hepatocytes had a decreased capacity to proliferate upon mitogenic stimulation. This decreased proliferative response was accompanied by a reduction in the total fraction of proliferating hepatocytes as well as by a decline in the induction of cyclin A, cyclin B and cdc2 gene expression. These data show that constitutive coexpression of c-myc and TGF-alpha accelerates age-related loss in the regenerative potential following PH and suggest that early replicative senescence of differentiated hepatocytes may have a role in providing a selective growth advantage to initiated cell populations in this model.