REPLICATIVE SENESCENCE AND HEPATIC TUMOR DEVELOPMENT

我们以前已经证明过表达c-myc和转化 双转基因小鼠肝脏中的生长因子-α（TGF-α） 导致严重的DNA损伤、异常的肝脏生长和发育 在比c-myc单克隆抗体中观察到的更年轻的年龄， 转基因小鼠我们现在报道，双转基因TGF-α/c-myc 肝细胞在促有丝分裂时迅速丧失其增殖能力 部分肝切除术（PH）后的刺激。在4周大的时候， PH后BrdU掺入的总体速率与以下各项相当： c-myc和TGF-α/c-myc肝脏，超过野生型 (WT)小鼠然而，到10周龄时，c-myc单转基因小鼠 肝细胞的增殖优势超过WT细胞 而TGF-α/c-myc双转基因肝细胞的凋亡率降低， 有丝分裂刺激后增殖的能力。该减小 增殖反应伴随着总的 增殖肝细胞的分数以及通过下降， 诱导细胞周期蛋白A、细胞周期蛋白B和cdc 2基因表达。这些数据 表明c-myc和TGF-α组成型共表达加速了 PH后再生电位的年龄相关损失，并建议 分化肝细胞的早期复制性衰老可能 在为启动细胞提供选择性生长优势中的作用 人口在这个模型中。

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.