人胚肺二倍体成纤维细胞衰老过程中Wnt信号抑制因子DKK4的表达

Declined DKK4 Expression During Replicative Senescence in Human Embryonic Lung Diploid Fibroblasts

Dickkopf家族蛋白DKK4是经典Wnt信号通路的抑制因子.为研究其在人胚肺二倍体成纤维细胞(2BS)复制性衰老过程中的作用机制及生理学意义,使用Wnt/β-联蛋白通路的激活剂氯化锂(LiCl)和抑制剂DKK1作用于2BS,同时利用免疫荧光技术分析衰老过程中细胞因子的定位.结果显示,在2BS复制性衰老的过程中,DKK4表达水平下降,而这种下降是β-联蛋白/TCF介导完成的.而在衰老过程或较高的过氧化物水平下,细胞核内转录因子FoxO4增多.由此得出结论:在衰老过程中,β-联蛋白/TCF下游靶基因DKK4表达下调,降低了对经典Wnt通路的抑制,使胞内β-联蛋白处于较高水平.较高水平的β-联蛋白在高过氧化物的微环境中,与FOXO家族转录因子相互作用,激活其下游靶基因,促进了衰老的发生发展.

DKK4,a member of Dickkopf family,is an inhibitor of the canonical Wnt signaling.To find out the function of DKK4 in replicative senescence,human embryonic lung diploid fibroblast （2BS） was treated with known activators or inhibitors of the Wnt pathway.The cellular location of a forkhead box O transcription factor, FoxO4, in young, senescent and premature 2BS was examined by immunofluoresence.The results demonstrated that low-level of β-catenin/TCF induced DKK4 was detected in 2BS during replicative senescence,and increased FoxO4 was observed in the nucleus of senescent and premature cells.We conclude that the decrease of DKK4 targeted by β-cat/TCF was able to retain β-catenin in cytoplast in replicative senescent 2BS cells,thus to influence the interaction of β-catenin with transcription factor FoxO and accelerate cell senescence.