REVERSIBLE CELLULAR SENESCENCE - IMPLICATIONS FOR IMMORTALIZATION OF NORMAL HUMAN-DIPLOID FIBROBLASTS
REVERSIBLE CELLULAR SENESCENCE - IMPLICATIONS FOR IMMORTALIZATION OF NORMAL HUMAN-DIPLOID FIBROBLASTS
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DOI：
10.1128/mcb.9.7.3088
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发表时间：
1989-07-01
影响因子：
5.3
通讯作者：
SHAY, JW
中科院分区：
文献类型：
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作者：
WRIGHT, WE;PEREIRASMITH, OM;SHAY, JW
用类固醇诱导的小鼠乳腺肿瘤病毒驱动的猴病毒40t抗原转染正常人二倍体成纤维细胞IMR-90，经危机处理获得永生细胞系。在细胞危机前和永生化后的延长生命周期中，生长依赖于诱导剂（地塞米松）的存在。地塞米松去除后，不朽细胞分裂1 - 2次，聚集于G1。这些结果最好用细胞衰老的两阶段模型来解释。死亡阶段1 （M1）导致有丝分裂原反应性丧失和G1/S界面附近的阻滞，可以被T抗原的细胞DNA合成刺激活性绕过或克服。死亡阶段2 （M2）是一种独立的机制，在危机期间负责细胞分裂失败。M2的失活是一种罕见的事件，可能是人类细胞的突变起源，与T抗原的表达无关或仅间接相关。在这种假设下，t抗原永生化细胞包含一个活跃但被绕过的M1机制和一个灭活的M2机制。这些细胞依赖于T抗原的持续表达来维持不朽，其原因与危机前细胞依赖T抗原生长的原因相同：两者都含有活性M1机制。
IMR-90 normal human diploid fibroblasts, transfected with a steroid inducible mouse mammary tumor virus-driven simian virus 40 T antigen, were carried through crisis to yield an immortal cell line. Growth was dependent on the presence of the inducer (dexamethasone) during both the extended precrisis life spon of the cells and after immortalization. After dexamethasone removal, immortal cells divided once or twice and then accumulated in G1. These results are best explained by a two-stage model for cellular senescence. Mortality stage 1 (M1) causes a loss of mitogen responsiveness and arrest near the G1/S interface and can be bypassed or overcome by the celllar DNA synthesis-stimulating activity of T antigen. Mortality stage 2 (M2) is an independent mechanism that is responsible for the failure of cell division during crisis. The inactivation of M2 is a rare event, probably of mutational origin in human cells, independent of or only indirectly related to the expression of T antigen. Under this hypothesis, T-antigen-immortalized cells contain an active but bypassed M1 mechanism and an inactivated M2 mechanism. These cells are dependent on the continued expression of T antigen for the maintenance of immortality for the same reason that precrisis cells are dependent on T antigen for growth: both contain an active M1 mechanism.