p16INK4a can initiate an autonomous senescence program
p16INK4a can initiate an autonomous senescence program
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DOI：
10.1038/sj.onc.1203438
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发表时间：
2000-03-23
期刊：
影响因子：
8
通讯作者：
Enders, GH
中科院分区：
文献类型：
--
作者：
Dai, CY;Enders, GH
肿瘤抑制因子p16（INK 4a）在瞬时表达研究中是细胞周期停滞的有效介质，在衰老细胞中被诱导，并且可以施加衰老的形态学特征。然而，目前尚不清楚p16（INK 4a）是否可以不可逆地阻断细胞增殖。我们探讨了这个问题，使用诱导型p16（INK 4a）表达的成骨肉瘤细胞克隆。p16（INK 4a）诱导1天后，大多数细胞被阻滞在G1期。如果随后中断诱导，则p16（INK 4a）水平恢复至基线，并且在3-5天内恢复稳健生长。当p16（INK 4a）被诱导6天时，DNA合成仍然受到强烈抑制，并且细胞获得衰老的形态特征。此外，如果此时中断p16（INK 4a）诱导，并对细胞进行12天以上的随访，大多数细胞保留了这些形态学特征，并且不能分裂或死亡。尽管p16（INK 4a）表达和视网膜母细胞瘤蛋白磷酸化迅速恢复到基线水平，但仍发生了这种情况。事实上，一些衰老细胞似乎进入S期。这些结果表明，p16（INK 4a）表达的持续时间在这种情况下足以对细胞增殖施加持久的阻断，并且这种状态变得独立于p16（INK 4a）表达、pRB的低磷酸化或严格的G1期阻滞。
The tumor suppressor p16(INK4a) is a potent mediator of cell cycle arrest in transient expression studies, is induced in senescing cells, and can impose morphological features of senescence, Nonetheless, it is unclear whether p16(INK4a) can block cell proliferation irreversibly. We explored this issue using osteogenic sarcoma cell clones with inducible p16(INK4a) expression. Induction of p16(INK4a) for 1 day arrested most cells in G1 phase. If the induction was then interrupted, p16(INK4a) levels returned to baseline and robust growth resumed within 3-5 days. When p16(INK4a) was induced for 6 days DNA synthesis remained strongly inhibited and the cells acquired morphological features of senescence. Moreover, if p16(INK4a) induction was interrupted at this point and the cells were followed for 12 more days, most cells retained these morphologic features and either failed to divide or died. This occurred despite the prompt return of p16(INK4a) expression and retinoblastoma protein phosphorylation toward baseline levels. In fact, some senescing cells appeared to enter S phase. These results demonstrate that a sustained period of p16(INK4a) expression is sufficient in this setting to impose a durable block to cell proliferation and that this state becomes independent of p16(INK4a) expression, hypophosphorylation of pRB, or a strict G1 arrest.