Agents that cause DNA double strand breaks lead to p16INK4a enrichment and the premature senescence of normal fibrolasts
Agents that cause DNA double strand breaks lead to p16INK4a enrichment and the premature senescence of normal fibrolasts
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DOI：
10.1038/sj.onc.1201862
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发表时间：
1998-03-05
期刊：
影响因子：
8
通讯作者：
Adami, GR
中科院分区：
文献类型：
--
作者：
Robles, SJ;Adami, GR
DNA双链断裂的发生诱导人类细胞周期停滞，在正常的、死亡的成纤维细胞中，这种抑制增殖是永久性的，它依赖于生长调节因子P53和P53诱导的一种蛋白，即细胞周期蛋白依赖的激酶抑制物p21。我们在这里表明，在致命的成纤维细胞DNA损伤之后，p21和p53的诱导在很大程度上是短暂的。在短暂接触DNA断链药物博莱霉素或放线菌素D 8天后，P53蛋白处于基线水平，而P53反式激活水平仅略高于基线水平，此时p21蛋白浓度从治疗后不久高达100倍下降到仅为基线水平的2-4倍，随着p21浓度的下降，肿瘤抑制基因p16(INK4a)的表达水平大幅上升。在这种情况下，p21的短暂增加之后是p16(INK4a)的延迟诱导，这种情况也发生在细胞衰老时发生的永久停滞。事实上，经DNA双链断裂处理的细胞与衰老细胞有许多额外的标记，我们的发现表明这些细胞与衰老细胞非常相似，除了p21和p53外，它们还具有维持细胞周期停滞的额外因子(S)。
The occurrence of DNA double strand breaks induces cell cycle arrest in mortal and immortal human cells, In normal, mortal fibroblasts this block to proliferation is permanent, It depends on the growth regulator p53 and a protein p53 induces, the cyclin dependent kinase inhibitor, p21. We show here that following DNA damage in mortal fibroblasts, the induction of p21 and p53 is to a large degree shortlived. By 8 days after a brief exposure to DNA strand breaking agents, bleomycin or actinomycin D, p53 protein is at baseline levels, while the p53 transactivation level is only slightly above its baseline, By this time the concentration of p21 protein, which goes up as high as 100-fold shortly after treatment, is down to just 2-4-fold over baseline levels, Following the drop in p21 concentration a large increase in the expression level of the tumor suppressor gene p16(INK4a) is observed. This scenario, where a transient increase in p21 is followed by a delayed induction of p16(INK4a), also happens with the permanent arrest that occurs with cellular senescence. In fact, these cells treated with agents that cause DNA double strand breaks share a number of additional markers with senescent cells, Our findings indicate that these cells are very similar to senescent cells and that they have additional factor(s) beside p21 and p53 that maintain cell cycle arrest.