Uncoupling of S phase and mitosis induced by anticancer agents in cells lacking p21
Uncoupling of S phase and mitosis induced by anticancer agents in cells lacking p21
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DOI：
10.1038/381713a0
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发表时间：
1996-06-20
期刊：
影响因子：
64.8
通讯作者：
Vogelstein, B
中科院分区：
文献类型：
--
作者：
Waldman, T;Lengauer, C;Vogelstein, B
真核细胞周期的S期和M期的精确协调不仅对于正常细胞分裂至关重要，而且对于在应激条件下的有效生长停滞也至关重要。当受损时，细胞必须向有丝分裂和DNA合成机制传递信号，以便有丝分裂阻滞之后不会出现额外的S期，反之亦然。调节这种协调的生化机制（称为检查点）已在低等真核生物中得到鉴定，但在哺乳动物细胞中基本未知（1-3）。在这里，我们表明p21（WAF 1/CIP 1），细胞周期蛋白依赖性激酶（CDKs）的原型抑制剂（4），是人类细胞中这种协调所必需的。在没有p21的情况下，DNA损伤的细胞停滞在G2样状态，但随后经历额外的S期而不干预正常的有丝分裂。因此，它们获得严重变形的多倍体细胞核，随后通过细胞凋亡死亡。也许不是巧合，可以导致S/M解偶联的DNA损伤剂在临床上被用来优先杀死癌细胞。
PRECISE coordination of the S and M phases of the eukaryotic cell cycle is critical not only for normal cell division, but also for effective growth arrest under conditions of stress. When damaged, a cell must communicate signals to both the mitotic and DNA synthesis machineries so that a mitotic block is not followed by an extra S phase, or vice versa. The biochemical mechanisms regulating this coordination, termed checkpoints, have been identified in lower eukaryotes, but are largely unknown in mammalian cells(1-3). Here we show that p21(WAF1/CIP1), the prototype inhibitor of cyclin-dependent kinases (CDKs)(4), is required for this coordination in human cells. In the absence of p21, DNA-damaged cells arrest in a G2-like state, but then undergo additional S phases without intervening normal mitoses. They thereby acquire grossly deformed, polyploid nuclei and subsequently die through apoptosis. Perhaps not by coincidence, the DNA-damaging agents that can cause S/M uncoupling are used in the clinic to kill cancer cells preferentially.