ES cells do not activate p53-dependent stress responses and undergo p53-independent apoptosis in response to DNA damage
ES cells do not activate p53-dependent stress responses and undergo p53-independent apoptosis in response to DNA damage
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DOI：
10.1016/s0960-9822(98)70061-2
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发表时间：
1998-01-29
期刊：
影响因子：
9.2
通讯作者：
Wahl, GM
中科院分区：
文献类型：
--
作者：
Aladjem, MI;Spike, BT;Wahl, GM
背景：胚胎干细胞（Embryonic stem cells，ES）是所有成体细胞的前体细胞.因此，ES细胞基因组的损伤可能导致严重的发育障碍。在体细胞中，细胞周期检查点通过在可能产生染色体畸变的条件下阻止DNA复制来限制DNA损伤，肿瘤抑制因子p53参与这种检查点控制，并且也需要避免高胚胎畸形率。我们的特点是细胞周期和DNA损伤的ES细胞的反应，以阐明机制，防止积累或损坏的基因组在development.Results传输：来自野生型小鼠的ES细胞没有经历细胞周期停滞在响应DNA损伤或核苷酸耗尽，虽然他们合成了大量的p53。ES细胞中的p53蛋白质是胞质的，并且在核苷酸耗尽时低效地易位到细胞核。从腺病毒载体表达高水平的活性p53不能触发细胞周期阻滞。相反，持续DNA损伤的ES细胞经历了p53非依赖性凋亡。抗代谢物诱导的p53依赖的逮捕反应恢复在ES细胞分化后。结论：细胞周期调控途径在早期胚胎分化的体细胞显着不同。在未分化的ES细胞中，p53检查点途径受到影响p53核定位的因素以及诱导细胞周期停滞所必需的下游因素的损失的影响。p53非依赖性程序性细胞死亡途径被有效地用于防止基因组受损的细胞对发育中的生物体有贡献。当分化发生时，p53介导的检查点控制变得重要。(C)当前生物有限公司
Background: Embryonic stem (ES) cells can contribute precursors to all adult cell lineages. Consequently, damage to ES cell genomes may cause serious developmental malfunctions. In somatic cells, cell-cycle checkpoints limit DNA damage by preventing DNA replication under conditions that may produce chromosomal aberrations, The tumor suppressor p53 is involved in such checkpoint controls and is also required to avoid a high rate of embryonic malformations. We characterized the cell-cycle and DNA-damage responses of ES cells to elucidate the mechanisms that prevent accumulation or transmission of damaged genomes during development.Results: ES cells derived from wild-type mice did not undergo cell-cycle arrest in response to DNA damage or nucleotide depletion, although they synthesized abundant quantities of p53. The p53 protein in ES cells was cytoplasmic and translocated inefficiently to the nucleus upon nucleotide depletion. Expression of high levels of active p53 from an adenovirus vector could not trigger cell-cycle arrest. Instead, ES cells that sustained DNA damage underwent p53-independent apoptosis. The antimetabolite-induced p53-dependent arrest response was restored in ES cells upon differentiation.Conclusions: Cell-cycle regulatory pathways in early embryos differ significantly from those in differentiated somatic cells. In undifferentiated ES cells, p53 checkpoint pathways are compromised by factors that affect the nuclear localization of p53 and by the loss of downstream factors that are necessary to induce cell-cycle arrest. A p53-independent programmed cell death pathway is effectively employed to prevent cells with damaged genomes from contributing to the developing organism. The p53-mediated checkpoint controls become important when differentiation occurs. (C) Current Biology Ltd.