p27Kip1 stabilization is essential for the maintenance of cell cycle arrest in response to DNA damage.
p27Kip1 stabilization is essential for the maintenance of cell cycle arrest in response to DNA damage.
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DOI：
10.1158/0008-5472.can-09-0729
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发表时间：
2009-11-15
期刊：
影响因子：
11.2
通讯作者：
Fernandez-Capetillo O
中科院分区：
文献类型：
--
作者：
Cuadrado M;Gutierrez-Martinez P;Swat A;Nebreda AR;Fernandez-Capetillo O
目前的癌症模型之一提出癌基因激活DNA损伤反应（DDR），这将限制肿瘤在其早期阶段的生长。在这种情况下，与专注于对一次性遗传毒性损伤的急性反应的研究相反，了解细胞如何对持续的DNA损伤源做出反应可能对该领域的未来研究至关重要。我们在这里报告发现了一种新的损伤反应途径，其中涉及p27 kip 1和视网膜母细胞瘤肿瘤抑制因子（TS），并且仅在持续暴露于断裂素后才实施。与其晚期激活一致，我们表明，这一途径对于DNA损伤引发的细胞周期停滞的维持-而不是启动-是至关重要的。有趣的是，这种迟发反应独立于典型的ATM和ATR依赖性DDR，但在p38 MAPK的下游。我们的研究结果可能有助于调和癌基因诱导的DNA损伤模型与临床证据，指出非DDR成员作为人类癌症中最重要的TS。
One of the current models of cancer proposes that oncogenes activate a DNA damage response (DDR), which would limit the growth of the tumor in its earliest stages. In this context, and in contrast to studies focused on the acute responses to a one-time genotoxic insult, understanding how cells respond to a persistent source of DNA damage might become critical for future studies in the field. We here report the discovery of a novel damage-responsive pathway, which involves p27kip1 and retinoblastoma tumour suppressors (TS), and which is only implemented after a persistent exposure to clastogens. In agreement with its late activation, we show that this pathway is critical for the maintenance –but not the initiation- of the cell cycle arrest triggered by DNA damage. Interestingly, this late response is independent of the canonical ATM- and ATR-dependent DDR, but downstream of p38 MAPK. Our results might help to reconcile the oncogene-induced DNA damage model with the clinical evidence that points to non-DDR members as the most important TSs in human cancer.