Alby F, Mazars R, de Rycke J, Guillou E, Baldin V, Darbon J M, Ducommun B
LBCMCP UMR5088, Université Paul Sabatier, CNRS, Toulouse, France.
FEBS Lett. 2001 Mar 2;491(3):261-5. doi: 10.1016/s0014-5793(01)02205-0.
The bacterial cytolethal distending toxin (CDT) triggers a G2/M cell cycle arrest in eukaryotic cells by inhibiting the CDC25C phosphatase-dependent CDK1 dephosphorylation and activation. We report that upon CDT treatment CDC25C is fully sequestered in the cytoplasmic compartment, an effect that is reminiscent of DNA damage-dependent checkpoint activation. We show that the checkpoint kinase CHK2, an upstream regulator of CDC25C, is phosphorylated and activated after CDT treatment. In contrast to what is observed with other DNA damaging agents, we demonstrate that the activation of CHK2 can only take place during S-phase. Use of wortmannin and caffeine suggests that this effect is not dependent on ATM but rather on another as yet unidentified PI3 kinase family member. These results confirm that the CDT is therefore responsible for specific genomic injuries that block cell proliferation by activating a cell cycle checkpoint.
细菌细胞致死性膨胀毒素（CDT）通过抑制依赖细胞周期蛋白依赖性激酶1（CDK1）去磷酸化和激活的细胞周期蛋白磷酸酶25C（CDC25C），在真核细胞中引发G2/M期细胞周期停滞。我们报告，在CDT处理后，CDC25C完全隔离在细胞质区室中，这种效应让人联想到依赖DNA损伤的检查点激活。我们表明，检查点激酶CHK2作为CDC25C的上游调节因子，在CDT处理后被磷酸化并激活。与其他DNA损伤剂所观察到的情况不同，我们证明CHK2的激活只能在S期发生。渥曼青霉素和咖啡因的使用表明，这种效应不依赖于共济失调毛细血管扩张症突变基因（ATM），而是依赖于另一个尚未确定的磷脂酰肌醇-3激酶（PI3激酶）家族成员。这些结果证实，CDT因此通过激活细胞周期检查点导致特定的基因组损伤，从而阻断细胞增殖。
