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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >The catalvtic subunit of DNA-dependent protein kinase selectively regulates p53-dependent apoptosis but not cell-cycle arrest
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The catalvtic subunit of DNA-dependent protein kinase selectively regulates p53-dependent apoptosis but not cell-cycle arrest

机译：DNA依赖性蛋白激酶的空洞亚基选择性调节p53依赖性凋亡，但不调节细胞周期阻滞

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DNA damage induced by ionizing radiation (lR) activates p53. leading to the regulation of downstream pathways that control cell-cycle progression and apoptosis. However, the mechanisms for the IR- induced p53 activation and the differential activation of pathways downstream of p53 are undear. Here we provide evidence that the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) serves as an upstream effector for p53 activation in response to IR, linking DNA damage to apoptosis. DNA-PKCS knockout (DNA-PKCS-/-) mice were exposed to whole-body lR. and the cell-cycle and apoptotic responses were examined in their thymuses. Our data show that IR induction of apoptosis and Bax expression. both mediated via p53, was significantly suppressed in the thymocytes of DNA-PKcr-/- mice. In contrast. lR-induced cell-cycle arrest and p21 expression were normal. Thus, DNA-PKcs deficiency selectively disrupts p53-depen- dent apoptosis but not cell-Cycle arrest. we also confirmed previous findings that p21 induction was attenuated and cell-Cycle arrest was defective in the thymotwes of whole body-irradiated Atffi-/- mice, but the apoptotic response was unperturbed. Taken together, our results support a model in which the upstream effectors DNA-PKcs and Atm selectively activate pS3 to differentially regulate cell-Cycle and apoptotic responses. Whereas Atm selects for cell-Cycle arrest but not apoptosis. DNA-PKcs selects for apoptosis but not cell-Cycle arrest.
机译：电离辐射（lR）诱导的DNA损伤激活了p53。导致控制细胞周期进程和凋亡的下游途径的调控。但是，IR诱导的p53激活和p53下游途径的差异激活的机制尚不清楚。在这里，我们提供的证据表明，DNA依赖性蛋白激酶（DNA-PKcs）的催化亚基可作为p53激活的上游效应物，响应IR，将DNA损伤与细胞凋亡联系起来。将DNA-PKCS敲除（DNA-PKCS-/-）小鼠暴露于全身lR。并检查其胸腺的细胞周期和凋亡反应。我们的数据表明IR诱导细胞凋亡和Bax表达。两者均通过p53介导，在DNA-PKcr-/-小鼠的胸腺细胞中被显着抑制。相反。 lR诱导的细胞周期停滞和p21表达正常。因此，DNA-PKcs的缺乏选择性地破坏了p53依赖性细胞凋亡，而不破坏细胞周期停滞。我们还证实了先前的发现，在全身照射的Atffi-/-小鼠的胸腺中，p21的诱导作用减弱，细胞周期停滞是有缺陷的，但是凋亡反应却没有受到干扰。综上所述，我们的结果支持了一种模型，其中上游效应物DNA-PKcs和Atm选择性激活pS3以差异调节细胞周期和凋亡反应。而Atm选择细胞周期阻滞，而不选择凋亡。 DNA-PKcs选择凋亡，而不选择细胞周期停滞。

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