Chromium-mediated apoptosis: Involvement of DNA-dependent protein kinase (DNA-PK) and differential induction of p53 target genes
Chromium-mediated apoptosis: Involvement of DNA-dependent protein kinase (DNA-PK) and differential induction of p53 target genes
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DOI：
10.1016/j.dnarep.2008.05.007
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发表时间：
2008-09-01
期刊：
影响因子：
3.8
通讯作者：
Lee, Patrick W. K.
中科院分区：
文献类型：
--
作者：
Hill, Richard;Leidal, Andrew M.;Lee, Patrick W. K.
细胞应激和DNA损伤上调并激活P53，P53是细胞周期控制、衰老、DNA修复和细胞凋亡的基础。在特定的脱氧核糖核酸损伤中，决定p53依赖的细胞周期停滞或p53依赖的细胞凋亡是否占上风的具体机制(S)还知之甚少。在这项研究中，我们研究了两种类型的DNA损伤，铬处理和伽玛辐射(IR)诱导了相似水平的P53，但介导了两种不同的P53依赖的细胞命运。铬暴露诱导了DNA依赖的蛋白激酶(DNA-PK)介导的细胞凋亡反应，伴随着细胞周期蛋白依赖的蛋白抑制因子1A(P21)的快速丢失，而IR诱导的细胞周期停滞是由p21的快速诱导所支持的。抑制DNA-PK能有效阻断铬诱导的P53稳定和激活，但不能阻断IR诱导的P53稳定和激活。相反，咖啡因抑制ATM和ATR具有阻断IR的相反作用，但不能阻断铬诱导的P53的稳定和激活。铬暴露使p21转录减弱，但PUMA和Bax转录与未损伤细胞相比显着增强。相反，IR处理除了PUMA和Bax mRNA的产生外，还能显著地刺激p21mRNA的合成。铬处理增强了P53和RNA聚合酶II(RNAPol II)与p21和PUMA启动子的结合，而RNAPol II仅沿PUMA基因延伸，而不是p21基因。相反，在IR处理后，在p21和PUMA上都观察到了RNA Pol II的延长。因此，铬诱导的细胞凋亡涉及DNA-PK介导的p53激活，然后是促凋亡的PUMA优先于抗凋亡的p21基因的转录。(C)2008爱思唯尔B.V.保留所有权利。
Cellular stress and DNA damage up-regulate and activate p53, fundamental for cell cycle control, senescence, DNA repair and apoptosis. The specific mechanism(s) that determine whether p53-dependent cell cycle arrest or p53-dependent apoptosis prevails in response to specific DNA damage are poorly understood. in this study, we investigated two types of DNA damage, chromium treatment and gamma irradiation (IR) that induced similar levels of p53, but that mediated two distinct p53-dependent cell fates. Chromium exposure induced a robust DNA-dependent protein kinase (DNA-PK)-mediated apoptotic response that was accompanied by the rapid loss of the cyclin-dependent kinase inhibitor 1A (p2l) protein, whereas IR treatment-induced cell cycle arrests that was supported by the rapid induction of p21. Inhibition of DNA-PK effectively blocked chromium-, but not IR-induced p53 stabilization and activation. In contrast, inhibition of ATM and ATR by caffeine had the inverse effect of blocking IR-, but not chromium -induced p53 stabilization and activation. Chromium exposure ablated p21 transcription but PUMA and Bax transcription was significantly enhanced compared to non-damaged cells. In contrast, IR treatment triggered significant p21 mRNA synthesis in addition to PUMA and Bax mRNA production. While chromium treatment enhanced the binding of p53 and RNA polymerase II (RNA Pol II) to both the p21 and PUMA promoters, RNA Pol II elongation was only observed along the PUMA gene and not the p21 gene. in contrast, following IR treatment, RNA Pol II elongation was observed on both p21 and PUMA. Chromium-induced apoptosis therefore involves DNA-PK-mediated p53 activation followed by preferential transcription of pro-apoptotic PUMA over anti-apoptotic p21 genes. (c) 2008 Elsevier B.V All rights reserved.