The radioprotective effect of the 24 kDa FGF-2 isoform in HeLa cells is related to an increased expression and activity of the DNA dependent protein kinase (DNA-PK) catalytic subunit
The radioprotective effect of the 24 kDa FGF-2 isoform in HeLa cells is related to an increased expression and activity of the DNA dependent protein kinase (DNA-PK) catalytic subunit
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DOI：
10.1038/sj.onc.1205838
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发表时间：
2002-09-19
期刊：
影响因子：
8
通讯作者：
Toulas, C
中科院分区：
文献类型：
--
作者：
Ader, I;Muller, C;Toulas, C
我们以前报道过，24 kDa的碱性成纤维细胞因子（或FGF-2）亚型的过表达提供了电离辐射（IR）的细胞毒性效应的保护。DNA双链断裂（DSB）是由红外辐射引起的细胞损伤，在人体细胞中主要通过非同源末端连接系统（NHEJ）修复。NHEJ反应依赖于在DNA损伤位点组装的DNA-PK全酶（由调节亚基Ku和催化亚基DNA-PKcs组成）。我们在这里证明，DNA-PK的活性增加了两倍，在两个独立的抗辐射细胞系，HeLa 3A和CAPAN A3，过表达24 kDa的FGF-2。这种增加与DNA-PKcs的过度表达有关，而Ku表达或活性未发生改变。这种过度表达是由于24 kDa FGF-2亚型上调DNA-PKcs基因转录所致。最后，HeLa 3A细胞表现出与活性DNA-PKcs过表达相关的表型变化的标志。事实上，在这些细胞中观察到DSB的修复速度更快，并且渥曼青霉素对IR具有增敏作用。我们的研究结果代表了一种新的机制，控制DNA修复和辐射抗性在人类肿瘤细胞依赖于24 kDa的FGF-2亚型的过度生产的表征。
We previously reported that overexpression of the 24 kDa basic fibroblast factor (or FGF-2) isoform provides protection from the cytotoxic effect of ionizing radiation (IR). DNA double-strand breaks (DSB), the IR-induced lethal lesions, are mainly repaired in human cells by non-homologous end joining system (NHEJ). NHEJ reaction is dependent on the DNA-PK holoenzyme (composed of a regulatory sub-unit, Ku, and a catalytic sub-unit, DNA-PKcs) that assembles at sites of DNA damage. We demonstrated here that the activity of DNA-PK was increased by twofold in two independent radioresistant cell lines, HeLa 3A and CAPAN A3, overexpressing the 24 kDa FGF-2. This increase was associated with an overexpression of the DNA-PKcs without modification of Ku expression or activity. This overexpression was due to an up-regulation of the DNA-PKcs gene transcription by the 24 kDa FGF-2 isoform. Finally, HeLa 3A cells exhibited the hallmarks of phenotypic changes associated with the overexpression of an active DNA-PKcs. Indeed, a faster repair rate of DSB and sensitization to IR by wortmannin was observed in these cells. Our results represent the characterization of a new mechanism of control of DNA repair and radioresistance in human tumor cells dependent on the overproduction of the 24 kDa FGF-2 isoform.