Epidermal growth factor sensitizes cells to ionizing radiation by down-regulating protein mutated in ataxia-telangiectasia
Epidermal growth factor sensitizes cells to ionizing radiation by down-regulating protein mutated in ataxia-telangiectasia
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DOI：
10.1074/jbc.m006190200
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发表时间：
2001-03-23
影响因子：
4.8
通讯作者：
Lavin, MF
中科院分区：
文献类型：
--
作者：
Gueven, N;Keating, KE;Lavin, MF
据报道，表皮生长因子 (EGF) 可以使细胞敏感或保护细胞免受电离辐射的影响。我们在此报告，EGF 增加人类成纤维细胞和淋巴母细胞的放射敏感性，并下调 ATM（在共济失调毛细血管扩张症 (A-T) 中突变）和 DNA 依赖性蛋白激酶 (DNA-PKcs) 的催化亚基。在用EGF预处理后，在A-T细胞中没有观察到进一步的放射增敏。 ATM 的下调发生在转录水平。伴随着ATM的下调，转录因子Spl的DNA结合活性降低。这些之间建立了因果关系：通过证明粒细胞/巨噬细胞集落刺激因子上调 Spl DNA 结合活性的观察结果，迅速逆转了 EGF 诱导的 ATM 蛋白减少，并将放射敏感性恢复到正常水平。未能使 EGF 处理的细胞达到与 A-T 细胞观察到的相同程度的放射敏感性，可以通过在照射后一段时间诱导 ATM 蛋白和激酶活性来解释。尽管电离辐射对 DNA 的损伤会迅速激活 ATM 激酶和细胞周期检查点，但我们首次提供了证据，表明 ATM 蛋白量的变化是对 EGF 和辐射暴露作出反应而发生的。总的来说，这些数据支持对 ATM 功能的复杂控制，这对于针对 ATM 提高放射治疗效果具有重要影响。
Epidermal growth factor (EGF) has been reported to either sensitize or protect cells against ionizing radiation. We report here that EGF increases radiosensitivity in both human fibroblasts and lymphoblasts and downregulates both ATM (mutated in ataxia-telangiectasia (A-T)) and the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs). No further radiosensitization was observed in A-T cells after pretreatment with EGF. The down-regulation of ATM occurs at the transcriptional level. Concomitant with the down-regulation of ATM, the DNA binding activity of the transcription factor Spl decreased. A causal relationship was established between these:observations by demonstrating that upregulation of Spl DNA binding activity by granulocyte/ macrophage colony-stimulating factor rapidly reversed the EGF-induced decrease in ATM protein and restored radiosensitivity to normal levels. Failure to radiosensitize EGF-treated cells to the same extent as observed for A-T cells ban be explained by induction of ATM protein and kinase activity with time post-irradiation, Although ionizing radiation damage to DNA rapidly activates ATM kinase and cell cycle checkpoints, we have provided evidence for the first time that alteration in the amount of ATM protein occurs in response to both EGF and radiation exposure. Taken together these data support complex control of ATM function that has important repercussions for targeting ATM to improve radiotherapeutic benefit.