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首页> 外文期刊>Radiotherapy and oncology: Journal of the European Society for Therapeutic Radiology and Oncology >The radioprotector O-phospho-tyrosine stimulates DNA-repair via epidermal growth factor receptor- and DNA-dependent kinase phosphorylation.
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The radioprotector O-phospho-tyrosine stimulates DNA-repair via epidermal growth factor receptor- and DNA-dependent kinase phosphorylation.

机译：放射防护剂O-磷酸酪氨酸通过表皮生长因子受体和DNA依赖性激酶磷酸化刺激DNA修复。

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摘要

BACKGROUND AND PURPOSE: Purpose of the study was to elucidate the underlying molecular mechanism of the radioprotector O-phospho-tyrosine (P-Tyr). METHODS: Molecular effects of P-Tyr at the level of EGFR responses were investigated in vitro with bronchial carcinoma cell line A549. Nuclear EGFR transport and DNA-PK activation were quantified after Western blotting. Residual DNA-damages were quantified by help of gammaH(2)AX focus assay. RESULTS: As determined by dose-response curves, treatment of cells with P-Tyr for 16h before irradiation results in radioprotection. Simultaneous treatment with EGFR blocking antibody Cetuximab abolished P-Tyr associated radioprotection. At the molecular level P-Tyr mediated a general phosphorylation of EGFR and a pronounced phosphorylation of nuclear EGFR at residue Thr No. 654, also observed after treatment with ionizing radiation. This phosphorylation was associated with nuclear EGFR accumulation. Moreover, P-Tyr-triggered EGFR nuclear accumulation was associated withphosphorylation of DNA-PK at Thr 2609. This activated form of DNA-PK was not DNA associated, but after radiation, DNA binding increased, particularly after P-Tyr pre-treatment. These molecular effects of P-Tyr resulted in a reduction of residual DNA-damage after irradiation. CONCLUSIONS: Radioprotection by P-Tyr is mediated through its stimulation of nuclear EGFR transport and concurrent, but DNA-damage independent, activation of DNA-PK. Thus, subsequent irradiation results in increased binding of DNA-PK to DNA, improved DNA-repair and increased cell survival.
机译：背景与目的：本研究的目的是阐明放射防护剂O-磷酸酪氨酸（P-Tyr）的潜在分子机制。方法：在体外用支气管癌细胞系A549研究了P-Tyr对EGFR反应的影响。 Western印迹后定量核EGFR转运和DNA PK激活。残留的DNA损伤通过gammaH（2）AX聚焦测定法进行定量。结果：通过剂量反应曲线确定，在照射前用P-Tyr处理细胞16小时可产生放射防护。 EGFR阻断抗体西妥昔单抗的同时治疗取消了P-Tyr相关的放射防护。在分子水平上，在电离辐射处理后也观察到P-Tyr在残基Thr No. 654上介导了EGFR的一般磷酸化和核EGFR的明显磷酸化。该磷酸化与核EGFR蓄积有关。此外，P-Tyr触发的EGFR核积累与Thr 2609处的DNA-PK磷酸化有关。这种DNA-PK的活化形式与DNA不相关，但是在辐射后，DNA结合增加，特别是在P-Tyr预处理后。 P-Tyr的这些分子效应导致照射后残留的DNA损伤减少。结论：P-Tyr的放射防护是通过其对核EGFR转运的刺激和同时但不依赖DNA损伤的DNA-PK激活介导的。因此，随后的照射导致DNA-PK与DNA的结合增加，DNA修复改善和细胞存活增加。

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