Activation of epidermal growth factor receptor and its downstream signaling pathway by nitric oxide in response to ionizing radiation
Activation of epidermal growth factor receptor and its downstream signaling pathway by nitric oxide in response to ionizing radiation
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DOI：
10.1158/1541-7786.mcr-08-0113
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发表时间：
2008-06-01
影响因子：
5.2
通讯作者：
Hong, Seok-Il
中科院分区：
文献类型：
--
作者：
Lee, Hyung-Chahn;An, Sungkwan;Hong, Seok-Il
电离辐射可激活表皮生长因子受体（EGFR），但其分子机制尚不清楚。我们发现，通过NO合成酶（NOS）在细胞内生成一氧化氮（NO）是IR快速激活EGFR磷酸化所必需的。用IR治疗A549肺癌细胞可在数分钟内增加NOS活性，并伴有NO升高。NO清除剂2-苯基-4,4,5,5，-四甲基咪唑啉-1-氧-3-氧化物和NOS抑制剂n - g -单甲基- l-精氨酸通过IR消除了细胞内NO的增加和EGFR的激活。此外，NO供体单独诱导EGFR磷酸化。用小干扰RNA瞬时转染内皮细胞NOS可减少ir诱导的NO生成并抑制ir诱导的EGFR激活。内皮细胞NOS的过表达增加了ir诱导的NO生成和EGFR激活：这些结果表明，ir诱导的NO通过NOS产生激活EGFR的一种新的分子机制。
Epidermal growth factor receptor (EGFR) is activated by ionizing radiation (IR), but the molecular mechanism for this effect is unknown. We have found that intracellular generation of nitric oxide (NO) by NO synthase (NOS) is required for the rapid activation of EGFR phosphorylation by IR. Treatment of A549 lung cancer cells with IR increased NOS activity within minutes, accompanied by an increase of NO. 2-Phenyl-4,4,5,5,-tetramethylimidazolline-1-oxyl-3-oxide, an NO scavenger, and N-G-monomethyl-L-arginine, an NOS inhibitor, abolished the increase in intracellular NO and activation of EGFR by IR. In addition, an NO donor alone induced EGFR phosphorylation. Transient transfection with small interfering RNA for endothelial NOS reduced IR-induced NO production and suppressed IR-induced EGFR activation. Overexpression of endothelial NOS increased IR-induced NO generation and EGFR activation: These results indicate a novel molecular mechanism for EGFR activation by IR-induced NO production via NOS.