Activation of epidermal growth factor receptor and its downstream signaling pathway by nitric oxide in response to ionizing radiation |
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Authors: | Lee Hyung-Chahn An Sungkwan Lee Hansoo Woo Sang-Hyeok Jin Hyeon-Ok Seo Sung-Keum Choe Tae-Boo Yoo Doo-Hyun Lee Su-Jae Hong Young-Joon Park Myung-Jin Rhee Chang-Hun Park In-Chul Hong Seok-Il |
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Institution: | Laboratory of Functional Genomics, Korea Institute of Radiological and Medical Sciences, 215-4 Gongneung-Dong, Nowon-Ku, Seoul 139-706, Korea. |
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Abstract: | 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 NG-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. |
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