Activation of epidermal growth factor receptor and its downstream signaling pathway by nitric oxide in response to ionizing radiation.
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.
Laboratory of Functional Genomics, Korea Institute of Radiological and Medical Sciences, 215-4 Gongneung-Dong, Nowon-Ku, Seoul 139-706, Korea.
Hyung-Chahn
HC
Lee
Sungkwan
S
An
Hansoo
H
Lee
Sang-Hyeok
SH
Woo
Hyeon-Ok
HO
Jin
Sung-Keum
SK
Seo
Tae-Boo
TB
Choe
Doo-Hyun
DH
Yoo
Su-Jae
SJ
Lee
Young-Joon
YJ
Hong
Myung-Jin
MJ
Park
Chang-Hun
CH
Rhee
In-Chul
IC
Park
Seok-Il
SI
Hong
D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D011839:Radiation, Ionizing; D015398:Signal Transduction
D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D066246:ErbB Receptors