Extremely low-dose ionizing radiation causes activation of mitogen-activated protein kinase pathway and enhances proliferation of normal human diploid cells.
We demonstrated here that X-ray irradiation at very low doses of between 2 and 5 cGy stimulated proliferation of normal human diploid cells and human tumor cells. Higher doses of irradiation at >1 Gy accumulated p53 protein and induced phosphorylation of extracellular signal-regulated kinase (ERK) 1/2. Phosphorylation of ERK1/2 decreased with dose down to 50 cGy, however, doses of between 5 cGy and 2 cGy phosphorylated ERK1/2 as efficiently as higher doses of X-rays, whereas the p53 protein level was not changed by doses <50 cGy. We found that mitogen-activated protein /ERK kinase (MEK) 1 was phosphorylated with both 2 cGy and 6 Gy of X-rays, and that activated ERK1/2 augmented phosphorylation of Elk-1 protein. The specific epidermal growth factor receptor tyrosine kinase inhibitor, AG1478, decreased phosphorylation of the ERK1/2 proteins induced by 2 cGy or 6 Gy of X-rays, and similar suppressive effect was observed with MEK inhibitor, PD98059. Suppression of ERK1/2 phosphorylation with these inhibitors alleviated enhanced proliferation of normal human cells by low-dose irradiation. Furthermore, overexpression of ERK2 in NCI-H1299 human lung carcinoma cells potentiated enhanced proliferation, whereas down-regulation of ERK2 using the antisense ERK2 gene abrogated the stimulative effect of low-dose irradiation. These results indicate that a limited range of low-dose ionizing radiation differentially activates ERK1/2 kinases via activation of epidermal growth factor receptor and MEK, which causes enhanced proliferation of cells receiving very low doses of ionizing radiation.
Suzuki
K
K
Laboratory of Radiation and Life Science, Department of Health Sciences, School of Pharmaceutical Sciences, Nagasaki University, Nagasaki 852-8521, Japan. kzsuzuki@neet.nagasaki-u.ac.jp
Kodama
S
S
Watanabe
M
M
D002455:Cell Division / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects*; D002460:Cell Line; D002470:Cell Survival / Q000528:radiation effects; D016373:DNA, Antisense / Q000235:genetics; D004268:DNA-Binding Proteins; D004171:Diploidy; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004789:Enzyme Activation / Q000187:drug effects / Q000528:radiation effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D015870:Gene Expression; D006801:Humans; D020935:MAP Kinase Signaling System / Q000528:radiation effects; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects / Q000528:radiation effects; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D011799:Quinazolines; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism / Q000528:radiation effects; D020032:Tyrphostins / Q000494:pharmacology; D050807:ets-Domain Protein Elk-1
D016373:DNA, Antisense; D004268:DNA-Binding Proteins; C494112:ELK1 protein, human; D004791:Enzyme Inhibitors; D005419:Flavonoids; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D020032:Tyrphostins; D050807:ets-Domain Protein Elk-1; C101044:RTKI cpd; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one