Co-activation of ERK, NF-kappaB, and GADD45beta in response to ionizing radiation.
NF-kappaB has been well documented to play a critical role in signaling cell stress reactions. The extracellular signal-regulated kinase (ERK) regulates cell proliferation and survival. GADD45beta is a primary cell cycle element responsive to NF-kappaB activation in anti-apoptotic responses. The present study provides evidence demonstrating that NK-kappaB, ERK and GADD45beta are co-activated by ionizing radiation (IR) in a pattern of mutually dependence to increase cell survival. Stress conditions generated in human breast cancer MCF-7 cells by the administration of a single exposure of 5 Gy IR resulted in the activation of ERK but not p38 or JNK, along with an enhancement of the NF-kappaB transactivation and GADD45beta expression. Overexpression of dominant negative Erk (DN-Erk) or pre-exposure to ERK inhibitor PD98059 inhibited NF-kappaB. Transfection of dominant negative mutant IkappaB that blocks NF-kappaB nuclear translocation, inhibited ERK activity and GADD45beta expression and increased cell radiosensitivity. Interaction of p65 and ERK was visualized in living MCF-7 cells by bimolecular fluorescence complementation analysis. Antisense inhibition of GADD45beta strikingly blocked IR-induced NF-kappaB and ERK but not p38 and JNK. Overall, these results demonstrate a possibility that NF-kappaB, ERK, and GADD45beta are able to coordinate in a loop-like signaling network to defend cells against the cytotoxicity induced by ionizing radiation.
Wang
Tieli
T
Division of Radiation Oncology, Beckman Research Institute and City of Hope National Medical Center, Duarte, California 91010, USA.
Hu
Yu-Chang
YC
Dong
Shaozhong
S
Fan
Ming
M
Tamae
Daniel
D
Ozeki
Munetaka
M
Gao
Qian
Q
Gius
David
D
Li
Jian Jian
JJ
D021581:Active Transport, Cell Nucleus; D000943:Antigens, Differentiation / Q000378:metabolism*; D017209:Apoptosis; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D005799:Genes, Dominant; D005816:Genetic Complementation Test; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D015151:Immunoblotting; D016328:NF-kappa B / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000737:chemistry / Q000494:pharmacology; D010957:Plasmids / Q000378:metabolism; D011839:Radiation, Ionizing; D013050:Spectrometry, Fluorescence; D013055:Spectrophotometry, Infrared; D013997:Time Factors; D015533:Transcriptional Activation; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000097642:GADD45 Proteins
D000943:Antigens, Differentiation; D004791:Enzyme Inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases; D005419:Flavonoids; D020672:I-kappa B Proteins; D016328:NF-kappa B; D016376:Oligonucleotides, Antisense; D048051:p38 Mitogen-Activated Protein Kinases; C086470:GADD45B protein, human; D000097642:GADD45 Proteins; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one