A novel ionizing radiation-induced signaling pathway that activates the transcription factor NF-kappaB.
The signaling pathway through which ionizing radiation induces NF-kappaB activation is not fully understood. IkappaB-alpha, an inhibitory protein of NF-kappaB mediates the activation of NF-kappaB in response to various stimuli, including cytokines, mitogens, oxidants and other stresses. We have now identified an ionizing radiation-induced signaling pathway that is independent of TNF-alpha. IkappaB-alpha degradation is rapid in response to TNF-alpha induction, but it is absent in response to ionizing radiation exposure in cells from individuals with ataxia-telangiectasia (AT). Overexpression of wild-type ATM, the product of the gene defective in AT patients, restores radiation-induced degradation of IkappaB-alpha. Furthermore, phosphorylation of IkappaB-alpha by immunoprecipitated ATM kinase is increased in control fibroblasts and transfected AT cells following ionizing radiation exposure. These data provide support for a novel ionizing radiation-induced signaling pathway for activation of NF-kappaB and a molecular basis for the sensitivity of AT patients to oxidative stresses.
Department of Radiation Medicine, Vincent T. Lombardi Cancer Center, Georgetown University Medical Center, Washington, DC 20007, USA.
S J
SJ
Lee
A
A
Dimtchev
M F
MF
Lavin
A
A
Dritschilo
M
M
Jung
D000111:Acetylcysteine / Q000378:metabolism; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D002460:Cell Line; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019833:Genistein / Q000494:pharmacology; D006801:Humans; D051550:I-kappa B Kinase; D016328:NF-kappa B / Q000378:metabolism* / Q000528:radiation effects; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011506:Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000528:radiation effects*; D019311:Staurosporine / Q000494:pharmacology; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D025521:Tumor Suppressor Proteins
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D011506:Proteins; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; D019833:Genistein; D011505:Protein-Tyrosine Kinases; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; D019311:Staurosporine; D000111:Acetylcysteine