title: Ionizing radiation can induce GSK-3beta phosphorylation and NF-kappaB transcriptional transactivation in ATM-deficient fibroblasts.
abstract: DNA damage by ionizing radiation (IR) can induce activations of both NF-kappaB and p53 through the upstream kinase ataxia telangiectasia mutated (ATM). NF-kappaB activation could also be signaled through two distinct or overlapped pathways; IkappaB kinases (IKKs)-IkappaBalpha and Akt-glycogen synthase kinase-3 (GSK-3). In the present study, however, we show that activation of Akt1 and the subsequent phosphorylation and inactivation of GSK-3beta by IR could also occur in ATM-deficient AT5BIVA cells as well as in normal MRC5CV1 fibroblasts. Similarly, lithium chloride (LiCl) was found to increase the phosphorylation of GSK-3beta independently of ATM. Transfection with either wild-type or kinase dead mutant GSK-3beta to the cells further indicated that phosphorylations of Akt1 and GSK-3beta were closely associated with the transcriptional transactivation of NF-kappaB in response to ionizing radiation. On the other hand, LiCl, having no effect on caspase-3 activation, significantly increased p53 phosphorylation and apoptotic death of the normal MRC5CV1 cells while IR, activating both caspase-3 and p53, profoundly affected AT5BIVA cell death. Hence, our data suggest that although ATM-mediated IKK-IkappaBalpha pathway might be a typical pathway for IR-induced NF-kappaB activation, GSK-3beta phosphorylation could also partially contribute to the transcriptional transactivation of NF-kappaB in an ATM-independent manner and that GSK-3beta phosphorylation could induce ATM-mediated cell apoptosis through the activation of p53.
authors.affiliation: Korea Research Institute of Bioscience and Biotechnology, Yuseong, Daejeon, 305-806, Republic of Korea.
authors.forename: Osong
authors.initials: O
authors.lastname: Kwon
authors.forename: Kyung A
authors.initials: KA
authors.lastname: Kim
authors.forename: Long
authors.initials: L
authors.lastname: He
authors.forename: Sun Ok
authors.initials: SO
authors.lastname: Kim
authors.forename: Min Soo
authors.initials: MS
authors.lastname: Kim
authors.forename: Eun Young
authors.initials: EY
authors.lastname: Cha
authors.forename: Byung Dae
authors.initials: BD
authors.lastname: Yoon
authors.forename: Dai Eun
authors.initials: DE
authors.lastname: Sok
authors.forename: Mira
authors.initials: M
authors.lastname: Jung
authors.forename: Jong Seog
authors.initials: JS
authors.lastname: Ahn
authors.forename: Bo Yeon
authors.initials: BY
authors.lastname: Kim
mesh_terms: D017209:Apoptosis / Q000528:radiation effects; D064007:Ataxia Telangiectasia Mutated Proteins; D002166:Camptothecin / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000378:metabolism*; D004789:Enzyme Activation; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000528:radiation effects*; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D018021:Lithium Chloride / Q000494:pharmacology; D009154:Mutation; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011839:Radiation, Ionizing; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects*; D015533:Transcriptional Activation / Q000187:drug effects / Q000528:radiation effects*; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D016328:NF-kappa B; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C494918:AKT1 protein, human; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D053148:Caspase 3; D018021:Lithium Chloride; D002166:Camptothecin