title: ATM is required for IkappaB kinase (IKKk) activation in response to DNA double strand breaks.
abstract: Following challenge with proinflammatory stimuli or generation of DNA double strand breaks (DSBs), transcription factor NF-kappaB translocates from the cytoplasm to the nucleus to activate expression of target genes. In addition, NF-kappaB plays a key role in protecting cells from proapoptotic stimuli, including DSBs. Patients suffering from the genetic disorder ataxia-telangiectasia, caused by mutations in the ATM gene, are highly sensitive to inducers of DSBs, such as ionizing radiation. Similar hypersensitivity is displayed by cell lines derived from ataxia-telangiectasia patients or Atm knockout mice. The ATM protein, a member of the phosphatidylinositol 3-kinase (PI3K)-like family, is a multifunctional protein kinase whose activity is stimulated by DSBs. As both ATM and NF-kappaB deficiencies result in increased sensitivity to DSBs, we examined the role of ATM in NF-kappaB activation. We report that ATM is essential for NF-kappaB activation in response to DSBs but not proinflammatory stimuli, and this activity is mediated via the IkappaB kinase complex. DNA-dependent protein kinase, another member of the PI3K-like family, PI3K itself, and c-Abl, a nuclear tyrosine kinase, are not required for this response.
authors: Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California at San Diego, La Jolla, California 92093-0636, USA.
authors: N
authors: N
authors: Li
authors: S
authors: S
authors: Banin
authors: H
authors: H
authors: Ouyang
authors: G C
authors: GC
authors: Li
authors: G
authors: G
authors: Courtois
authors: Y
authors: Y
authors: Shiloh
authors: M
authors: M
authors: Karin
authors: G
authors: G
authors: Rotman
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D002460:Cell Line; D004249:DNA Damage; D004268:DNA-Binding Proteins; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D051550:I-kappa B Kinase; D051379:Mice; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D025521:Tumor Suppressor Proteins; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse; D000077191:Wortmannin