title: Loss of PIDD limits NF-κB activation and cytokine production but not cell survival or transformation after DNA damage.
abstract: Activation of NF-κB (nuclear factor of kappa light chain gene enhancer in B cells) in response to DNA damage is considered to contribute to repair of genetic lesions, increased cell survival and cytokine release. The molecular mechanisms orchestrating this cytoplasmic event involve core components of the nuclear DNA damage response machinery, including ATM-kinase (ataxia telangiectasia mutated kinase) and PARP-1 (poly (ADP-ribose) polymerase 1). The physiological consequences of defective NF-κB activation in this context, however, remain poorly investigated. Here we report on the role of the 'p53-induced protein with a death domain', PIDD, which appears rate limiting in this process, as is PARP-1. Despite impaired NF-κB activation, DNA damage did not increase cell death or reduce clonal survival of various cell types lacking PIDD, such as mouse embryonic fibroblasts or stem and progenitor cells of the hematopoietic system. Furthermore, lymphomagenesis induced by γ-irradiation (IR) was unaffected by deficiency for PIDD or PARP-1, indicating that loss of DNA damage-triggered NF-κB signalling does not affect IR-driven tumorigenesis. However, loss of either gene compromised cytokine release after acute IR injury. Hence, we propose that NF-κB's most notable function after DNA damage in primary cells is related to the release of cytokines, thereby contributing to sterile inflammation.
authors.affiliation: Division of Developmental Immunology, Biocenter, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: F J
authors.initials: FJ
authors.lastname: Bock
authors.forename: G
authors.initials: G
authors.lastname: Krumschnabel
authors.forename: C
authors.initials: C
authors.lastname: Manzl
authors.forename: L
authors.initials: L
authors.lastname: Peintner
authors.forename: M C
authors.initials: MC
authors.lastname: Tanzer
authors.forename: N
authors.initials: N
authors.lastname: Hermann-Kleiter
authors.forename: G
authors.initials: G
authors.lastname: Baier
authors.forename: L
authors.initials: L
authors.lastname: Llacuna
authors.forename: J
authors.initials: J
authors.lastname: Yelamos
authors.forename: A
authors.initials: A
authors.lastname: Villunger
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000528:radiation effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D004249:DNA Damage / Q000528:radiation effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism*; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D011839:Radiation, Ionizing; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000378:metabolism; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D016207:Cytokines; D004268:DNA-Binding Proteins; D053418:Death Domain Receptor Signaling Adaptor Proteins; D016328:NF-kappa B; C414729:Pidd1 protein, mouse; D034741:RNA, Small Interfering; D051996:Transcription Factor RelA; D025521:Tumor Suppressor Proteins; D016179:Granulocyte Colony-Stimulating Factor; D016173:Macrophage Colony-Stimulating Factor; D011065:Poly(ADP-ribose) Polymerases; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; D051550:I-kappa B Kinase