title: PIDDosome-independent tumor suppression by Caspase-2.
abstract: The PIDDosome, a multiprotein complex constituted of the 'p53-induced protein with a death domain (PIDD), 'receptor-interacting protein (RIP)-associated ICH-1/CED-3 homologous protein with a death domain' (RAIDD) and pro-Caspase-2 has been defined as an activating platform for this apoptosis-related protease. PIDD has been implicated in p53-mediated cell death in response to DNA damage but also in DNA repair and nuclear factor kappa-light-chain enhancer (NF-κB) activation upon genotoxic stress, together with RIP-1 kinase and Nemo/IKKγ. As all these cellular responses are critical for tumor suppression and deregulated expression of individual PIDDosome components has been noted in human cancer, we investigated their role in oncogenesis induced by DNA damage or oncogenic stress in gene-ablated mice. We observed that Pidd or Caspase-2 failed to suppress lymphoma formation triggered by γ-irradiation or 3-methylcholanthrene-driven fibrosarcoma development. In contrast, Caspase-2 showed tumor suppressive capacity in response to aberrant c-Myc expression, which did not rely on PIDD, the BH3-only protein Bid (BH3 interacting domain death agonist) or the death receptor ligand Trail (TNF-related apoptosis-inducing ligand), but associated with reduced rates of p53 loss and increased extranodal dissemination of tumor cells. In contrast, Pidd deficiency associated with abnormal M-phase progression and delayed disease onset, indicating that both proteins are differentially engaged upon oncogenic stress triggered by c-Myc, leading to opposing effects on tumor-free survival.
authors.affiliation: Division of Developmental Immunology, BIOCENTER, Medical University Innsbruck, Austria.
authors.forename: C
authors.initials: C
authors.lastname: Manzl
authors.forename: L
authors.initials: L
authors.lastname: Peintner
authors.forename: G
authors.initials: G
authors.lastname: Krumschnabel
authors.forename: F
authors.initials: F
authors.lastname: Bock
authors.forename: V
authors.initials: V
authors.lastname: Labi
authors.forename: M
authors.initials: M
authors.lastname: Drach
authors.forename: A
authors.initials: A
authors.lastname: Newbold
authors.forename: R
authors.initials: R
authors.lastname: Johnstone
authors.forename: Andreas
authors.initials: A
authors.lastname: Villunger
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D053420:CRADD Signaling Adaptor Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D053143:Caspase 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004249:DNA Damage; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020690:GTPase-Activating Proteins / Q000378:metabolism; D005720:Gamma Rays; D045325:HCT116 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008748:Methylcholanthrene / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D051023:BH3 Interacting Domain Death Agonist Protein; D053420:CRADD Signaling Adaptor Protein; C484481:Cradd protein, mouse; D053418:Death Domain Receptor Signaling Adaptor Proteins; D020690:GTPase-Activating Proteins; D047908:Intracellular Signaling Peptides and Proteins; C514981:NEMO protein, mouse; D016328:NF-kappa B; C414729:Pidd1 protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; C490620:Ralbp1 protein, mouse; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D016159:Tumor Suppressor Protein p53; D008748:Methylcholanthrene; D051550:I-kappa B Kinase; D053143:Caspase 2