PIDDosome-independent tumor suppression by Caspase-2.
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.
Division of Developmental Immunology, BIOCENTER, Medical University Innsbruck, Austria.
SourceCell death and differentiation 19:10 2012 Oct pg 1722-32
BH3 Interacting Domain Death Agonist Protein
CRADD Signaling Adaptor Protein
Death Domain Receptor Signaling Adaptor Proteins
I-kappa B Kinase
Intracellular Signaling Peptides and Proteins
Mice, Inbred C57BL
Proto-Oncogene Proteins c-myc
RNA, Small Interfering
Receptors, TNF-Related Apoptosis-Inducing Ligand
Tumor Suppressor Protein p53
Pub Type(s)Journal Article
Research Support, Non-U.S. Gov't