title: Death of p53-defective cells triggered by forced mitotic entry in the presence of DNA damage is not uniquely dependent on Caspase-2 or the PIDDosome.
abstract: Much effort has been put in the discovery of ways to selectively kill p53-deficient tumor cells and targeting cell cycle checkpoint pathways has revealed promising candidates. Studies in zebrafish and human cell lines suggested that the DNA damage response kinase, checkpoint kinase 1 (Chk1), not only regulates onset of mitosis but also cell death in response to DNA damage in the absence of p53. This effect reportedly relies on ataxia telangiectasia mutated (ATM)-dependent and PIDDosome-mediated activation of Caspase-2. However, we show that genetic ablation of PIDDosome components in mice does not affect cell death in response to γ-irradiation. Furthermore, Chk1 inhibition largely failed to sensitize normal and malignant cells from p53(-/-) mice toward DNA damaging agents, and p53 status did not affect the death-inducing activity of DNA damage after Chk1 inhibition in human cancer cells. These observations argue against cross-species conservation of a Chk1-controlled cell survival pathway demanding further investigation of the molecular machinery responsible for cell death elicited by forced mitotic entry in the presence of DNA damage in different cell types and model organisms.
authors: Division of Developmental Immunology, Biocenter, Innsbruck Medical University, Innsbruck, Austria.
authors: C
authors: C
authors: Manzl
authors: L L
authors: LL
authors: Fava
authors: G
authors: G
authors: Krumschnabel
authors: L
authors: L
authors: Peintner
authors: M C
authors: MC
authors: Tanzer
authors: C
authors: C
authors: Soratroi
authors: F J
authors: FJ
authors: Bock
authors: F
authors: F
authors: Schuler
authors: B
authors: B
authors: Luef
authors: S
authors: S
authors: Geley
authors: A
authors: A
authors: Villunger
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism; D053143:Caspase 2 / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology; D004249:DNA Damage / Q000235:genetics / Q000502:physiology*; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000235:genetics / Q000378:metabolism; D015151:Immunoblotting; D051379:Mice; D008810:Mice, Inbred C57BL; D008938:Mitosis / Q000235:genetics / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D053418:Death Domain Receptor Signaling Adaptor Proteins; C414729:Pidd1 protein, mouse; D016159:Tumor Suppressor Protein p53; D064007:Ataxia Telangiectasia Mutated Proteins; D053143:Caspase 2