title: p53 regulates a non-apoptotic death induced by ROS.
abstract: DNA damage induced by reactive oxygen species and several chemotherapeutic agents promotes both p53 and poly (ADP-ribose) polymerase (PARP) activation. p53 activation is well known to regulate apoptotic cell death, whereas robust activation of PARP-1 has been shown to promote a necrotic cell death associated with energetic collapse. Here we identify a novel role for p53 in modulating PARP enzymatic activity to regulate necrotic cell death. In mouse embryonic fibroblasts, human colorectal and human breast cancer cell lines, loss of p53 function promotes resistance to necrotic, PARP-mediated cell death. We therefore demonstrate that p53 can regulate both necrotic and apoptotic cell death, mutations or deletions in this tumor-suppressor protein may be selected by cancer cells to provide not only their resistance to apoptosis but also to necrosis, and explain resistance to chemotherapy and radiation even when it kills via non-apoptotic mechanisms.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02115, USA.
authors.forename: J
authors.initials: J
authors.lastname: Montero
authors.forename: C
authors.initials: C
authors.lastname: Dutta
authors.forename: D
authors.initials: D
authors.lastname: van Bodegom
authors.forename: D
authors.initials: D
authors.lastname: Weinstock
authors.forename: A
authors.initials: A
authors.lastname: Letai
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D016923:Cell Death / Q000502:physiology; D004249:DNA Damage; D045325:HCT116 Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D061986:MCF-7 Cells; D009154:Mutation; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D017382:Reactive Oxygen Species; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D006861:Hydrogen Peroxide; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases