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      Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor.

      Science (New York, N.Y.)

      Active Transport, Cell Nucleus, Animals, Antibodies, immunology, Apoptosis, Apoptosis Inducing Factor, Caspase Inhibitors, Caspases, metabolism, Cell Nucleus, Cells, Cultured, Cytochrome c Group, Enzyme Activation, Enzyme Inhibitors, pharmacology, Flavoproteins, Hydrogen Peroxide, Membrane Potentials, Membrane Proteins, Methylnitronitrosoguanidine, Mice, Mice, Knockout, Mitochondria, physiology, N-Methylaspartate, NAD, Neurons, cytology, Oxidative Stress, Poly(ADP-ribose) Polymerases, antagonists & inhibitors, genetics, Proto-Oncogene Proteins c-bcl-2, Receptors, N-Methyl-D-Aspartate

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          Abstract

          Poly(ADP-ribose) polymerase-1 (PARP-1) protects the genome by functioning in the DNA damage surveillance network. PARP-1 is also a mediator of cell death after ischemia-reperfusion injury, glutamate excitotoxicity, and various inflammatory processes. We show that PARP-1 activation is required for translocation of apoptosis-inducing factor (AIF) from the mitochondria to the nucleus and that AIF is necessary for PARP-1-dependent cell death. N-methyl-N'-nitro-N-nitrosoguanidine, H2O2, and N-methyl-d-aspartate induce AIF translocation and cell death, which is prevented by PARP inhibitors or genetic knockout of PARP-1, but is caspase independent. Microinjection of an antibody to AIF protects against PARP-1-dependent cytotoxicity. These data support a model in which PARP-1 activation signals AIF release from mitochondria, resulting in a caspase-independent pathway of programmed cell death.

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          Journal
          12114629
          10.1126/science.1072221

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