title: Cell death and autophagy under oxidative stress: roles of poly(ADP-Ribose) polymerases and Ca(2+).
abstract: On the cellular level, oxidative stress may cause various responses, including autophagy and cell death. All of these outcomes involve disturbed Ca(2+) signaling. Here we show that the nuclear enzymes poly(ADP-ribose) polymerase 1 (PARP1) and PARP2 control cytosolic Ca(2+) shifts from extracellular and intracellular sources associated with autophagy or cell death. The different Ca(2+) signals arise from the transient receptor potential melastatin 2 (TRPM2) channels located in the cellular and lysosomal membranes. They induce specific stress kinase responses of canonical autophagy and cell death pathways. Autophagy is under the control of PARP1, which operates as an autophagy suppressor after oxidative stress. Cell death is activated downstream of extracellular signal-regulated kinase 1/2 (ERK1/2) and AKT, whereas cell survival correlates with the phosphorylation of p38, stress-activated protein kinase/Jun amino-terminal kinase (SAPK/JNK), and cyclic AMP response element-binding protein (CREB) with its activating transcription factor (ATF-1). Our results highlight an important role for PARP1 and PARP2 in the epigenetic control of cell death and autophagy pathways.
authors: Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse, Zurich, Switzerland.
authors: Philippe
authors: P
authors: Wyrsch
authors: Christian
authors: C
authors: Blenn
authors: Jessica
authors: J
authors: Bader
authors: Felix R
authors: FR
authors: Althaus
mesh_terms: D000818:Animals; D001343:Autophagy; D002118:Calcium / Q000378:metabolism*; D016923:Cell Death; D002460:Cell Line; D003600:Cytosol / Q000378:metabolism; D053960:DNA Breaks; D017353:Gene Deletion; D006861:Hydrogen Peroxide / Q000378:metabolism; D051379:Mice; D018384:Oxidative Stress; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D050053:TRPM Cation Channels / Q000378:metabolism
chemical_list: D050053:TRPM Cation Channels; C544443:TRPM2 protein, mouse; D006861:Hydrogen Peroxide; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D019869:Phosphatidylinositol 3-Kinases; D002118:Calcium