title: Suppression of hypoxic cell death by APIP-induced sustained activation of AKT and ERK1/2.
abstract: Apaf-1-interacting protein (APIP) was previously isolated as an inhibitor of mitochondrial cell death interacting with Apaf-1. Here, we report a hypoxia-selective antiapoptotic activity of APIP that induces the activation of AKT and extracellular signal-regulated kinase (ERK)1/2. Stable expression of APIP in C2C12 (C2C12/APIP) cells suppressed cell death induced by hypoxia and etoposide. Unlike etoposide, however, APIP induces the sustained activation of AKT and ERK1/2 and the phosphorylation of caspase-9 during hypoxia. Inhibition of AKT and ERK1/2 activation by the treatments with phosphatidylinositol 3'-kinase and mitogen-activated protein kinase kinase (MEK)1/2 inhibitors sensitized C2C12/APIP cells to hypoxic cell death and abolished the hypoxia-induced phosphorylation of caspase-9. Further, overexpression of phosphorylation-mimic caspase-9 mutants (caspase-9-T125E and caspase-9-S196D), but not phosphorylation-defective caspase-9 mutants (caspase-9-T125A and caspase-9-S196A), effectively suppressed hypoxia-induced death of C2C12 cells. These results elucidate a novel Apaf-1-independent antiapoptotic activity of APIP during hypoxic cell death, inducing the sustained activation of AKT and ERK1/2 and leading to caspase-9 phosphorylation.
authors.affiliation: Department of Life Science, Gwangju Institute of Science and Technology, Gwangju, Korea.
authors.forename: D-H
authors.initials: DH
authors.lastname: Cho
authors.forename: H-J
authors.initials: HJ
authors.lastname: Lee
authors.forename: H-J
authors.initials: HJ
authors.lastname: Kim
authors.forename: S-H
authors.initials: SH
authors.lastname: Hong
authors.forename: J-O
authors.initials: JO
authors.lastname: Pyo
authors.forename: C
authors.initials: C
authors.lastname: Cho
authors.forename: Y-K
authors.initials: YK
authors.lastname: Jung
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis; D053477:Apoptotic Protease-Activating Factor 1 / Q000235:genetics / Q000378:metabolism*; D053453:Caspase 9 / Q000235:genetics / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D015180:Electrophoresis, Gel, Two-Dimensional; D004789:Enzyme Activation; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D000860:Hypoxia; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C506593:Apaf1 protein, mouse; D053477:Apoptotic Protease-Activating Factor 1; D005047:Etoposide; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D053453:Caspase 9; D020169:Caspases