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- Title
Suppression of hypoxic cell death by APIP-induced sustained activation of AKT and ERK1/2.
- Authors
Cho, D.-H.; Lee, H.-J.; Kim, H.-J.; Hong, S.-H.; Pyo, J.-O.; Cho, C.; Jung, Y.-K.
- 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.Oncogene (2007) 26, 2809–2814. doi:10.1038/sj.onc.1210080; published online 6 November 2006
- Subjects
CELL death; HYPOXEMIA; PHOSPHORYLATION; ETOPOSIDE; PROTEIN kinases
- Publication
Oncogene, 2007, Vol 26, Issue 19, p2809
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/sj.onc.1210080