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.
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Acknowledgements
This work was supported by the grants from Brain Research Center of 21C Frontier Research Program, Basic Research Program and Functional Cellulomics Research Center of the Korea Science and Engineering Foundation.
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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).
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Cho, DH., Lee, HJ., Kim, HJ. et al. Suppression of hypoxic cell death by APIP-induced sustained activation of AKT and ERK1/2. Oncogene 26, 2809–2814 (2007). https://doi.org/10.1038/sj.onc.1210080
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DOI: https://doi.org/10.1038/sj.onc.1210080
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