Suppression of hypoxic cell death by APIP-induced sustained activation of AKT and ERK1/2
Suppression of hypoxic cell death by APIP-induced sustained activation of AKT and ERK1/2
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DOI：
10.1038/sj.onc.1210080
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发表时间：
2007-04-26
期刊：
影响因子：
8
通讯作者：
Jung, Y.-K.
中科院分区：
文献类型：
--
作者：
Cho, D.-H.;Lee, H.-J.;Jung, Y.-K.
Apaf-1相互作用蛋白（APIP）先前被分离为与Apaf-1相互作用的线粒体细胞死亡抑制剂。在这里，我们报告了缺氧选择性抗凋亡活性的APIP，诱导AKT和细胞外信号调节激酶（ERK）1/2的激活。APIP在C2 C12细胞中的稳定表达（C2 C12/APIP）抑制缺氧和依托泊苷诱导的细胞死亡。然而，与依托泊苷不同，APIP在缺氧期间诱导AKT和ERK 1/2的持续活化和caspase-9的磷酸化。通过用磷脂酰肌醇3 '-激酶和促分裂原活化蛋白激酶激酶（MEK）12抑制剂处理来抑制AKT和ERK 12活化使C2 C12/APIP细胞对缺氧细胞死亡敏感，并消除缺氧诱导的caspase-9磷酸化。此外，过表达磷酸化模拟的半胱天冬酶-9突变体（半胱天冬酶-9-T125 E和半胱天冬酶-9-S196 D），而不是磷酸化缺陷的半胱天冬酶-9突变体（半胱天冬酶-9-T125 A和半胱天冬酶-9-S196 A），有效地抑制缺氧诱导的C2 C12细胞死亡。这些结果阐明了APIP在缺氧细胞死亡过程中的一种新的Apaf-1-独立的抗凋亡活性，诱导AKT和ERK 1/2的持续激活，并导致caspase- 9磷酸化。
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.