Inhibition of NGF deprivation-induced death by low oxygen involves suppression of BIMEL and activation of HIF-1.
Inhibition of NGF deprivation-induced death by low oxygen involves suppression of BIMEL and activation of HIF-1.
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DOI：
10.1083/jcb.200407079
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发表时间：
2005-03-14
影响因子：
7.8
通讯作者：
Freeman, Robert S
中科院分区：
文献类型：
--
作者：
Xie, Liang;Johnson, Randall S;Freeman, Robert S
氧分压的变化可以显著影响细胞的存活，但这些影响背后的机制尚不清楚。在这里，我们报告了在低氧条件下维持交感神经元抑制由NGF剥夺引起的细胞凋亡。低氧暴露可抑制NGF停用后细胞色素c的释放，部分是通过抑制BIMEL的上调。强制表达BIMEL解除了对细胞色素c释放的阻断，但不能阻止低O2的保护作用。低氧还可激活低氧诱导因子和稳定形式的低氧诱导因子-1α(HIF-1αPP→AG)的表达，抑制常氧、神经生长因子缺乏的细胞的死亡。靶向缺失HIF-1α部分抑制低O2的保护作用，而缺失HIF-1α并强制表达BIMEL则完全逆转低O2抑制细胞死亡的能力。这些数据提出了一个新的模型，说明氧气压力如何影响营养因子剥夺诱导的细胞死亡背后的凋亡事件。
Changes in O2 tension can significantly impact cell survival, yet the mechanisms underlying these effects are not well understood. Here, we report that maintaining sympathetic neurons under low O2 inhibits apoptosis caused by NGF deprivation. Low O2 exposure blocked cytochrome c release after NGF withdrawal, in part by suppressing the up-regulation of BIMEL. Forced BIMEL expression removed the block to cytochrome c release but did not prevent protection by low O2. Exposing neurons to low O2 also activated hypoxia-inducible factor (HIF) and expression of a stabilized form of HIF-1α (HIF-1αPP→AG) inhibited cell death in normoxic, NGF-deprived cells. Targeted deletion of HIF-1α partially suppressed the protective effect of low O2, whereas deletion of HIF-1α combined with forced BIMEL expression completely reversed the ability of low O2 to inhibit cell death. These data suggest a new model for how O2 tension can influence apoptotic events that underlie trophic factor deprivation–induced cell death.