Hypoxia-inducible factor-1α mediates hypoxia-induced delayed neuronal death that involves p53
Hypoxia-inducible factor-1α mediates hypoxia-induced delayed neuronal death that involves p53
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DOI：
10.1523/jneurosci.19-16-06818.1999
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发表时间：
1999-08-15
影响因子：
5.3
通讯作者：
Federoff, HJ
中科院分区：
文献类型：
--
作者：
Halterman, MW;Miller, CC;Federoff, HJ
已知缺氧诱导的迟发性神经元死亡需要从头基因表达;然而，所涉及的分子介质仍不确定。转录因子缺氧诱导因子-1 α（HIF-1 α）除了在缺氧条件下促进适应性基因的表达外，还被认为是肿瘤中p53介导的细胞死亡的必要组分。使用疱疹病毒扩增子介导的基因转移在皮层神经元培养，我们证明，交付的显性负性形式的HIF-1 α（HIFdn），能够破坏缺氧依赖性转录，减少迟发性神经元死亡后缺氧应激。相反，缺氧抗性p53-null原代培养物不受HIFdn表达的保护。这些数据表明，在缺氧神经元中，HIF-1 α和p53共同促进导致细胞死亡的病理序列。
Hypoxia-induced delayed neuronal death is known to require de novo gene expression; however, the molecular mediators that are involved remain undefined. The transcription factor hypoxia-inducible factor-1 alpha (HIF-1 alpha), in addition to promoting the expression of adaptive genes under conditions of hypoxia, has been implicated as being a necessary component in p53-mediated cell death in tumors. Using herpes amplicon-mediated gene transfer in cortical neuronal cultures, we demonstrate that delivery of a dominant-negative form of HIF-1 alpha (HIFdn), capable of disrupting hypoxia-dependent transcription, reduces delayed neuronal death that follows hypoxic stress. In contrast, hypoxia-resistant p53-null primary cultures are not protected by HIFdn expression. These data indicate that, in hypoxic neurons, HIF-1 alpha and p53 conspire to promote a pathological sequence resulting in cell death.