The Endoplasmic Reticulum Stress Response Factor CHOP-10 Protects against Hypoxia-induced Neuronal Death
The Endoplasmic Reticulum Stress Response Factor CHOP-10 Protects against Hypoxia-induced Neuronal Death
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DOI：
10.1074/jbc.m109.095299
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发表时间：
2010-07-09
影响因子：
4.8
通讯作者：
Federoff, Howard J.
中科院分区：
文献类型：
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作者：
Halterman, Marc W.;Gill, Molly;Federoff, Howard J.
缺氧诱导的基因表达是脑卒中后神经元存活的关键决定因素。了解控制适应性和病理性转录的细胞自主遗传程序可能具有重要的治疗意义。为了确定缺氧损伤后迟发性神经元凋亡的调节因素，我们开发了一种体外培养模型，该模型重现了这些不同的反应，并利用微阵列表征了基因表达变化的序列。缺氧诱导了不成比例的bZIP转录因子和相关的目标参与内质网应激反应。虽然ATF4表达的时间和空间方面与神经元损失相关，但我们的结果并不支持延迟CHOP表达的预期病理作用。相反，CHOP缺失增强了神经元对缺氧和毒胡萝卜素介导的损伤的易感性，并减弱了脑源性神经营养因子诱导的神经保护作用。此外，强制表达的CHOP开始缺氧前保护野生型文化随后的损伤。总的来说，这些发现表明CHOP在神经元对缺氧应激的反应中起着更复杂的作用，涉及缺血预处理和延迟神经保护。
Hypoxia-induced gene expression is a critical determinant of neuron survival after stroke. Understanding the cell autonomous genetic program controlling adaptive and pathological transcription could have important therapeutic implications. To identify the factors that modulate delayed neuronal apoptosis after hypoxic injury, we developed an in vitro culture model that recapitulates these divergent responses and characterized the sequence of gene expression changes using microarrays. Hypoxia induced a disproportionate number of bZIP transcription factors and related targets involved in the endoplasmic reticulum stress response. Although the temporal and spatial aspects of ATF4 expression correlated with neuron loss, our results did not support the anticipated pathological role for delayed CHOP expression. Rather, CHOP deletion enhanced neuronal susceptibility to both hypoxic and thapsigargin-mediated injury and attenuated brain-derived neurotrophic factor-induced neuroprotection. Also, enforced expression of CHOP prior to the onset of hypoxia protected wild-type cultures against subsequent injury. Collectively, these findings indicate CHOP serves a more complex role in the neuronal response to hypoxic stress with involvement in both ischemic preconditioning and delayed neuroprotection.