Expression of the gene encoding the proapoptotic Nip3 protein is induced by hypoxia
Expression of the gene encoding the proapoptotic Nip3 protein is induced by hypoxia
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DOI：
10.1073/pnas.97.16.9082
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发表时间：
2000-08-01
影响因子：
11.1
通讯作者：
Bruick, RK
中科院分区：
文献类型：
--
作者：
Bruick, RK
感知和响应氧气供应变化的能力对许多发育、生理和病理过程至关重要，包括血管生成。控制血压、脑缺血和心肌缺血。低氧诱导因子-1α(HIF-1α)是一种碱性-螺旋-环-螺旋(BHLH)转录因子，属于Per-Arnt-SIM(PAS)转录因子家族，在低氧反应中发挥重要作用。缺氧诱导因子-1α及其近亲HIF-2α/内皮PAS结构域蛋白(EPAS)和HIF-3α在缺氧条件下被诱导，并协同激活靶基因的表达，其产物促进细胞在缺氧条件下的生存。当细胞暴露在慢性缺氧中时，这种保护反应可能会失败，导致细胞凋亡。这项研究表明，编码Nip3的基因转录。细胞死亡因子Bcl2家族中的促凋亡成员，在低氧条件下被强烈诱导。Nip3启动子含有一个功能性的HIF-1反应元件(HRE)，可被缺氧和HIF-1α的强制表达所激活。培养的细胞暴露在慢性低氧中会导致Nip3抗体所识别的蛋白质的积累。本研究证实了HIF-1α与Bcl2家族促凋亡成员之间的直接联系，并为包括Nip3及其近亲Nix在内的Bcl2亚家族成员提供了合理的生理功能。这些观察表明，Nip3可能在缺血损伤后观察到的缺氧介导的细胞凋亡的病理过程中发挥专门的作用。
The ability to sense and respond to changes in oxygen availability is critical for many developmental, physiological, and pathological processes, including angiogenesis. control of blood pressure, and cerebral and myocardial ischemia. Hypoxia-inducible factor-1 alpha (HIF-1 alpha) is a basic-helix-loop-helix (bHLH)containing member of the PER-ARNT-SIM (PAS) family of transcription factors that plays a central role in the response to hypoxia. HIF-1 alpha, and its relatives HIF-2 alpha/endothelial PAS domain protein (EPAS) and HIF-3 alpha, are induced in response to hypoxia and serve to coordinately activate the expression of target genes whose products facilitate cell survival under conditions of oxygen deprivation. When cells are exposed to chronic hypoxia, the protective response can fail, resulting in apoptosis. This study shows that transcription of the gene encoding Nip3. a proapoptotic member of the Bcl-2 family of cell death factors, is strongly induced in response to hypoxia. The Nip3 promoter contains a functional HIF-1-responsive element (HRE) and is potently activated by both hypoxia and forced expression of HIF-1 alpha. Exposure of cultured cells to chronic hypoxia results in the accumulation of a protein recognized by antibodies raised against Nip3. This study demonstrates a direct link between HIF-1 alpha and a proapoptotic member of the Bcl-2 family and offers a reasonable physiological function for members of the Bcl-2 subfamily, including Nip3 and its close relative Nix. These observations indicate that Nip3 may play a dedicated role in the pathological progression of hypoxia-mediated apoptosis, as observed after ischemic injury.