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首页> 外文期刊>Molecular and Cellular Biology >Identification of the Hypoxia-Inducible Factor 1α-Responsive HGTD-P Gene as a Mediator in the Mitochondrial Apoptotic Pathway
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Identification of the Hypoxia-Inducible Factor 1α-Responsive HGTD-P Gene as a Mediator in the Mitochondrial Apoptotic Pathway

机译：缺氧诱导因子1α响应HGTD-P基因作为线粒体细胞凋亡途径中的介体的鉴定。

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Hypoxia-inducible factor 1α (HIF-1α) controls the cellular responses to hypoxia, activating transcription of a range of genes involved in adaptive processes such as increasing glycolysis and promoting angiogenesis. However, paradoxically, HIF-1α also participates in hypoxic cell death. Several gene products, such as BNip3, RTP801, and Noxa, were identified as HIF-1α-responsive proapoptotic proteins, but the complicated hypoxic cell death pathways could not be completely explained by the few known genes. Moreover, molecules linking the proapoptotic signals of HIF-1α directly to mitochondrial permeability transition are missing. In this work, we report the identification of an HIF-1α-responsive proapoptotic molecule, HGTD-P. Its expression was directly regulated by HIF-1α through a hypoxia-responsive element on the HGTD-P promoter region. When overexpressed, HGTD-P was localized to mitochondria and facilitated apoptotic cell death via typical mitochondrial apoptotic cascades, including permeability transition, cytochrome c release, and caspase 9 activation. In the process of permeability transition induction, the death-inducing domain of HGTD-P physically interacted with the voltage-dependent anion channel. In addition, suppression of HGTD-P expression by small interfering RNA or antisense oligonucleotides protected against hypoxic cell death. Taken together, our data indicate that HGTD-P is a new HIF-1α-responsive proapoptotic molecule that activates mitochondrial apoptotic cascades.
机译：缺氧诱导因子1α（HIF-1α）控制细胞对缺氧的反应，激活一系列参与适应性过程的基因的转录，这些过程包括增加糖酵解和促进血管生成。然而，矛盾的是，HIF-1α也参与了缺氧细胞的死亡。几种基因产物，例如BNip3，RTP801和Noxa被鉴定为HIF-1α反应性促凋亡蛋白，但是复杂的低氧细胞死亡途径无法由少数已知基因完全解释。此外，缺少将HIF-1α的促凋亡信号直接与线粒体通透性转变相关的分子。在这项工作中，我们报告了HIF-1α反应性凋亡分子HGTD-P的鉴定。 HIF-1α通过其在HGTD-P启动子区域的缺氧反应元件直接调节其表达。当过表达时，HGTD-P定位于线粒体并通过典型的线粒体凋亡级联反应促进凋亡细胞死亡，包括通透性转变，细胞色素 c 释放和胱天蛋白酶9活化。在渗透性转变诱导过程中，HGTD-P的死亡诱导域与电压依赖性阴离子通道发生物理相互作用。此外，小分子干扰RNA或反义寡核苷酸抑制HGTD-P的表达可防止缺氧细胞死亡。综上所述，我们的数据表明HGTD-P是一种新的HIF-1α反应性促凋亡分子，可激活线粒体凋亡级联反应。

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