Up-regulation of apoptosis inhibitory protein IAP-2 by hypoxia - HIF-1-independent mechanisms
Up-regulation of apoptosis inhibitory protein IAP-2 by hypoxia - HIF-1-independent mechanisms
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DOI：
10.1074/jbc.m011774200
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发表时间：
2001-06-01
影响因子：
4.8
通讯作者：
Nishiyama, J
中科院分区：
文献类型：
--
作者：
Dong, Z;Venkatachalam, MA;Nishiyama, J
缺氧是肿瘤发展和器官缺血期间组织病理学的关键决定因素。然而，关于直接参与细胞死亡或死亡抗性的基因的低氧调节知之甚少。在这里，我们报告了显着的诱导严重缺氧的抗凋亡蛋白IAP-2。IAP-2表达上调的低分化细胞对凋亡具有抵抗性。IAP-2是由缺氧本身诱导的，而不是由缺氧的继发性效应，包括ATP耗竭和细胞损伤。诱导反应不涉及细胞的氧化还原状态或逮捕线粒体呼吸的改变。另一方面，IAP-2诱导被放线菌素D减弱，表明基因转录的作用。体外细胞核连续试验表明，在缺氧暴露后IAP-2转录活性的特异性增加。HIF-1是在缺氧条件下负责多基因激活的主要转录因子，在IAP-2表达中没有作用。HIF-1和IAP-2可在不同程度的缺氧条件下诱导表达，IAP-2的诱导需要重度缺氧或缺氧。此外，氯化钴和去铁胺激活HIF-1，但不IAP-2。最后，IAP-2在缺乏HIF-1的小鼠胚胎干细胞中被严重缺氧诱导。因此，这项研究不仅提供了抗凋亡基因的缺氧调节的第一个证明，但也表明新的缺氧反应的转录机制的参与。
Hypoxia is a key determinant of tissue pathology during tumor development and organ ischemia. However, little is known regarding hypoxic regulation of genes that are directly involved in cell death or death resistance. Here we report the striking induction by severe hypoxia of the anti-apoptotic protein IAP-2. Hypoxic cells with IAP-2 up-regulation became resistant to apoptosis. IAP-2 was induced by hypoxia per se rather than by the secondary effects of hypoxia, including ATP depletion and cell injury. The inductive response did not relate to alterations of cellular redox status or arrest of mitochondrial respiration. On the other hand, IAP-2 induction was attenuated by actinomycin D, suggesting a role for gene transcription. In vitro nuclear run-on assays demonstrated specific increases in IAP-2 transcriptional activity after hypoxia exposure. HIF-1, the primary transcription factor that is responsible for multiple gene activation under hypoxia, does not have a role in IAP-2 expression. HIF-1 and IAP-2 were induced by different degrees of hypoxia; severe hypoxia or anoxia was required for IAP-2 induction. Moreover, cobalt chloride and desferrioxamine activated HIF-1 but not IAP-2. Finally, IAP-2 was induced by severe hypoxia in mouse embryonic stem cells that were deficient of HIF-1. Thus, this study not only provides the first demonstration of hypoxic regulation of an anti-apoptotic gene but also suggests the participation of novel hypoxia-responsive transcription mechanisms.