Inhibitory PAS domain protein (IPAS) is a hypoxia-inducible splicing variant of the hypoxia-inducible factor-3α locus
Inhibitory PAS domain protein (IPAS) is a hypoxia-inducible splicing variant of the hypoxia-inducible factor-3α locus
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DOI：
10.1074/jbc.c200328200
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发表时间：
2002-09-06
影响因子：
4.8
通讯作者：
Poellinger, L
中科院分区：
文献类型：
--
作者：
Makino, Y;Kanopka, A;Poellinger, L
抑制性 PAS (Per/Arnt/Sim) 结构域蛋白 IPAS 通过与那些无法与靶基因缺氧反应元件结合的蛋白质形成复合物，充当缺氧诱导转录因子 (HIF) 的显性负调节因子。我们之前观察到IPAS主要在小鼠小脑浦肯野细胞和眼睛角膜上皮中表达，它似乎在血管生成的负调节和无血管表型的维持中发挥作用。小鼠 IPAS 基因组结构的测序表明，IPAS 是 HIF-3alpha 基因座的剪接变体。因此，除了三个独特的外显子（1a、4a 和 16）之外，IPAS 还与 HIF-3α 共享三个外显子（2、4 和 5），以及外显子 3 和 6 的选择性剪接变体。在使用正常小鼠和暴露于缺氧 (6% O-2) 6 小时的小鼠的实验中，我们观察到心脏和肺中 HIF-3alpha 转录物的选择性剪接。选择性剪接转录物仅在缺氧条件下才能观察到，从而定义了缺氧依赖性基因表达调节的新机制。重要的是，这种机制可能会在这些组织中建立对缺氧/缺血的适应性反应的负反馈回路调节。
The inhibitory PAS (Per/Arnt/Sim) domain protein, IPAS, functions as a dominant negative regulator of hypoxia-inducible transcription factors (HIFs) by forming complexes with those proteins that fail to bind to hypoxia response elements of target genes. We have previously observed that IPAS is predominantly expressed in mice in Purkinje cells of the cerebellum and in corneal epithelium of the eye where it appears to play a role in negative regulation of angiogenesis and maintenance of an avascular phenotype. Sequencing of the mouse IPAS genomic structure revealed that IPAS is a splicing variant of the HIF-3alpha locus. Thus, in addition to three unique exons (1a, 4a, and 16) IPAS shares three exons (2, 4, and 5) with HIF-3alpha as well as alternatively spliced variants of exons 3 and 6. In experiments using normal mice and mice exposed to hypoxia (6% O-2) for 6 h we observed alternative splicing of the HIF-3alpha transcript in the heart and lung. The alternatively spliced transcript was only observed under hypoxic conditions, thus defining a novel mechanism of hypoxia-dependent regulation of gene expression. Importantly, this mechanism may establish negative feedback loop regulation of adaptive responses to hypoxia/ischemia in these tissues.