Inhibitory PAS domain protein is a negative regulator of hypoxia-inducible gene expression
Inhibitory PAS domain protein is a negative regulator of hypoxia-inducible gene expression
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DOI：
10.1038/35107085
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发表时间：
2001-11-29
期刊：
影响因子：
64.8
通讯作者：
Poellinger, L
中科院分区：
文献类型：
--
作者：
Makino, Y;Cao, RH;Poellinger, L
基因表达的改变是低氧适应性反应的重要组成部分。这些反应由缺氧诱导转录因子（HIF）介导（1，2）。在这里，我们描述了抑制PAS（Per/Arnt/Sim）结构域蛋白，IPAS，这是一个基本的螺旋-环-螺旋（bHLH）/PAS蛋白结构相关的HIF。IPAS不含内源性反式激活功能，但对HIF介导的基因表达控制具有显性负调控作用。IPAS在肝癌细胞中的异位表达选择性地损害参与适应低氧环境的基因的诱导，特别是血管内皮生长因子（VEGF）基因，并导致体内肿瘤生长和肿瘤血管密度延迟。在小鼠中，IPAS主要在小脑的浦肯野细胞和眼睛的角膜上皮中表达。IPAS在角膜中的表达与缺氧条件下VEGF基因的低水平表达相关。在正常氧条件下，将IPAS反义寡核苷酸应用于小鼠角膜诱导血管生成，并证明缺氧角膜细胞中VEGF基因表达的缺氧依赖性诱导。这些结果表明了一个以前未知的负调控血管生成和维持无血管表型的机制。
Alteration of gene expression is a crucial component of adaptive responses to hypoxia. These responses are mediated by hypoxia-inducible transcription factors (HIFs)(1,2). Here we describe an inhibitory PAS (Per/Arnt/Sim) domain protein, IPAS, which is a basic helix-loop-helix (bHLH)/PAS protein structurally related to HIFs. IPAS contains no endogenous transactivation function but demonstrates dominant negative regulation of HIF-mediated control of gene expression. Ectopic expression of IPAS in hepatoma cells selectively impairs induction of genes involved in adaptation to a hypoxic environment, notably the vascular endothelial growth factor (VEGF) gene, and results in retarded tumour growth and tumour vascular density in vivo. In mice, IPAS was predominantly expressed in Purkinje cells of the cerebellum and in corneal epithelium of the eye. Expression of IPAS in the cornea correlates with low levels of expression of the VEGF gene under hypoxic conditions. Application of an IPAS antisense oligonucleotide to the mouse cornea induced angiogenesis under normal oxygen conditions, and demonstrated hypoxia-dependent induction of VEGF gene expression in hypoxic corneal cells. These results indicate a previously unknown mechanism for negative regulation of angiogenesis and maintenance of an avascular phenotype.