Hypoxia-inducible factor-1 mediates transcriptional activation of the heme oxygenase-1 gene in response to hypoxia
Hypoxia-inducible factor-1 mediates transcriptional activation of the heme oxygenase-1 gene in response to hypoxia
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DOI：
10.1074/jbc.272.9.5375
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发表时间：
1997-02-28
影响因子：
4.8
通讯作者：
Choi, AMK
中科院分区：
文献类型：
--
作者：
Lee, PJ;Jiang, BH;Choi, AMK
大鼠暴露于低氧(7%O-2)后，几种组织中血红素氧合酶-1(HO-1)的mRNA水平显著升高。大鼠主动脉血管平滑肌细胞暴露于1%O-2后也可观察到HO-1转录本的积聚，这种诱导依赖于基因转录，目前所测试的所有药物对小鼠HO-1基因的激活都是由两个5‘-增强子序列SX2和AB1介导的，但这两个片段都不对VSM细胞的缺氧有反应。氯霉素乙酰转移酶(CAT)报告基因的低氧诱导是由位于转录起始点上游约9.5kb的163个碱基的片段介导的。该片段含有两个潜在的低氧诱导因子1(HIF-1)结合位点，HIF-1在HO-1基因调控中的作用是通过以下观察确定的：1)HIF-1特异性地与跨越这些序列的寡核苷酸结合，2)这些序列的突变取消了VSM细胞中HIF-1结合和低氧依赖的基因激活，3)低氧增加了VSM细胞中HIF-1α和HIF-1β的蛋白水平，以及4)在缺乏HIF-1 DNA结合活性的突变肝癌细胞中没有观察到低氧依赖的HO-1mRNA积累，这些数据表明，低氧诱导了动物组织和细胞培养中HO-1的表达，并提示HIF-1参与了这一反应。
Exposure of rats to hypoxia (7% O-2) markedly increased the level of heme oxygenase-1 (HO-1) mRNA in several tissues. Accumulation of HO-1 transcripts was also observed after exposure of rat aortic vascular smooth muscle (VSM) cells to 1% O-2, and this induction was dependent on gene transcription, Activation of the mouse HO-1 gene by all agents thus far tested is mediated by two 5'-enhancer sequences, SX2 and AB1, but neither fragment was responsive to hypoxia in VSM cells. Hypoxia-dependent induction of the chloramphenicol acetyltransferase (CAT) reporter gene was mediated by a 163-bp fragment located approximately 9.5 kilobases upstream of the transcription start site. This fragment contains two potential binding sites for hypoxia-inducible factor 1 (HIF-1), A role for HIF-1 in HO-1 gene regulation was established by the following observations: 1) HIF-1 specifically bound to an oligonucleotide spanning these sequences, 2) mutation of these sequences abolished HIF-1 binding and hypoxia-dependent gene activation in VSM cells, 3) hypoxia increased HIF-1 alpha and HIF-1 beta protein levels in VSM cells, and 4) hypoxia-dependent HO-1 mRNA accumulation was not observed in mutant hepatoma cells lacking HIF-1 DNA-binding activity, Taken together, these data demonstrate that hypoxia induces HO-1 expression in animal tissues and cell cultures and implicate HIF-1 in this response.