Hypoxia-inducible factor-1 mediates transcriptional activation of the heme oxygenase-1 gene in response to hypoxia

被引:645
作者
Lee, PJ
Jiang, BH
Chin, BY
Iyer, NV
Alam, J
Semenza, GL
Choi, AMK
机构
[1] ALTON OCHSNER MED FDN & OCHSNER CLIN,DEPT MOL GENET,NEW ORLEANS,LA 70121
[2] JOHNS HOPKINS UNIV,SCH MED,DEPT MED,DIV PULM & CRIT CARE,BALTIMORE,MD 21205
[3] JOHNS HOPKINS UNIV,SCH MED,DEPT MED,CTR GENET MED,BALTIMORE,MD 21205
[4] JOHNS HOPKINS UNIV,SCH MED,DEPT PEDIAT,BALTIMORE,MD 21205
关键词
D O I
10.1074/jbc.272.9.5375
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
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页码:5375 / 5381
页数:7
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