OXYGEN-REGULATED CONTROL ELEMENTS IN THE PHOSPHOGLYCERATE KINASE-1 AND LACTATE-DEHYDROGENASE-A GENES - SIMILARITIES WITH THE ERYTHROPOIETIN 3' ENHANCER
OXYGEN-REGULATED CONTROL ELEMENTS IN THE PHOSPHOGLYCERATE KINASE-1 AND LACTATE-DEHYDROGENASE-A GENES - SIMILARITIES WITH THE ERYTHROPOIETIN 3' ENHANCER
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DOI：
10.1073/pnas.91.14.6496
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发表时间：
1994-07-05
影响因子：
11.1
通讯作者：
RATCLIFFE, PJ
中科院分区：
文献类型：
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作者：
FIRTH, JD;EBERT, BL;RATCLIFFE, PJ
在缺氧刺激下产生的糖蛋白激素促红细胞生成素（Epo）几乎完全局限于肝脏和肾脏内的特定细胞，然而Epo基因3'上的转录增强子在转染到多种培养细胞后显示出缺氧诱导的活性。这一发现的含义是，许多不产生Epo的细胞含有一个类似的（如果不是完全相同的话）氧调节控制系统，这表明同样的系统也参与了其他基因的调节。我们报道了人磷酸甘油酸激酶1和小鼠乳酸脱氢酶A基因在缺氧诱导下具有类似Epo基因诱导的特征。在每种情况下，表达都是由钴诱导的，而不是由氰化物诱导的，并且缺氧诱导被蛋白质合成抑制剂环己亚胺阻断。我们发现相关的顺式作用控制序列位于两个基因的5‘侧区，我们在磷酸甘油酸激酶1基因的5’侧序列中定义了一个18bp的元件，该元件对于缺氧反应是必要的和充分的，并且与Epo 3'增强子内的缺氧诱导因子1结合位点具有序列和蛋白质结合相似性。
Production of the glycoprotein hormone erythropoietin (Epo) in response to hypoxic stimuli is almost entirely restricted to particular cells within liver and kidney, yet the transcriptional enhancer lying 3' to the Epo gene shows activity inducible by hypoxia after transfection into a wide variety of cultured cells. The implication of this finding is that many cells which do not produce Epo contain a similar, if not identical, oxygen regulated control system, suggesting that the same system is involved in the regulation of other genes. We report that the human phosphoglycerate kinase 1 and mouse lactate dehydrogenase A genes are induced by hypoxia with characteristics which resemble induction of the Epo gene. In each case expression is induced by cobalt, but not by cyanide, and hypoxic induction is blocked by the protein-synthesis inhibitor cycloheximide. We show that the relevant cis-acting control sequences are located in the 5' flanking regions of the two genes, and we define an 18-bp element in the 5' flanking sequence of the phosphoglycerate kinase 1 gene which is both necessary and sufficient for the hypoxic response, and which has sequence and protein-binding similarities to the hypoxia-inducible factor 1 binding site within the Epo 3' enhancer.