Stabilization of hepatocyte growth factor mRNA by hypoxia-inducible factor 1
Stabilization of hepatocyte growth factor mRNA by hypoxia-inducible factor 1
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DOI：
10.1007/s11033-008-9406-1
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发表时间：
2009-09-01
影响因子：
2.8
通讯作者：
Qiu, Jian-Hua
中科院分区：
文献类型：
--
作者：
Chu, Sheng-Hua;Feng, Dong-Fu;Qiu, Jian-Hua
缺氧通过增加肝细胞生长因子（HGF）的转录和稳定其mRNA来调节其表达。尽管缺氧诱导因子1 （HIF-1）在缺氧反应基因的转录激活中起着关键作用，但HIF-1是否介导缺氧诱导的HGF mRNA稳定尚不清楚。我们构建了表达野生型HIF-1 α (Ad2/HIF-1 α /FL)、组成稳定的HIF-1 α杂交形式（Ad2/HIF-1 α /VP16）或非转基因（Ad2/CMVEV）的腺病毒载体。在大鼠胶质瘤（C6）细胞、人胶质瘤（U251）细胞、人心脏、血管平滑肌和内皮细胞中，Ad2/HIF-1 α /VP16或Ad2/HIF-1 α /FL感染HGF mRNA和蛋白水平均升高。常压条件下，C6和U251细胞中HGF mRNA的半衰期为43 min。缺氧和Ad2/HIF-1 α /VP16分别使HGF mRNA的半衰期延长至3.2和2.8 h，而Ad2/CMVEV对HGF mRNA的半衰期无影响。这些研究首次证明过表达HIF-1 α可增加HGF mRNA的稳定性。我们的研究结果还表明，缺氧对HGF mRNA的稳定至少部分是由HIF-1介导的。
Hypoxia regulates expression of hepatocyte growth factor (HGF) by increasing its transcription and by stabilizing its mRNA. Despite the pivotal role of hypoxia-inducible factor 1 (HIF-1) in transcriptional activation of hypoxia-responsive genes, it is not known whether HIF-1 mediates hypoxia-induced stabilization of HGF mRNA. We constructed adenoviral vectors expressing either the wild-type HIF-1 alpha (Ad2/HIF-1 alpha/FL), a constitutively stable hybrid form of HIF-1 alpha (Ad2/HIF-1 alpha/VP16), or no transgene (Ad2/CMVEV). In rat glioma (C6) cells, human glioma (U251) cells human cardiac, vascular smooth muscle, and endothelial cells, infection with Ad2/HIF-1 alpha/VP16 or Ad2/HIF-1 alpha/FL increased HGF expression at both the mRNA and protein levels. Under normoxic conditions, the half-life of HGF mRNA was 43 min in C6 and U251 cells. Hypoxia and Ad2/HIF-1 alpha/VP16 increased the half-life of HGF mRNA to 3.2 and 2.8 h, respectively, while Ad2/CMVEV had no effect. These studies are the first to demonstrate that overexpression of HIF-1 alpha increases HGF mRNA stability. Our results also suggest that stabilization of HGF mRNA by hypoxia is mediated, at least in part, by HIF-1.