The ternary complex factor Net/Elk-3 participates in the transcriptional response to hypoxia and regulates HIF-1α
The ternary complex factor Net/Elk-3 participates in the transcriptional response to hypoxia and regulates HIF-1α
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DOI：
10.1038/sj.onc.1210736
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发表时间：
2008-02-21
期刊：
影响因子：
8
通讯作者：
Wasylyk, B.
中科院分区：
文献类型：
--
作者：
Gross, C.;Dubois-Pot, H.;Wasylyk, B.
三元复合因子Net/Elk3在低氧条件下下调表达，参与c-fos、血管内皮生长因子和EGR-1等基因的诱导。然而，Net在低氧中的整体作用仍有待阐明。在使用微阵列对RNA表达进行的大规模分析中，我们已经确定了370多个基因在低氧条件下受Net调控。为了深入了解Net在低氧中的作用，我们平行分析了HIF-1α调控的基因，HIF-1α是参与低氧反应的经典因子。我们鉴定了大约190个在缺氧状态下受HIF-1α调控的基因。令人惊讶的是，当我们比较缺氧诱导的需要Net或HIF-1α的基因时，大多数是相同的(75%)，这表明这两个因素的功能密切相关。有趣的是，在低氧条件下，Net调节几个已知控制HIF-1α稳定性的基因的表达，包括PHD2，PHD3和Siah2，这表明Net调节HIF-1α的稳定性。我们发现，在低氧条件下，RNAi抑制Net导致HIF-1α在蛋白水平的表达降低。这些结果表明，Net通过调节HIF-1α蛋白的稳定性参与了对低氧的转录反应。
The ternary complex factor Net/Elk3 is downregulated in hypoxia and participates in the induction by hypoxia of several genes, including c-fos, vascular endothelial growth factor and egr-1. However, the global role of Net in hypoxia remains to be elucidated. We have identified, in a large-scale analysis of RNA expression using microarrays, more than 370 genes that are regulated by Net in hypoxia. In order to gain insights into the role of Net in hypoxia, we have analysed in parallel the genes regulated by HIF-1 alpha, the classical factor involved in the response to hypoxia. We identified about 190 genes that are regulated by HIF-1 alpha in hypoxia. Surprisingly, when we compare the genes induced by hypoxia that require either Net or HIF-1 alpha, the majority are the same (75%), suggesting that the functions of both factors are closely linked. Interestingly, in hypoxia, Net regulates the expression of several genes known to control HIF-1 alpha stability, including PHD2, PHD3 and Siah2, suggesting that Net regulates the stability of HIF-1 alpha. We found that inhibition of Net by RNAi leads to decreased HIF-1 alpha expression at the protein level in hypoxia. These results indicate that Net participates in the transcriptional response to hypoxia by regulation of HIF-1 alpha protein stability.