c-Jun and hypoxia-inducible factor 1 functionally cooperate in hypoxia-induced gene transcription
c-Jun and hypoxia-inducible factor 1 functionally cooperate in hypoxia-induced gene transcription
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DOI：
10.1128/mcb.22.1.12-22.2002
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发表时间：
2002-01-01
影响因子：
5.3
通讯作者：
Landázuri, MO
中科院分区：
文献类型：
--
作者：
Alfranca, A;Gutiérrez, MD;Landázuri, MO
在低氧条件下，细胞发展出一种适应性程序，导致几种基因的诱导，这些基因在转录上受缺氧诱导因子1（HIF-1）调节。另一方面，还有其他因子通过与其启动子中存在的顺式作用基序结合来调节HIF-1介导的某些基因的诱导。在这里，我们表明，c-Jun功能合作与HIF-1在不同类型的细胞的转录活性。有趣的是，缺乏其反式激活结构域的c-Jun的显性负突变体部分抑制HIF-1介导的转录。这种协同作用不是由于HIF-1 α亚基的核数量增加，也不需要c-jun与DNA的直接结合。c-jun和HIF-1 α能够在体内而非体外结合，表明这种相互作用涉及额外蛋白质的参与和/或这些因子的翻译后修饰。在这种情况下，缺氧诱导内皮细胞中c-jun在Ser（63）处的磷酸化。该过程涉及其协同作用，因为JNK途径的特异性阻断和c-Jun在Ser（63）和Ser（73）处的突变损害了其与HIF-1的功能性合作。c-Jun和HIF-1之间的功能相互作用为一些基因的调节提供了新的见解，例如VEGF，这是肿瘤血管生成的关键调节因子。
Under low-oxygen conditions, cells develop an adaptive program that leads to the induction of several genes, which are transcriptionally regulated by hypoxia-inducible factor 1 (HIF-1). On the other hand, there are other factors which modulate the HIF-1-mediated induction of some genes by binding to cis-acting motifs present in their promoters. Here, we show that c-Jun functionally cooperates with HIF-1 transcriptional activity in different cell types. Interestingly, a dominant-negative mutant of c-Jun which lacks its transactivation domain partially inhibits HIF-1-mediated transcription. This cooperative effect is not due to an increase in the nuclear amount of the HIF-1 alpha subunit, nor does it require direct binding of c-jun to DNA. c-jun and HIF-1 alpha are able to associate in vivo but not in vitro, suggesting that this interaction involves the participation of additional proteins and/or a posttranslational modification of these factors. In this context, hypoxia induces phosphorylation of c-jun at Ser(63) in endothelial cells. This process is involved in its cooperative effect, since specific blockade of the JNK pathway and mutation of c-Jun at Ser(63) and Ser(73) impair its functional cooperation with HIF-1. The functional interplay between c-Jun and HIF-1 provides a novel insight into the regulation of some genes, such as the one for VEGF, which is a key regulator of tumor angiogenesis.