首页> 美国卫生研究院文献>Molecular and Cellular Biology >The Regulation of Hypoxic Genes by Calcium Involves c-Jun/AP-1 Which Cooperates with Hypoxia-Inducible Factor 1 in Response to Hypoxia
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The Regulation of Hypoxic Genes by Calcium Involves c-Jun/AP-1 Which Cooperates with Hypoxia-Inducible Factor 1 in Response to Hypoxia

机译:钙对缺氧基因的调控涉及c-Jun / AP-1它与缺氧诱导因子1协同作用以应对缺氧

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摘要

Hypoxia causes the accumulation of the transcription factor hypoxia-inducible factor 1 (HIF-1), culminating in the expression of hypoxia-inducible genes such as those for vascular endothelial growth factor (VEGF) and NDRG-1/Cap43. Previously, we have demonstrated that intracellular calcium (Ca2+) is required for the expression of hypoxia-inducible genes. Here we found that, unlike with hypoxia or hypoxia-mimicking conditions, the elevation of intracellular Ca2+ neither induced the HIF-1α protein nor stimulated HIF-1-dependent transcription. Furthermore, the elevation of intracellular Ca2+ induced NDRG-1/Cap43 mRNA in HIF-1α-deficient cells. It also increased levels of c-Jun protein, causing its phosphorylation. The protein kinase inhibitor K252a abolished c-Jun induction and activator protein 1 (AP-1)-dependent reporter expression caused by Ca2+ ionophore or hypoxia. K252a also significantly decreased hypoxia-induced VEGF and NDRG-1/Cap43 gene expression in both human and mouse cells. Using a set of deletion VEGF-Luc promoter constructs, we found that both HIF-1 and two AP-1 sites contribute to hypoxia-mediated induction of transcription. In contrast, only AP-1 sites contributed to Ca2+-mediated VEGF-Luc induction. A dominant-negative AP-1 prevented Ca2+-dependent transcription and partially impaired hypoxia-mediated transcription. In addition, dominant-negative AP-1 diminished the expression of the NDRG-1/Cap43 gene following hypoxia. We conclude that during hypoxia, an increase in intracellular Ca2+ activates a HIF-1-independent signaling pathway that involves AP-1-dependent transcription. Cooperation between the HIF-1 and AP-1 pathways allows fine regulation of gene expression during hypoxia.
机译:缺氧导致转录因子缺氧诱导因子1(HIF-1)的积累,最终导致缺氧诱导基因的表达,例如血管内皮生长因子(VEGF)和NDRG-1 / Cap43的基因。以前,我们已经证明了缺氧诱导基因的表达需要细胞内钙(Ca 2 + )。在这里,我们发现,与缺氧或模拟缺氧的条件不同,细胞内Ca 2 + 的升高既不诱导HIF-1α蛋白也不刺激HIF-1依赖性转录。此外,细胞内Ca 2 + 的升高在HIF-1α缺陷细胞中诱导了NDRG-1 / Cap43 mRNA的表达。它还增加了c-Jun蛋白的水平,导致其磷酸化。蛋白激酶抑制剂K252a消除了由Ca 2 + 离子载体或缺氧引起的c-Jun诱导和激活蛋白1(AP-1)依赖的报告基因表达。 K252a还显着降低了缺氧诱导的人和小鼠细胞中的VEGF和NDRG-1 / Cap43基因表达。使用一组删除的VEGF-Luc启动子构建体,我们发现HIF-1和两个AP-1位点都有助于缺氧介导的转录诱导。相比之下,只有AP-1位点参与Ca 2 + 介导的VEGF-Luc的诱导。显性负性AP-1阻止Ca 2 + 依赖的转录,部分损害缺氧介导的转录。此外,低氧后,显性阴性AP-1减少了NDRG-1 / Cap43基因的表达。我们得出的结论是,在缺氧期间,细胞内Ca 2 + 的增加会激活HIF-1独立的信号传导途径,涉及AP-1依赖的转录过程。 HIF-1和AP-1途径之间的合作允许在缺氧期间对基因表达进行精细调节。

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