AMP-activated protein kinase activity is critical for hypoxia-inducible factor-1 transcriptional activity and its target gene expression under hypoxic conditions in DU145 cells (Retracted article. See vol. 293, pg. 18013, 2018)
AMP-activated protein kinase activity is critical for hypoxia-inducible factor-1 transcriptional activity and its target gene expression under hypoxic conditions in DU145 cells (Retracted article. See vol. 293, pg. 18013, 2018)
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DOI：
10.1074/jbc.m306104200
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发表时间：
2003-10-10
影响因子：
4.8
通讯作者：
Ha, JH
中科院分区：
文献类型：
--
作者：
Lee, M;Hwang, JT;Ha, JH
腺苷酸活化蛋白激酶（AMPK）作为能量传感器在缺氧等ATP缺乏条件下提供代谢适应。在本研究中，我们认为AMPK在适应性反应缺氧的作用，通过检查AMPK是否参与调节缺氧诱导因子-1（HIF-1），异二聚体转录因子，缺氧诱导的生理重要基因是至关重要的。我们证明，缺氧或氯化钴迅速激活DU 145人前列腺癌细胞中的AMPK，其激活先于HIF-1 α表达的诱导。在这些条件下，通过药理学或分子方法阻断AMPK活性可显著减弱缺氧诱导的反应，如HIF-1靶基因表达、血管内皮生长因子分泌、葡萄糖摄取和HIF-1依赖性报告基因表达，表明AMPK对HIF-1转录活性及其靶基因表达至关重要。在几种不同的癌细胞系中也证明了其对HIF-1活性的功能需求，但单独的AMPK活化不足以刺激HIF-1转录活性。我们进一步提出的数据表明，AMPK通过一个信号传导途径，是独立的磷脂酰肌醇3-激酶/AKT和几个丝裂原活化蛋白激酶传递HIF-1活性的阳性信号。综上所述，我们的研究结果表明，AMPK是一种新的和HIF-1调节的关键组成部分，这意味着它在氧调节的细胞现象的新角色。
AMP-activated protein kinase ( AMPK) functions as an energy sensor to provide metabolic adaptations under the ATP-deprived conditions such as hypoxia. In the present study, we considered a role of AMPK in the adaptive response to hypoxia by examining whether AMPK is involved in the regulation of hypoxia-inducible factor-1 (HIF-1), a heterodimeric transcription factor that is critical for hypoxic induction of physiologically important genes. We demonstrate that hypoxia or CoCl2 rapidly activated AMPK in DU145 human prostate cancer cells, and its activation preceded the induction of HIF-1alpha expression. Under these conditions, blockade of AMPK activity by a pharmacological or molecular approach significantly attenuated hypoxia-induced responses such as HIF-1 target gene expression, secretion of vascular endothelial growth factor, glucose uptake, and HIF-1-dependent reporter gene expression, indicating that AMPK is critical for the HIF-1 transcriptional activity and its target gene expression. Its functional requirement for HIF-1 activity was also demonstrated in several different cancer cell lines, but AMPK activation alone was not sufficient to stimulate the HIF-1 transcriptional activity. We further present data showing that AMPK transmits a positive signal for HIF-1 activity via a signaling pathway that is independent of phosphatidylinositol 3-kinase/AKT and several mitogen-activated protein kinases. Taken together, our results suggest that AMPK is a novel and critical component of HIF-1 regulation, implying its new roles in oxygen-regulated cellular phenomena.