Copper Regulation of Hypoxia-Inducible Factor-1 Activity
Copper Regulation of Hypoxia-Inducible Factor-1 Activity
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DOI：
10.1124/mol.108.051516
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发表时间：
2009-01-01
影响因子：
3.6
通讯作者：
Kang, Y. James
中科院分区：
文献类型：
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作者：
Feng, Wenke;Ye, Fei;Kang, Y. James
以往的研究表明，铜上调缺氧诱导因子1（HIF-1）。本研究旨在验证铜是HIF-1激活所必需的这一假设。用铜螯合剂四亚乙基五胺（TEPA）或针对超氧化物歧化酶1（CCS）的铜分子伴侣的短干扰RNA处理HepG 2细胞抑制缺氧诱导的HIF-1活化。加入过量的铜可以缓解TEPA的抑制作用，但不能缓解CCS基因沉默的抑制作用，这表明铜对HIF-1的激活是依赖于CCS的。铜剥夺不影响HIF-1 α的产生或稳定性，但减少HIF-1 α与靶基因的缺氧反应元件（HRE）和HIF-1转录复合物的组成部分p300的结合。铜可能通过抑制HIF-1抑制因子的作用，促进HIF-1转录复合物的形成。因此，本研究确定铜是通过调节HIF-1 α与HRE的结合和HIF-1转录复合物的形成来激活HIF-1所必需的。
Previous studies have demonstrated that copper up-regulates hypoxia-inducible factor 1 (HIF-1). The present study was undertaken to test the hypothesis that copper is required for HIF-1 activation. Treatment of HepG2 cells with a copper chelator tetraethylenepentamine (TEPA) or short interfering RNA targeting copper chaperone for superoxide dismutase 1 (CCS) suppressed hypoxia-induced activation of HIF-1. Addition of excess copper relieved the suppression by TEPA, but not that by CCS gene silencing, indicating the requirement of copper for activation of HIF-1, which is CCS-dependent. Copper deprivation did not affect production or stability of HIF-1 alpha but reduced HIF-1 alpha binding to the hypoxia-responsive element (HRE) of target genes and to p300, a component of HIF-1 transcriptional complex. Copper probably inhibits the factor inhibiting HIF-1 to ensure the formation of HIF-1 transcriptional complex. This study thus defines that copper is required for HIF-1 activation through the regulation of HIF-1 alpha binding to the HRE and the formation of the HIF-1 transcriptional complex.