...
首页> 外文期刊>Toxicology and Applied Pharmacology >Effects of 12 metal ions on iron regulatory protein 1 (IRP-1) and hypoxia-inducible factor-1 alpha (HIF-1alpha) and HIF-regulated genes.
【24h】

Effects of 12 metal ions on iron regulatory protein 1 (IRP-1) and hypoxia-inducible factor-1 alpha (HIF-1alpha) and HIF-regulated genes.

机译:12种金属离子对铁调节蛋白1(IRP-1)和缺氧诱导因子1α(HIF-1alpha)和HIF调控基因的影响。

获取原文
获取原文并翻译 | 示例

摘要

Several metal ions that are carcinogenic affect cellular iron homeostasis by competing with iron transporters or iron-regulated enzymes. Some metal ions can mimic a hypoxia response in cells under normal oxygen tension, and induce expression of HIF-1alpha-regulated genes. This study investigated whether 12 metal ions altered iron homeostasis in human lung carcinoma A549 cells as measured by an activation of IRP-1 and ferritin level. We also studied hypoxia signaling by measuring HIF-1alpha protein levels, hypoxia response element (HRE)-driven luciferase reporter activity, and Cap43 protein level (an HIF-1alpha responsive gene). Our results show the following: (i) Ni(II), Co(II), V(V), Mn(II), and to a lesser extent As(III) and Cu(II) activated the binding of IRP-1 to IRE after 24 h, while the other metal ions had no effect; (ii) 10 of 12 metal ions induced HIF-1alpha protein but to strikingly different degrees. Two of these metal ions, Al(III) and Cd(II), did not induce HIF-1alpha protein; however, as indicated below, only Ni(II), Co (II), and to lesser extent Mn(II) and V(V) activated HIF-1alpha-dependent transcription. The combined effects of both [Ni(II) + As(III)] and [Ni(II) + Cr(VI)] on HIF-1alpha protein were synergistic; (iii) Addition of Fe(II) with Ni(II), Co(II), and Cr(VI) attenuated the induction of HIF-1alpha after 4 h treatment; (iv) Ni(II), Co(II), and Mn(II) significantly decrease ferritin level after 24 h exposure; (v) Ni(II), Co(II), V(V), and Mn(II) activated HRE reporter gene after 20 h treatment; (vi) Ni(II), Co(II), V(V), and Mn(II) increased the HIF-1-dependent Cap43 protein level after 24 h treatment. In conclusion, only Ni (II), Co (II), and to a lesser extent Mn(II) and V(V) significantly stabilized HIF-1alpha protein, activated IRP, decreased the levels of ferritin, induced the transcription of HIF-dependent reporter, and increased the expression of Cap43 protein levels (HIF-dependent gene). The mechanism for the significant stabilization and elevation of HIF-1alpha protein which drives these other parameters was previously shown by us and others to involve a loss of cellular Fe as well as inhibition of HIF-1alpha-dependent prolyl hydroxylases which target the binding of VHL ubiquitin ligase and degrade HIF-1alpha. Even though there were small effects of some of the other metals on IRP and HIF-1alpha, downstream effects of HIF-1alpha activation and therefore robust hypoxia signaling were only observed with Ni(II), Co(II), and to much lesser extents with Mn(II) and V(V) in human A549 lung cells. It is of interest that the metal ions that were most effective in activating hypoxia signaling were the ones that were poor inducers of metallothionein protein and also decreased Ferritin levels, since both of these proteins can bind metal ions and protect the cell against toxicity in human lung cells. It is important to study effects of these metals in human lung cells since this represents a major route of human environmental and occupational exposure to these metal ions.
机译:几种致癌金属离子通过与铁转运蛋白或铁调节酶竞争而影响细胞铁稳态。一些金属离子可以模拟正常氧张力下细胞的缺氧反应,并诱导HIF-1alpha调控基因的表达。这项研究调查了12种金属离子是否通过激活IRP-1和铁蛋白水平来测定人肺癌A549细胞中的铁稳态。我们还通过测量HIF-1alpha蛋白水平,缺氧反应元件(HRE)驱动的荧光素酶报道分子活性和Cap43蛋白水平(一种HIF-1alpha响应基因)来研究缺氧信号传导。我们的结果表明:(i)Ni(II),Co(II),V(V),Mn(II),并且在较小程度上As(III)和Cu(II)激活了IRP-1的结合24小时后到达IRE,而其他金属离子则没有影响; (ii)12种金属离子中的10种诱导HIF-1alpha蛋白,但程度不同。这些金属离子中的两个Al(III)和Cd(II)不会诱导HIF-1alpha蛋白。但是,如下所示,只有Ni(II),Co(II)以及较小程度的Mn(II)和V(V)激活了HIF-1alpha依赖性转录。 [Ni(II)+ As(III)]和[Ni(II)+ Cr(VI)]对HIF-1alpha蛋白的联合作用是协同的; (iii)在处理4小时后,将Fe(II)与Ni(II),Co(II)和Cr(VI)添加可减弱HIF-1α的诱导; (iv)暴露24小时后,Ni(II),Co(II)和Mn(II)会显着降低铁蛋白水平; (v)处理20小时后,Ni(II),Co(II),V(V)和Mn(II)激活的HRE报告基因; (vi)处理24小时后,Ni(II),Co(II),V(V)和Mn(II)增加了HIF-1依赖性Cap43蛋白的水平。总之,只有Ni(II),Co(II)以及较小程度的Mn(II)和V(V)才能显着稳定HIF-1alpha蛋白,激活IRP,降低铁蛋白水平,诱导HIF-依赖的记者,并增加了Cap43蛋白水平(HIF依赖的基因)的表达。我们和其他人先前已经证明了驱动这些其他参数的HIF-1α蛋白显着稳定和升高的机制涉及细胞铁的损失以及对以VHL结合为目标的HIF-1alpha依赖性脯氨酰羟化酶的抑制泛素连接酶并降解HIF-1alpha。即使某些其他金属对IRP和HIF-1alpha的影响很小,但仅在Ni(II),Co(II)的情况下,才能观察到HIF-1alpha激活的下游影响以及因此而产生的强大的缺氧信号传导,并且程度较小在人A549肺细胞中具有Mn(II)和V(V)。令人感兴趣的是,在激活缺氧信号方面最有效的金属离子是金属硫蛋白的弱诱导剂,并且还降低了铁蛋白水平,因为这两种蛋白均可结合金属离子并保护细胞免受人肺毒性细胞。研究这些金属在人肺细胞中的作用非常重要,因为这是人类环境和职业中接触这些金属离子的主要途径。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱:kefu@zhangqiaokeyan.com

京公网安备:11010802029741号 ICP备案号:京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有
  • 客服微信

  • 服务号