Zinc Induces the Accumulation of Hypoxia-Inducible Factor (HIF)-1α, but Inhibits the Nuclear Translocation of HIF-1β, Causing HIF-1 Inactivation

Chun, Yang Sook; Choi, Eunhee; Kim, Gi Tae; Lee, Minjae; Lee, Min Joung; Lee, Sang Eun; Kim, Myung Suk; Park, Jong-Wan

doi:10.1006/bbrc.2000.2180

Cited by 59 publications

(43 citation statements)

References 18 publications

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“…Several Fe(II)-dependent enzymes, such as the HIF-prolyl hydroxylase (PHD 1-3) and asparagine hydroxylase (FIH-1), regulate HIF-1α stability and activation. Numerous studies have shown that HIF-1α is not only regulated by oxygen tension, but also by various other stimuli, such as transition metals, which can mimic hypoxia to stabilize HIF-1α protein in cultured cells (Horiguchi et al, 1996;Oshiro et al, 1998;Chun et al, 2000;Hossain et al, 2000;Gao et al, 2002bGao et al, , 2004Yuan et al, 2003;Hwang et al, 2004;van Heerden et al, 2004;Zhao et al, 2004). Since Fe(II) is an important cofactor for these hydroxylases and loosely bound to two histidine sites in these enzymes, non-iron metal ions may decrease the activity of these enzymes by either decreasing cellular iron level or directly replacing iron in the enzymes that hydroxylate HIF.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, iron deficiency is also known to stabilize HIF-1α protein (Wang and Semenza, 1993). Numerous studies have shown that several metals such as As(III), Cr(VI), Cu(II), Zn(II), V(V), Co(II), Mn (II), and Ni(II) can mimic hypoxia by stabilizing HIF-1α protein but to very different extents depending upon the cell line and other conditions (Chun et al, 2000;Salnikow et al, 2000;Gao et al, 2002aGao et al, , 2002bSkinner et al, 2004;Martin et al, 2005). However, many of these studies have not examined the impact of HIF-1α stabilization on downstream targets and its relationship to Fe metabolism.…”

Section: Introductionmentioning

confidence: 99%

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

Chen

Huang

et al. 2006

Toxicology and Applied Pharmacology

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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-1α-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-1α protein levels, hypoxia response element (HRE)-driven luciferase reporter activity, and Cap43 protein level (an HIF-1α 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-1α protein but to strikingly different degrees. Two of these metal ions, Al(III) and Cd(II), did not induce HIF-1α protein; however, as indicated below, only Ni(II), Co (II), and to lesser extent Mn(II) and V(V) activated HIF-1α-dependent transcription. The combined effects of both [Ni(II) + As(III)] and [Ni (II) + Cr(VI)] on HIF-1α protein were synergistic; (iii) Addition of Fe(II) with Ni(II), Co(II), and Cr (VI) attenuated the induction of HIF-1α 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-1α 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-1α 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-1α-dependent prolyl hydroxylases which target the binding of VHL ubiquitin ligase and degrade HIF-1α. Even though there were small effects of some of the other metals on IRP and HIF-1α, downstream effects of HIF-1α 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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Chen

Huang

et al. 2006

Toxicology and Applied Pharmacology

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“…TEPA also has a remarkably higher selectivity for Cu(II) over Zn(II) (K i TEPA-copper /K i TEPA-zinc : approximately 8 orders of magnitude) than clioquinol (K i clioquinol-copper /K i clioquinol-zinc : approximately 3 orders of magnitude). In addition, zinc has been shown to be a negative regulator of HIF-1 activation (Chun et al, 2000). Taken together, the discrepancy between TEPA and clioquinol in the regulation of FIH-1 may be, at least in part, due to a remarkable difference in copper selectivity and affinity.…”

Section: Downloaded Frommentioning

confidence: 99%

Copper Regulation of Hypoxia-Inducible Factor-1 Activity

et al. 2008

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Copper deficiency suppresses and copper addition enhances the expression of vascular endothelial growth factor (VEGF), which is primarily controlled by hypoxia‐inducible factor 1 (HIF‐1) transcription factor. The regulatory subunit of HIF‐1α senses oxygen availability and is also affected by various transition metals. The purpose of this study was to determine whether or not copper is required for activation of HIF‐1. Copper depletion by copper chelator tetraethylenepentamine (TEPA) decreased the hypoxia‐induced transactivity of HIF‐1, assessed by hypoxia responsive element‐dependent luciferase reporter assay, but not HIF‐1α protein level in HepG2 cells. Further examination showed that one of the copper chaperonesfor Cu,Zn‐SOD (CCS) is also involved in the HIF‐1 activation. CCS depletion by siRNA attenuated HIF‐1 transactivity along with decreases in VEGF expression under both normoxic and hypoxic conditions. HIF‐1α could be co‐immunoprecipitated by anti‐CCS antibody in the nuclear extract of HepG2 cells under hypoxic conditions, implying a direct interaction between HIF‐1α and CCS. These results suggested that copper is required for HIF‐1α transcriptional activation and the copper chaperone CCS is critically involved. Supported by NIH grants HL59225 and HL63760 and Kentucky Science and Engineering Foundation Grant 008‐888.

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“…The elute was electrophoresed on 7% SDS-polyacrylamide gels, and then the proteins were transferred to Immobilon-P membranes (Millipore), which were then incubated with 5% skim milk in Tris-buffered saline for 2 hours to block nonspecific binding. The membranes were incubated overnight at 4°C with a rat anti-HIF-1␣ antibody (1:5000), as described previously, 20 and re-incubated with a goat anti-rat IgG antiserum conjugated with horseradish peroxidase (1:5000) for 2 hours. Immunoreactive protein bands were visualized using the enhanced chemiluminescence plus detection system (ECLplus, Amersham-Pharmacia).…”

Section: Immunoprecipitation and Immunoblot Analysis For Hif-1␣mentioning

confidence: 99%

Early Expression of Myocardial HIF-1α in Response to Mechanical Stresses

Kim

Cho

Chun

et al. 2002

Circulation Research

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187

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Abstract-Vascular endothelial growth factor (VEGF) expression is upregulated by hypoxia-inducible factor-1 (HIF-1) in ischemic tissues and growing tumors. Normally, HIF-1 activity depends on the amount of HIF-1␣ subunit, which is tightly regulated by the oxygen tension. In the myocardium, VEGF expression has been shown to be induced under nonhypoxic conditions by mechanical stresses. However, the cellular mechanism of stress-mediated VEGF induction remains unclear. Therefore, we examined the possible involvement of HIF-1 in stress-mediated VEGF induction in rat hearts. In this study, we increased the left ventricular wall tension using 3 different methods, namely by inducing regional ischemia, by expanding an intraventricular balloon, and by producing hemodynamic overload using an aortocaval shunt. In all cases, HIF-1␣ accumulated in the nuclei of cardiac myocytes in the early phase, and this was followed by VEGF induction. Phosphatidylinositol 3-kinase (PI3K)-dependent Akt phosphorylation was found to be activated by mechanical stress and completely blocked by wortmannin (a PI3K inhibitor). Moreover, the stress-mediated induction of HIF-1␣ and VEGF was suppressed by gadolinium (a stretch-activated channel inhibitor), wortmannin, and rapamycin (a FRAP inhibitor). Our results suggest that HIF-1␣ plays an important role in the induction of VEGF in nonischemic and mechanically stressed myocardium, and that this is regulated by stretch-activated channels and the PI3K/Akt/FRAP pathway. Moreover, this signaling pathway, which induces HIF-1␣, seems to play an important role in the adaptation of the myocardium to stresses. The full text of this article is available at http://www.circresaha.org. Key Words: hypoxia-inducible factor-1␣ Ⅲ vascular endothelial growth factor Ⅲ phosphatidylinositol 3-kinase Ⅲ heart Ⅲ mechanical stress

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Zinc Induces the Accumulation of Hypoxia-Inducible Factor (HIF)-1α, but Inhibits the Nuclear Translocation of HIF-1β, Causing HIF-1 Inactivation

Cited by 59 publications

References 18 publications

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

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

Copper Regulation of Hypoxia-Inducible Factor-1 Activity

Early Expression of Myocardial HIF-1α in Response to Mechanical Stresses

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