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Issue 10, 2014
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Copper-dependent and -independent hypoxia-inducible factor-1 regulation of gene expression

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Abstract

Hypoxia-inducible factor-1 (HIF-1) regulates the expression of the vascular endothelial growth factor (VEGF), a process requiring copper (Cu) participation. HIF-1 is also involved in the expression of more than a hundred of genes, but it is unknown how HIF-1 differentially controls the expression of these genes timely and spatially. The present study was undertaken to test the hypothesis that Cu is not required for the expression of all HIF-1-regulated genes, thus exploring mechanistic insights into the differential control of multiple gene expression by one transcription factor. Human umbilical vein endothelial cells (HUVECs) were treated with siRNA targeting HIF-1α to define the essential role of HIF-1 in the regulation of BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3) and insulin-like growth factor 2 (IGF-2) expression. A Cu chelator, tetraethylenepentamine (TEPA), was used to reduce intracellular availability of Cu. In comparison, a zinc chelator, N,N,N′,N′-tetrakis(2-pyridylmethyl) ethylenediamine (TPEN), was used to reduce intracellular zinc concentration. The expression of both BNIP3 and IGF-2 was completely suppressed in the HIF-1α deficient cells. The removal of Cu suppressed the expression of BNIP3, but did not affect that of IGF-2. The reduction of intracellular zinc did not cause the same effect. Further screening identified a group of genes whose expression required Cu and the others did not need Cu. The present study thus demonstrates Cu-dependent and -independent HIF-1 regulation of gene expression, indicating a mechanism for differential control of multiple gene expression by one transcription factor.

Graphical abstract: Copper-dependent and -independent hypoxia-inducible factor-1 regulation of gene expression

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Publication details

The article was received on 26 Feb 2014, accepted on 28 Jul 2014 and first published on 28 Jul 2014


Article type: Paper
DOI: 10.1039/C4MT00052H
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Citation: Metallomics, 2014,6, 1889-1893

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    Copper-dependent and -independent hypoxia-inducible factor-1 regulation of gene expression

    Z. Zhang, L. Qiu, C. Lin, H. Yang, H. Fu, R. Li and Y. J. Kang, Metallomics, 2014, 6, 1889
    DOI: 10.1039/C4MT00052H

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