title: Copper-dependent and -independent hypoxia-inducible factor-1 regulation of gene expression.
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.
authors.affiliation: Regenerative Medicine Research Center, Sichuan University, Chengdu, Sichuan 610041, P. R. China. yjkang01@louisville.edu.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhang
authors.forename: Liying
authors.initials: L
authors.lastname: Qiu
authors.forename: Chen
authors.initials: C
authors.lastname: Lin
authors.forename: Hong
authors.initials: H
authors.lastname: Yang
authors.forename: Haiying
authors.initials: H
authors.lastname: Fu
authors.forename: Rui
authors.initials: R
authors.lastname: Li
authors.forename: Y James
authors.initials: YJ
authors.lastname: Kang
mesh_terms: D003300:Copper / Q000378:metabolism*; D015536:Down-Regulation; D005786:Gene Expression Regulation; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007335:Insulin-Like Growth Factor II / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: C090121:BNIP3 protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D007335:Insulin-Like Growth Factor II; D003300:Copper