PMID- 25100165 OWN - NLM STAT- MEDLINE VI - 6 IP - 10 TI - Copper-dependent and -independent hypoxia-inducible factor-1 regulation of gene expression. PG - 1889-93 LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - England TA - Metallomics JT - Metallomics : integrated biometal science JID - 101478346 IS - 1756-591X (Electronic) LID - 10.1039/c4mt00052h [doi] FAU - Zhang, Zhen AU - Zhang Z AD - Regenerative Medicine Research Center, Sichuan University, Chengdu, Sichuan 610041, P. R. China. yjkang01@louisville.edu. FAU - Qiu, Liying AU - Qiu L FAU - Lin, Chen AU - Lin C FAU - Yang, Hong AU - Yang H FAU - Fu, Haiying AU - Fu H FAU - Li, Rui AU - Li R FAU - Kang, Y James AU - Kang YJ IS - 1756-5901 (Linking) RN - 0 (BNIP3 protein, human) RN - 0 (Hypoxia-Inducible Factor 1, alpha Subunit) RN - 0 (Membrane Proteins) RN - 0 (Proto-Oncogene Proteins) RN - 0 (RNA, Small Interfering) RN - 67763-97-7 (Insulin-Like Growth Factor II) RN - 789U1901C5 (Copper) SB - IM MH - Copper/*metabolism MH - Down-Regulation MH - *Gene Expression Regulation MH - Human Umbilical Vein Endothelial Cells MH - Humans MH - Hypoxia-Inducible Factor 1, alpha Subunit/genetics/*metabolism MH - Insulin-Like Growth Factor II/*genetics MH - Membrane Proteins/*genetics MH - Proto-Oncogene Proteins/*genetics MH - RNA Interference MH - RNA, Small Interfering/genetics DCOM- 20150603 LR - 20140925 DP - 2014 Oct DEP - 20140807 AB - 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.