title: Featured Article: Hypoxia-inducible factor-1α dependent nuclear entry of factor inhibiting HIF-1.
abstract: The regulation of hypoxia-inducible factor-1 (HIF-1) transcriptional activity in the nucleus is related to factor inhibiting HIF-1 (FIH-1). FIH-1 hydrolyzes asparagine at the C-terminal of HIF-1α, preventing the interaction between HIF-1α and its associated cofactors, and leading to suppressed activation of HIF-1. FIH-1 is a cytosolic protein and its entry to the nucleus has to be coordinated with HIF-1α. The present study was undertaken to examine the correlation between HIF-1α and FIH-1 in their nuclear entry. Human umbilical vein endothelial cells were treated with dimethyloxalylglycine at a final concentration of 100 µM for 4 h, resulting in an accumulation of HIF-1α and an increase of FIH-1 in the nucleus as determined by Western blot analysis. Pretreatment of the cells with copper (Cu) chelator tetraethylenepentamine at 50 µM in cultures for 24 h reduced both HIF-1α protein levels and the HIF-1α entry to the nucleus, along with decreased FIH-1 protein levels in the nucleus but no changes in the total FIH-1 protein levels in the cells. These effects were prevented by simultaneous addition of 50 µM CuSO4 with tetraethylenepentamine. Gene-silencing of HIF-1α significantly inhibited FIH-1 entry to the nucleus, but did not affect the total protein levels of FIH-1 in the cells. This work demonstrates that the nuclear entry of FIH-1 depends on HIF-1α. Cu deficiency caused a decrease of HIF-1α, leading to suppression of FIH-1 entry to the nucleus.
authors: Regenerative Medicine Research Center, Sichuan University West China Hospital, Chengdu, Sichuan 610041, China.
authors: Ke
authors: K
authors: Liang
authors: Regenerative Medicine Research Center, Sichuan University West China Hospital, Chengdu, Sichuan 610041, China.
authors: Xue-Qin
authors: XQ
authors: Ding
authors: Regenerative Medicine Research Center, Sichuan University West China Hospital, Chengdu, Sichuan 610041, China.
authors: Chen
authors: C
authors: Lin
authors: Regenerative Medicine Research Center, Sichuan University West China Hospital, Chengdu, Sichuan 610041, China yjkang01@louisville.edu.
authors: Y James
authors: YJ
authors: Kang
mesh_terms: D021581:Active Transport, Cell Nucleus; D000600:Amino Acids, Dicarboxylic / Q000737:chemistry; D001216:Asparagine / Q000737:chemistry; D002467:Cell Nucleus / Q000378:metabolism; D002614:Chelating Agents / Q000737:chemistry; D003300:Copper / Q000737:chemistry; D019327:Copper Sulfate / Q000737:chemistry; D003593:Cytoplasm / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D005029:Ethylenediamines / Q000737:chemistry; D020868:Gene Silencing; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D006868:Hydrolysis; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D000600:Amino Acids, Dicarboxylic; D002614:Chelating Agents; D005029:Ethylenediamines; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D001216:Asparagine; D003300:Copper; D006899:Mixed Function Oxygenases; C439790:HIF1AN protein, human; D019327:Copper Sulfate; C040947:oxalylglycine; C034269:tetraethylenepentamine
keywords: Copper; FIH-1; HIF-1; gene silencing; nuclear entry; tetraethylenepentamine