NDLI: Copper levels affect targeting of hypoxia-inducible factor 1α to the promoters of hypoxia-regulated genes

Content Provider	Journal of Biological Chemistry (JBC)
Author	Liu, Xiaojuan Zhang, Wenjing Wu, Zhijuan Yang, Yutao Kang, Y. James
Abstract	Hypoxia-inducible factor 1α (HIF-1α) is a transcription factor that regulates cellular responses to hypoxia. It controls the expression of both BCL2/adenovirus E1B 19-kDa protein–interacting protein 3 (BNIP3) and insulin-like growth factor 2 (IGF2). Previous studies have demonstrated that in hypoxia, copper is required for the expression of BNIP3 but not for that of IGF2. Here, using ChIP assays, computational analyses, luciferase reporter assays, and real-time quantitative RT-PCR, we sought to better understand how copper regulates the differential target gene selectivity of HIF-1α. Human umbilical vein endothelial cells (HUVECs) were exposed to CoCl2 or hypoxia conditions to increase HIF-1α accumulation. The binding of HIF-1α to hypoxia-responsive element (HRE) sites in the BNIP3 or IGF2 gene promoter in high- or low-copper conditions was examined. Our analyses revealed three and two potential HRE sites in the BNIP3 and IGF2 promoters, respectively. We identified that HRE (−412/−404) in the BNIP3 promoter and HRE (−354/−347) in the IGF2 promoter are the critical binding sites of HIF-1α. Tetraethelenepentamine (TEPA)-mediated reduction in copper concentration did not affect hypoxia- or CoCl2-induced HIF-1α accumulation. However, the copper reduction did suppress the binding of HIF-1α to the HRE (−412/−404) in BNIP3 but not the binding of HIF-1α to the HRE (−354/−347) in IGF2. In summary, our findings uncovered the mechanistic basis for differential HIF-1α–mediated regulation of BNIP3 and IGF2, indicating that copper regulates target gene selectivity of HIF-1α at least in part by affecting HIF-1α binding to its cognate HRE in the promoters of these two genes.
Related Links	http://www.jbc.org/content/293/38/14669.abstract
Ending Page	14677
Starting Page	14669
Page Count	9
File Format	HTM / HTML PDF
ISSN	00219258
Journal	Journal of Biological Chemistry (JBC)
Issue Number	38
Volume Number	293
DOI	10.1074/jbc.RA118.001764
e-ISSN	1083351X
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2018-09-21
Access Restriction	Open
Subject Keyword	Hypoxia-inducible factor (HIF) Copper Transcription target gene Chromatin immunoprecipitation (ChIP) Gene regulation BNIP3 Hypoxia responsive element IGF2 Cell Biology
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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