NDLI: Transcription factors Sp1 and Hif2 mediate induction of the copper-transporting ATPase (Atp7a) gene in intestinal epithelial cells during hypoxia.

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Transcription factors Sp1 and Hif2 mediate induction of the copper-transporting ATPase (Atp7a) gene in intestinal epithelial cells during hypoxia.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Collins, James F. Xie, Liwei
Description	Author Affiliation: Xie L ( Food Science and Human Nutrition Department, University of Florida, Gainesville, Florida 32611, USA.)
Abstract	Genes with G/C-rich promoters were up-regulated in the duodenal epithelium of iron-deficient rats including those encoding iron (e.g. Dmt1 and Dcytb) and copper (e.g. Atp7a and Mt1) metabolism-related proteins. It was shown previously that an intestinal copper transporter (Atp7a) was co-regulated with iron transport-related genes by a hypoxia-inducible transcription factor, Hif2 . In the current study, we sought to test the role of Sp1 in transcriptional regulation of Atp7a expression during iron deprivation/hypoxia. Initial studies in IEC-6 cells showed that mithramycin, an Sp1 inhibitor, reduced expression of Atp7a and iron transport-related genes (Dmt1, Dcytb, and Fpn1) and blocked their induction by CoCl2, a hypoxia mimetic. Consistent with this, overexpression of Sp1 increased endogenous Atp7a mRNA and protein expression and stimulated Atp7a, Dmt1, and Dcytb promoter activity. Site-directed mutagenesis and functional analysis of a basal Atp7a promoter construct revealed four functional Sp1 binding sites that were necessary for Hif2 -mediated induction of promoter activity. Furthermore, chromatin immunoprecipitation (ChIP) assays confirmed that Sp1 specifically interacts with the Atp7a promoter in IEC-6 cells and in rat duodenal enterocytes. This investigation has thus revealed a novel aspect of Atp7a gene regulation in which Sp1 may be necessary for the HIF-mediated induction of gene transcription during iron deficiency/hypoxia. Understanding regulation of Atp7a expression may help further clarify the physiological role of copper in the maintenance of iron homeostasis. Furthermore, this Sp1/Hif2 regulatory mechanism may have broader implications for understanding the genetic response of the intestinal epithelium to maintain whole-body iron homeostasis during states of deficiency.
ISSN	00219258
e-ISSN	1083351X
Journal	Journal of Biological Chemistry
Issue Number	33
Volume Number	288
Language	English
Publisher	American Society for Biochemistry and Molecular Biology (United States)
Publisher Date	2013-08-16
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Adenosine Triphosphatases Genetics Basic Helix-Loop-Helix Transcription Factors Metabolism Cation Transport Proteins Epithelial Cells Cytology Gene Expression Regulation Intestinal Mucosa Sp1 Transcription Factor Animals Binding Sites Biological Transport Drug Effects Cell Hypoxia Cell Line Chromatin Immunoprecipitation Cobalt Pharmacology Copper Deficiency Phosphorylation Plicamycin Promoter Regions, Genetic Protein Binding RNA, Messenger Rats, Sprague-Dawley Up-Regulation Research Support, N.I.H., Extramural Biochemistry Molecular Biology
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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