Iron-dependent regulation of the divalent metal ion transporter.
The first step in intestinal iron absorption is mediated by the H(+)-coupled Fe(2+) transporter called divalent cation transporter 1/divalent metal ion transporter 1 (DCT1/DMT1) (also known as natural resistance-associated macrophage protein 2). DCT1/DMT1 mRNA levels in the duodenum strongly increase in response to iron depletion. To study the mechanism of iron-dependent DCT1/DMT1 mRNA regulation, we investigated the endogenous expression of DCT1/DMT1 mRNA in various cell types. We found that only the iron responsive element (IRE)-containing form, which corresponds to one of two splice forms of DCT1/DMT1, is responsive to iron treatment and this responsiveness was cell type specific. We also examined the interaction of the putative 3'-UTR IRE with iron responsive binding proteins (IRP1 and IRP2), and found that IRP1 binds to the DCT1/DMT1-IRE with higher affinity compared to IRP2. This differential binding of IRP1 and IRP2 was also reported for the IREs of transferrin receptors, erythroid 5-aminolevulinate synthase and mitochondrial aconitase. We propose that regulation of DCT1/DMT1 mRNA by iron involves post-transcriptional regulation through the binding of IRP1 to the transporter's IRE, as well as other as yet unknown factors.
Gunshin
H
H
Membrane Biology Program and Renal Division, Brigham and Women's Hospital and Harvard Medical School, Harvard Institutes of Medicine, 77 Avenue Louis Pasteur, Boston, MA 02115, USA. gunshin@rascal.med.harvard.edu
Allerson
C R
CR
Polycarpou-Schwarz
M
M
Rofts
A
A
Rogers
J T
JT
Kishi
F
F
Hentze
M W
MW
Rouault
T A
TA
Andrews
N C
NC
Hediger
M A
MA
D020413:3' Untranslated Regions; D001692:Biological Transport; D018938:Caco-2 Cells; D027682:Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism; D002413:Cations, Divalent / Q000378:metabolism; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D007501:Iron / Q000378:metabolism*; D035941:Iron Regulatory Protein 1; D035942:Iron Regulatory Protein 2; D033862:Iron-Binding Proteins; D035925:Iron-Regulatory Proteins; D007506:Iron-Sulfur Proteins / Q000378:metabolism; D009690:Nucleic Acid Conformation; D011485:Protein Binding; D012323:RNA Processing, Post-Transcriptional; D016601:RNA-Binding Proteins / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid; D000099236:Solute Carrier Family 11, Member 2
D020413:3' Untranslated Regions; D027682:Cation Transport Proteins; D002413:Cations, Divalent; D007501:Iron; D035941:Iron Regulatory Protein 1; D035942:Iron Regulatory Protein 2; D033862:Iron-Binding Proteins; D035925:Iron-Regulatory Proteins; D007506:Iron-Sulfur Proteins; D016601:RNA-Binding Proteins; D000099236:Solute Carrier Family 11, Member 2