Iron‐dependent regulation of the divalent metal ion transporter

Gunshin, Hiromi; Allerson, Charles R.; Polycarpou‐Schwarz, Maria; Rofts, Andreas; Rogers, Jack T.; Kishi, Fumio; Hentze, Matthias W.; Rouault, Tracey A.; Andrews, Nancy C.; Hediger, Matthias A.

doi:10.1016/s0014-5793(01)03189-1

Cited by 277 publications

(246 citation statements)

References 43 publications

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“…Interestingly, only the IRE form has been found to be upregulated in the duodenum of iron-deficient animals, suggesting that the IRE plays a similar role as in TfR mRNA and mediates iron regulation of DMT1 mRNA stability (7,13). However, the IRE-containing DMT1 mRNA has displayed only a minor degree of iron regulation in Hep3B cells (14), and no change of endogenous DMT1 mRNA expression was observed in LMTK fibroblasts after changes in iron concentration or exposure to NO, although these stimuli effectively regulated TfR expression in these cells (15).…”

mentioning

confidence: 99%

Previously uncharacterized isoforms of divalent metal transporter (DMT)-1: Implications for regulation and cellular function

Hubert

Hentze

2002

Proc. Natl. Acad. Sci. U.S.A.

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376

318

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Divalent metal transporter 1 (DMT1) mediates apical iron uptake into duodenal enterocytes and also transfers iron from the endosome into the cytosol after cellular uptake via the transferrin receptor. Hence, mutations in DMT1 cause systemic iron deficiency and anemia. DMT1 mRNA levels are increased in the duodenum of iron-deficient animals. This regulation has been observed for DMT1 mRNA harboring an iron-responsive element (IRE) in its 3 UTR, but not for a processing variant lacking a 3 UTR IRE, suggesting that the IRE regulates the expression of DMT1 mRNA in response to iron levels. Here, we show that iron regulation of DMT1 involves the expression of a previously unrecognized upstream 5 exon (exon 1A) of the human and murine DMT1 gene. The expression of this previously uncharacterized 5 exon is tissue-specific and particularly prevalent in the duodenum and kidney. It adds an in-frame AUG translation initiation codon extending the DMT1 ORF by a conserved sequence of 29 -31 amino acids. In combination with the IRE-and non-IRE variants in the 3 UTR, our results reveal the existence of four DMT1 mRNA isoforms predicting the synthesis of four different DMT1 proteins. We show that two regulatory regions, the 5 promoter͞exon 1A region and the IRE-containing terminal exon participate in iron regulation of DMT1 expression, which operate in a tissue-specific way. These results uncover an unexpected complexity of DMT1 expression and regulation, with implications for understanding the physiology, cell biology, and pathophysiology of mammalian iron metabolism.

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confidence: 99%

Previously uncharacterized isoforms of divalent metal transporter (DMT)-1: Implications for regulation and cellular function

Hubert

Hentze

2002

Proc. Natl. Acad. Sci. U.S.A.

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376

318

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“…The absorption of dietary iron begins with its transport across the duodenal brush-border membrane mediated by the duodenal metal transporter-1 (DMT-1), the major iron transporter responsible for iron absorption in the duodenum. 4 DMT-1 has been detected also in the endosomal compartment of different cells, suggesting that it participates in the transport of transferrin (Tf)-bound iron across the cellular membrane of acidified endosomes, resulting in the release of iron into the cytoplasm. 5,6 After entering enterocytes, iron is used for essential metabolic purposes, stored in ferritin or translocated to the portal blood by ferroportin-1 (Fpn-1).…”

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confidence: 99%

Ferroportin-1 is a ‘nuclear'-negative acute-phase protein in rat liver: a comparison with other iron-transport proteins

Naz

Malik

Sheikh

et al. 2012

Laboratory Investigation

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Liver is the central organ of iron metabolism. During acute-phase-response (APR), serum iron concentration rapidly decreases. The current study aimed to compare expression and localization of iron transport protein ferroportin-1 (Fpn-1) and of other iron import proteins after experimental tissue damage induced by injecting turpentine oil in the hind limbs of rats and mice. Serum and spleen iron concentration decreased with an increase in total liver, cytoplasmic and nuclear iron concentration. In liver, mRNA amount of Fpn-1, Fpn-1a, Fpn-1b, HFE, hemojuvelin (HJV) and hephaestin (heph) genes showed a rapid decrease. Hepcidin, divalent metal transporter-1 (DMT-1), transferrin (Tf) and Tf-receptor-1 (TfR1), TfR-2 (TfR2) gene expression was increased. Western blot analysis of liver tissue lysate confirmed the changes observed at mRNA level. In spleen, a rapid decrease in gene expression of Fpn-1, Fpn-1a, Fpn-1b, DMT-1, Tf, TfR1 and TfR2, and an increase in hepcidin was observed. Immunohistochemistry of DMT-1 and TfR2 were mainly detected in the nucleus of rat liver and spleen, whereas TfR1 was clearly localized in the plasma membrane. Fpn-1 was mostly found in the nuclei of liver cells, whereas in spleen, the protein was mainly detected in the cell membrane. Western blot analysis of liver fractions confirmed immunohistochemical results. In livers of wild-type mice, gene expression of Fpn-1, Fpn-1a and Fpn-1b was downregulated, whereas hepcidin gene expression was increased. In contrast, these changes were less pronounced in IL-6ko-mice. Cytokine (IL-6, IL-1b and TNF-a) treatment of rat hepatocytes showed a downregulation of Fpn-1, Fpn-1a and Fpn-1b, and upregulation of hepcidin gene expression. Moreover, western blot analysis of cell lysate of IL-6-treated hepatocytes detected, as expected, an increase of a2-macroglobulin (positive acute-phase protein), whereas albumin (negative acute-phase protein) and Fpn-1 were downregulated. Our results demonstrate that liver behaves as a 'sponge' for iron under acute-phase conditions, and Fpn-1 behaves as a negative acute-phase protein in rat hepatocytes mainly, but not exclusively, because of the effect of IL-6. These changes could explain iron retention in the cytoplasm and in the nucleus of hepatocytes during APR. The liver is the central organ for iron metabolism. 1 Liver cells (hepatocytes) take up iron absorbed from the diet, and Kupffer cells take up iron from aged erythrocytes and distribute it to different organs. Iron is an important co-factor for oxygen transport, heme and non-heme iron proteins, electron transfer, neurotransmitter synthesis, myelin production, energy metabolism and mitochondrial function, as well as for the production of reactive-oxygen species. 2,3 As a result, its metabolism is tightly regulated. Iron homeostasis is controlled by a large group of iron-regulatory proteins. The absorption of dietary iron begins with its transport across the duodenal brush-border membrane mediated by the duodenal metal transporter-1 (DMT-1), the major iron transporte...

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“…The expression of DMT1 in the small intestine is negatively regulated by iron status (Tandy et al, 2000;Trinder et al, 2000;Yeh et al, 2000;Gunshin et al, 2001). However, DMT1 expression in hepatocytes is positively regulated by iron at the posttranscriptional level (Trinder et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

“…In LMTK-, RAW264.7 and J774 cells, iron has no significant effect on DMT1 expression Richardson, 1999, 2000). Gunshin et al (2001) reported that the response of DMT1 (1IRE) to iron was tissue specific and cell type specific. The cell and tissue specificity of DMT1 expression also occurred in perinatal rat brain, and it was found that iron deficiency increased the expression of DMT1 in hippocampus and cerebral cortex, but had no effect on other regions (Siddappa et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have been focused on the effect of iron status on the expression of DMT1 in peripheral organs, tissues, and cell lines (Wardrop and Richardson, 1999;Yeh et al, 2000;Gambling et al, 2001;Gunshin et al, 2001;Hubert and Hentze, 2002;Siddappa et al, 2003). They have produced controversial results because of the different isoforms of DMT1 in different organisms or tissues and have found an unexpected complexity of DMT1 expression and regulation.…”

mentioning

confidence: 99%

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Effects of Intracerebroventricular Injection of Iron Dextran on the Iron Concentration and Divalent Metal Transporter 1 Expression in the Caudate Putamen and Substantia Nigra of Rats

Chang

Miao

et al. 2008

The Anatomical Record

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The cellular localization of DMT1 and its functional characterization suggest that DMT1 may play an important role in the physiological brain iron transport. But the regulation of DMT1 expression by iron in the brain is still not clearly understood. In this study, both the contents of ferric and ferrous iron as well as DMT1 expression were evaluated in CPu and SN after ICV of 500 mg iron dextran/rat/day for 3 or 7 days. It was found that the iron levels in CPu and SN were not altered obviously until ICV for 7 days. Immunohistochemistry results indicated that the expression of DMT1 (2IRE) in CPu and SN was not altered significantly after 3 days of ICV. Whereas the expression of DMT1 (2IRE) decreased significantly after 7 days of ICV when ferrous iron was increased significantly. Contrary to that of DMT1 (2IRE) in the same regions, there were no significant alterations in DMT1 (1IRE) expression in CPu and SN in spite of the existence of the altered iron levels, compared with that of control groups. The results demonstrate that DMT1 (2IRE) expression was correlated probably with brain iron levels; especially, its regulation was Abbreviations used: CG 5 saline-injected control groups; CNS 5 central nervous system; CPu 5 caudate putamen; DCT1 5 divalent cation transporter; DMT1 5 divalent metal transporter 1; Ft 5 ferritin; ICV 5 intracerebroventricular injection; IG 5 iron dextran-injected groups; IHC 5 immunohistochemistry; IRE 5 iron-responsive element; Nramp2 5 natural resistance associated macrophage protein 2; PBS 5 phosphate buffered saline; PD 5 Parkinson's disease; Slc11a2 5 solute carrier family 11, member a2; SN 5 substantia nigra; Tf 5 transferrin; TfR 5 transferrin receptor; UTR 5 untranslated regions.

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Iron‐dependent regulation of the divalent metal ion transporter

Cited by 277 publications

References 43 publications

Previously uncharacterized isoforms of divalent metal transporter (DMT)-1: Implications for regulation and cellular function

Previously uncharacterized isoforms of divalent metal transporter (DMT)-1: Implications for regulation and cellular function

Ferroportin-1 is a ‘nuclear'-negative acute-phase protein in rat liver: a comparison with other iron-transport proteins

Effects of Intracerebroventricular Injection of Iron Dextran on the Iron Concentration and Divalent Metal Transporter 1 Expression in the Caudate Putamen and Substantia Nigra of Rats

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