2000 Fiscal Year Final Research Report Summary
CLONING OF THE GENE RELATED TO MITOCHONDRIAL IRON DEPOSITION IN MYELODYSPLASTIC SYNDROME
| Project/Area Number |
10470207
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| Research Category |
Grant-in-Aid for Scientific Research (B).
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Hematology
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| Research Institution | ASAHIKAWA MEDICAL COLLEGE |
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Principal Investigator |
KOHGO Yutaka ASAHIKAWA MEDICAL COLLEGE, DEPARTMENT OF MEDICIME, PROFESSOR, 医学部, 教授 (10133183)
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| Co-Investigator(Kenkyū-buntansha) |
SAITO Hiroyuki ASAHIKAWA MEDICAL COLLEGE, DEPARTMENT OF MEDICIME, INSTRACTOR, 医学部, 助手 (20311532)
TORIMOTO Yoshihiro ASAHIKAWA MEDICAL COLLEGE, DEPARTMENT OF MEDICIME, ASSISTANT PROFESSOR, 医学部, 講師 (00281882)
NAKAMURA Masao ASAHIKAWA MEDICAL COLLEGE, DEPARTMENT OF MEDICIME, PROFESSOR, 医学部, 教授 (30109516)
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| Project Period (FY) |
1998 – 2000
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| Keywords | TRANSFERRIN RECEPTOR / HFE / NRAMP2 / MYELODYSPLASTIC SYNDROME / TRANSFERRIN |
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| Research Abstract |
To investigate the mechanisms of intracellular iron overload, we analyzed the functional molecules involved in intracellular iron transport. We found that the expression of transferrin receptor (TfR), which is the most important cell surface molecule for iron transport, was upregulated by inflammatory cytokines and alcohol independent of intracellular iron concentration. We then examined the functional regulation of TfR by HFE.HFE is known to associate with TfR and the mutation of HFE causes hereditary hemochromatosis. We isolated the HFE cDNA from human hepatocyte cell line and established the human hepatoma cells overexpressing HFE protein by HFE gene transfection. Cell surface TfR expression and affinity of transferrin to TfR were significantly decreased and led to reduce the transferrin bound iron uptake in these cells. We found that the HFE protein slowed the rate of TfR recycling, especially return from endosome to surface, in these cells. These results strongly suggested an additional role of HFE on transferrin receptor recycling in addition to the decrease of receptor affinity, resulting in the reduced cellular iron. Finally, we examined that the roles of Nramp2 (DMT-1) on TfR-mediated iron transport. Nramp2 is a major iron transporter from intestinal lumen to intestinal epithelial cells and is believed that free iron of endosome is transported to cytoplasm by Nramp2 in variety of cells. We established the Nramp2 gene transfected human hepatoma cells and analyzed the iron uptake by transferrin-TfR system. Nramp2 overexpression did not alter the iron uptake and TfR recycling. Because we did not analyzed the free iron uptake as analyzed by intestinal epithelial cells, it is possible that Nramp2 may have the function as a free iron transporter from cell surface to cytoplasm in these cells. To analyze the mechanisms of mitochondrial iron deposition, it would be useful to clarify the mechanisms of intracellular iron overload..
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Research Products
(3 results)
