title: Mouse HFE inhibits Tf-uptake and iron accumulation but induces non-transferrin bound iron (NTBI)-uptake in transformed mouse fibroblasts.
abstract: Iron-uptake and storage are tightly regulated to guarantee sufficient iron for essential cellular processes and to prevent the production of damaging free radicals. A non-classical class I MHC molecule, the hemochromatosis factor (HFE), has been shown to regulate iron metabolism, potentially via its interaction with the transferrin receptor. Whereas, the effect of human HFE (hHFE) on transferrin/transferrin receptor association, as well as on transferrin receptor recycling and the level of cellular iron pools in various cell lines was analyzed, very little is known about the mouse HFE (mHFE) protein. In the following study, our aim was to analyze in more detail the function of mHFE. Surprisingly, we observed that over-expression of mHFE, but not of hHFE, in a mouse transformed cell line, results in a most significant inhibition of transferrin-uptake which correlated with apoptotic cell death. mHFE inhibited transferrin-uptake immediately following transfection and this inhibition persisted in the surviving stable transfectants. Concomitantly, cellular iron derived from transferrin-iron uptake was dramatically limited. The activation of a non-transferrin bound iron-uptake pathway that functions in the stable mHFE-transfected clones could explain their normal growth curves and survival. The hypothesis that iron starvation can induce iron-uptake by a novel transferrin-independent pathway is discussed.
authors.affiliation: Department of Cell Research and Immunology, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Merav Gleit
authors.initials: MG
authors.lastname: Kielmanowicz
authors.forename: Nihay
authors.initials: N
authors.lastname: Laham
authors.forename: John E
authors.initials: JE
authors.lastname: Coligan
authors.forename: François
authors.initials: F
authors.lastname: Lemonnier
authors.forename: Rachel
authors.initials: R
authors.lastname: Ehrlich
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002461:Cell Line, Transformed; D002999:Clone Cells / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007501:Iron / Q000378:metabolism* / Q000493:pharmacokinetics; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D013045:Species Specificity; D014162:Transfection; D014168:Transferrin / Q000378:metabolism* / Q000493:pharmacokinetics
chemical_list: C103673:HFE protein, human; D000071020:Hemochromatosis Protein; C499535:Hfe protein, mouse; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D012097:Repressor Proteins; D014168:Transferrin; D007501:Iron