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Blood, 15 December 2004, Vol. 104, No. 13, pp. 4294-4299.
Prepublished online as a Blood First Edition Paper on August 19, 2004; DOI 10.1182/blood-2004-06-2481.
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Submitted June 30, 2004
Accepted August 6, 2004
Regulation of transferrin receptor 2 protein levels by transferrin
Aeisha Robb and Marianne Wessling-Resnick*
Department of Genetics & Complex Diseases, Harvard School of Public Health, Boston, MA, USA
* Corresponding author; email: wessling{at}hsph.harvard.edu.
Transferrin receptor 2 (TfR2) plays a critical role in iron homeostasis as patients carrying disabling mutations in the TFR2 gene suffer from hemochromatosis. In this study, iron-responsive regulation of TfR2 at the protein level was examined in vitro and in vivo. HepG2 cell TfR2 protein levels were upregulated after exposure to holo-Tf in a time- and dose-responsive manner. Apo-Tf or high iron treatment with non-Tf bound iron failed to elicit similar effects, suggesting that TfR2 regulation reflects interactions of the iron-bound ligand. Hepatic TfR2 protein levels also reflected an adaptive response to changing iron status in vivo. Liver TfR2 protein levels were down- and up-regulated in rats fed an iron-deficient and a high iron diet, respectively. TfR2 was also upregulated in Hfe-/- mice, an animal model that displays liver iron-loading. In contrast, TfR2 levels were reduced in hypotransferrinemic mice despite liver iron overload, supporting the idea that regulation of the receptor is Tf-dependent. This idea is confirmed by upregulation of TfR2 in b-thalassemic mice, which like hypotransferrinemic mice are anemic and incur iron loading, but have functional Tf. Based on these combined results, we hypothesize that TfR2 acts as a sensor of iron status such that receptor levels reflect Tf saturation.
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