Journal
BIOCHEMICAL JOURNAL
Volume 395, Issue -, Pages 501-507Publisher
PORTLAND PRESS LTD
DOI: 10.1042/BJ20060063
Keywords
ferritin H; iron homoeostasis; kidney; tetracycline; tissue-specific expression; transferrin receptor
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Funding
- NIDDK NIH HHS [K01 DK065876, R37 DK42412-15, 1K01 DK065876, R37 DK042412] Funding Source: Medline
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Ferritin is a ubiquitously distributed iron-binding protein. Cell culture studies have demonstrated that ferritin plays a role in maintenance of iron homoeostasis and in the protection against cytokine- and oxidant-induced stress. To test whether FerH (ferritin H) can regulate tissue iron homoeostasis in vivo, we prepared transgenic mice that conditionally express FerH and EGFP (enhanced green fluorescent protein) from a bicistronic tetracycline-inducible promoter. Two transgenic models were explored. In the first, the FerH and EGFP transgenes were controlled by the tTA(CMV) (Tet-OFF) (where tTA and CMV are tet transactivator protein and cytomegalovirus respectively). In skeletal muscle of mice bearing the FerH/EGFP and tTA(CMV) transgenes, Fer-H expression was increased 6.0 +/- 1.1-fold (mean +/- S.D.) compared with controls. In the second model, the FerH/ EGFP transgenes were controlled by an optimized Tet-ON transactivator, rtTA2(S)-S2(LAP) (where rtTA is reverse tTA and LAP is liver activator protein), resulting in expression predominantly in the kidney and liver. In mice expressing these transgenes, doxycycline induced FerH in the kidney by 14.2 +/- 4.8-fold (mean +/- S.D.). Notably, increases in ferritin in overexpressers versus control littermates were accompanied by an elevation of IRP (iron regulatory protein) activity of 2.3 +/- 0.9-fold (mean +/- S.D.), concurrent with a 4.5 +/- 2.1-fold (mean +/- S.D.) increase in transferrin receptor, indicating that overexpression of FerH is sufficient to elicit a phenotype of iron depletion. These results demonstrate that FerH not only responds to changes in tissue iron (its classic role), but can actively regulate overall tissue iron balance.
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