Tissue-specific expression of ferritin H regulates cellular iron homoeostasis in vivo.
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, FerH 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.
Wilkinson
John
J
Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA. jwilkins@wfubmc.edu
Di
Xiumin
X
Schönig
Kai
K
Buss
Joan L
JL
Kock
Nancy D
ND
Cline
J Mark
JM
Saunders
Thomas L
TL
Bujard
Hermann
H
Torti
Suzy V
SV
Torti
Frank M
FM
D000818:Animals; D003587:Cytomegalovirus / Q000235:genetics; D004318:Doxycycline / Q000494:pharmacology; D005293:Ferritins / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D006367:HeLa Cells; D006706:Homeostasis; D006801:Humans; D007501:Iron / Q000378:metabolism*; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism; D009929:Organ Size; D009928:Organ Specificity; D010641:Phenotype; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D014157:Transcription Factors; D005293:Ferritins; D007501:Iron; D004318:Doxycycline