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Papers In Press, published online ahead of print July 10, 2000
Laboratory for Cancer Medicine and University Department of Medicine, Royal Perth Hospital and University of Western Australia, Perth, WA 6001
Corresponding Author: peterl{at}cyllene.uwa.edu.au
Intracellular iron homeostasis is regulated, in part, by interactions between iron regulatory proteins (IRP1 and IRP2) and iron responsive elements (IREs) in ferritin and transferrin receptor mRNAs. In addition to iron, cellular oxidative stress induced by H2O2, nitric oxide and hypoxia, and hormonal activation by thyroid hormone (T3) and erythropoeitin have each been shown to regulate IRP binding to IREs. Hormonal signals, in particular mediated though PKC, play a central role in the modulation of IRP/IRE interactions since phorbol esters were shown to activate IRP binding (Eisenstein et al (1993) J Biol Chem 268, 27363-27370). In pituitary thyrotrophs (TtT97), we found that thyrotropin releasing hormone (TRH) and epidermal growth factor (EGF) increased IRP binding to a ferritin IRE, dependent on PKC and mitogen activated protein kinase (MAPK) activity. In contrast, TRH and EGF decreased IRP binding in pituitary lactotrophs (GH3), despite activation of PKC and MAPK. IRP1 and IRP2 levels remained constant and IRP2 binding was predominant throughout. TRH and EGF markedly decreased IRP binding in MAPK-kinase inhibitor treated GH3 cells, whereas, they increased IRP binding in phosphatase inhibitor-treated GH3 cells. IRE-dependent CAT reporter translational expression closely reflected IRP binding to the ferritin IRE in both GH3 and TtT97 cells. Interestingly, ferritin protein levels were regulated similarly by TRH in both cell lines. These data link two different cell receptor systems to common signaling pathways that regulate IRP binding and ferritin expression. Remarkably, for TRH and EGF, these effects may be PKC-dependent or -independent determined by the cell type.
J. Biol. Chem, 10.1074/jbc.M002354200
Submitted on March 21, 2000
Revised on June 14, 2000
Accepted on July 10, 2000
Thyrotropin-releasing hormone and epidermal growth factor regulate iron regulatory protein binding in pituitary cells via protein kinase C-dependent and -independent signaling pathways
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