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J. Biol. Chem., Vol. 283, Issue 35, 23589-23598, August 29, 2008

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Iron-independent Phosphorylation of Iron Regulatory Protein 2 Regulates Ferritin during the Cell Cycle^*

Michelle L. Wallander¹, Kimberly B. Zumbrennen¹, Eva S. Rodansky, S. Joshua Romney, and Elizabeth A. Leibold^¶2

From the Departments of Oncological Sciences and ^¶Medicine and the Eccles Program in Human Molecular Biology and Genetics, University of Utah, Salt Lake City, Utah 84112

Iron regulatory protein 2 (IRP2) is a key iron sensor that post-transcriptionally regulates mammalian iron homeostasis by binding to iron-responsive elements (IREs) in mRNAs that encode proteins involved in iron metabolism (e.g. ferritin and transferrin receptor 1). During iron deficiency, IRP2 binds IREs to regulate mRNA translation or stability, whereas during iron sufficiency IRP2 is degraded by the proteasome. Here, we identify an iron-independent IRP2 phosphorylation site that is regulated by the cell cycle. IRP2 Ser-157 is phosphorylated by Cdk1/cyclin B1 during G₂/M and is dephosphorylated during mitotic exit by the phosphatase Cdc14A. Ser-157 phosphorylation during G₂/M reduces IRP2 RNA-binding activity and increases ferritin synthesis, whereas Ser-157 dephosphorylation during mitotic exit restores IRP2 RNA-binding activity and represses ferritin synthesis. These data show that reversible phosphorylation of IRP2 during G₂/M has a role in modulating the iron-independent expression of ferritin and other IRE-containing mRNAs during the cell cycle.

Received for publication, April 18, 2008 , and in revised form, June 3, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant R01GM045201 (to E. A. L.). DNA sequencing and the syntheses of peptide and DNA oligonucleotides were performed by Core facilities supported by National Institutes of Health Cancer Center Support Grant 2P30CA42014. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental text and Figs. S1–S3.

¹ Supported by National Institutes of Health Research Training in Hematology Grant T32DK007115.

² To whom correspondence should be addressed: Eccles Program in Human Molecular Biology and Genetics, University of Utah, 15 North 2030 East, Rm. 3240A, Salt Lake City, UT 84112. Tel.: 801-585-5002; Fax: 801-585-3501; E-mail: betty.leibold{at}genetics.utah.edu.

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				K. B. Zumbrennen, M. L. Wallander, S. J. Romney, and E. A. Leibold Cysteine Oxidation Regulates the RNA-Binding Activity of Iron Regulatory Protein 2 Mol. Cell. Biol., April 15, 2009; 29(8): 2219 - 2229. [Abstract] [Full Text] [PDF]