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J. Biol. Chem., Vol. 281, Issue 32, 22865-22874, August 11, 2006

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Iron Regulation and the Cell Cycle

IDENTIFICATION OF AN IRON-RESPONSIVE ELEMENT IN THE 3'-UNTRANSLATED REGION OF HUMAN CELL DIVISION CYCLE 14A mRNA BY A REFINED MICROARRAY-BASED SCREENING STRATEGY^*

Mayka Sanchez, Bruno Galy, Thomas Dandekar^¶, Peter Bengert^¶||, Yevhen Vainshtein, Jens Stolte, Martina U. Muckenthaler¹, and Matthias W. Hentze²

From the European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, the Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Im Neuenheimer Feld 153, 69120 Heidelberg, the ^¶Department of Bioinformatics, Biozentrum, University of Würzburg, Am Hubland, 97074 Würzburg, and the ^||Biochemistry Centre, University of Heidelberg, Im Neuenheimer Feld 365, 69120 Heidelberg, Germany

Iron regulatory proteins (IRPs) 1 and 2 post-transcriptionally control mammalian iron homeostasis by binding to iron-responsive elements (IREs), conserved RNA stem-loop structures located in the 5'- or 3'-untranslated regions of genes involved in iron metabolism (e.g. FTH1, FTL, and TFRC). To identify novel IRE-containing mRNAs, we integrated biochemical, biocomputational, and microarray-based experimental approaches. IRP/IRE messenger ribonucleoproteins were immunoselected, and their mRNA composition was analyzed using an IronChip microarray enriched for genes predicted computationally to contain IRE-like motifs. Among different candidates, this report focuses on a novel IRE located in the 3'-untranslated region of the cell division cycle 14A mRNA. We show that this IRE motif efficiently binds both IRP1 and IRP2. Differential splicing of cell division cycle 14A produces IRE- and non-IRE-containing mRNA isoforms. Interestingly, only the expression of the IRE-containing mRNA isoforms is selectively increased by cellular iron deficiency. This work describes a new experimental strategy to explore the IRE/IRP regulatory network and uncovers a previously unrecognized regulatory link between iron metabolism and the cell cycle.

Received for publication, April 24, 2006 , and in revised form, May 24, 2006.

^* This work was supported by the Marie Curie, Quality of Life Programme, CORDIS FP5 (Grant QLGA-CT-2001-52011) and the Young Investigator Award of the medical faculty Heidelberg, University of Heidelberg (to M. S.); by the Forschungsschwerpunktprogramm des Landes Baden-Württemberg, 2005 (RNA and disease) (to M. U. M. and M. W. H.); and by funds from the Gottfried Wilhem Leibniz Prize (to M. W. H.). 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 Table S1 and Figs. S1-S3.

¹ To whom correspondence may be addressed. Tel.: 49-622-156-6923; Fax: 49-622-156-4580; E-mail: martina.muckenthaler{at}med.uni-heidelberg.de. ² To whom correspondence may be addressed. Tel.: 49-622-138-78501; Fax: 49-622-138-78518; E-mail: hentze{at}embl.de.

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