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J. Biol. Chem., Vol. 280, Issue 34, 30032-30045, August 26, 2005

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The Acute Box cis-Element in Human Heavy Ferritin mRNA 5'-Untranslated Region Is a Unique Translation Enhancer That Binds Poly(C)-binding Proteins^*

Andrew M. Thomson, Catherine M. Cahill¶, Hyun-Hee Cho¶, Kristin D. Kassachau¶, Michael R. Epis, Kenneth R. Bridges||, Peter J. Leedman**, and Jack T. Rogers¶||**

From the ^¶Genetics and Aging Research Unit, Departments of Psychiatry and Molecular Biology, Massachusetts General Hospital, Charlestown, Massachusetts 02129, ^||Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, and Laboratory for Cancer Medicine, School of Medicine and Pharmacology, the UWA Centre for Medical Research, Western Australian Institute for Medical Research and the University of Western Australia, Royal Perth Hospital, Perth, Western Australia 6000

Intracellular levels of the light (L) and heavy (H) ferritin subunits are regulated by iron at the level of message translation via a modulated interaction between the iron regulatory proteins (IRP1 and IRP2) and a 5'-untranslated region. Iron-responsive element (IRE). Here we show that iron and interleukin-1 (IL-1) act synergistically to increase H- and L-ferritin expression in hepatoma cells. A GC-rich cis-element, the acute box (AB), located downstream of the IRE in the H-ferritin mRNA 5'-untranslated region, conferred a substantial increase in basal and IL-1-stimulated translation over a similar time course to the induction of endogenous ferritin. A scrambled version of the AB was unresponsive to IL-1. Targeted mutation of the AB altered translation; reverse orientation and a deletion of the AB abolished the wild-type stem-loop structure and abrogated translational enhancement, whereas a conservative structural mutant had little effect. Labeled AB transcripts formed specific complexes with hepatoma cell extracts that contained the poly(C)-binding proteins, iso-CP1 and -CP2, which have well defined roles as translation regulators. Iron influx increased the association of CP1 with ferritin mRNA and decreased the CP2-ferritin mRNA interaction, whereas IL-1 reduced the association of CP1 and CP2 with H-ferritin mRNA. In summary, the H-ferritin mRNA AB is a key cis-acting translation enhancer that augments H-subunit expression in Hep3B and HepG2 hepatoma cells, in concert with the IRE. The regulated association of H-ferritin mRNA with the poly(C)-binding proteins suggests a novel role for these proteins in ferritin translation and iron homeostasis in human liver.

Received for publication, March 17, 2005 , and in revised form, June 20, 2005.

^* This work was also supported in part by National Institutes of Health R01 Grant AG20181. 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 Figs. 1 and 2.

Present address: Stem Cell and Developmental Biology, Genome Institute of Singapore, Singapore 138672.

^** Co-senior authors.

Supported by the American Federation for Aging Research and the Institute for the Study Of Aging (ISOA) and the Alzheimer's Association. To whom correspondence should be addressed: Center for Neuroscience, Rm. 3580, Mass General (East), Bldg. 114 16th St., 3850, Charlestown, MA 02129-4404. Tel.: 1-617-726-8838; Fax: 1-617-724-1823; E-mail: jtrogers{at}rics.bwh.harvard.edu.

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