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J. Biol. Chem., Vol. 282, Issue 41, 29927-29935, October 12, 2007

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A Ferritin-responsive Internal Ribosome Entry Site Regulates Folate Metabolism^*

Collynn F. Woeller, Jennifer T. Fox, Cheryll Perry, and Patrick J. Stover¹

From the Division of Nutritional Sciences and the Graduate Field of Biochemistry, Molecular and Cellular Biology, Cornell University, Ithaca, New York 14853

Cytoplasmic serine hydroxymethyltransferase (cSHMT) enzyme levels are elevated by the expression of the heavy chain ferritin (H ferritin) cDNA in cultured cells without corresponding changes in mRNA levels, resulting in enhanced folate-dependent de novo thymidylate biosynthesis and impaired homocysteine remethylation. In this study, the mechanism whereby H ferritin regulates cSHMT expression was determined. cSHMT translation is shown to be regulated by an H ferritin-responsive internal ribosome entry site (IRES) located within the cSHMT mRNA 5'-untranslated region (5'-UTR). The cSHMT 5'-UTR exhibited IRES activity during in vitro translation of bicistronic mRNA templates, and in MCF-7 and HeLa cells transfected with bicistronic mRNAs. IRES activity was depressed in H ferritin-deficient mouse embryonic fibroblasts and elevated in cells expressing the H ferritin cDNA. H ferritin was shown to interact with the mRNA-binding protein CUGBP1, a protein known to interact with the and subunits of eukaryotic initiation factor eIF2. Small interference RNA-mediated depletion of CUGBP1 decreased IRES activity from bicistronic templates that included the cSHMT 3'-UTR in the bicistronic construct. The identification of this H ferritin-responsive IRES represents a mechanism that accounts for previous observations that H ferritin regulates folate metabolism.

Received for publication, July 30, 2007 , and in revised form, August 13, 2007.

^* This work was supported by Public Health Service Grant DK58144. 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 Fig. S1.

¹ To whom correspondence should be addressed: Cornell University, 315 Savage Hall, Ithaca, NY 14853. Tel.: 607-255-8001; Fax: 607-255-9751; E-mail: pjs13{at}cornell.edu.

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