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J. Biol. Chem., Vol. 276, Issue 23, 19855-19861, June 8, 2001
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From the Division of Nutritional Sciences, Cornell University,
Ithaca, New York 14853
We have elucidated a biochemical mechanism
whereby changes in iron metabolism cause changes in
folate-dependent one-carbon metabolism. Although animal and
clinical studies have demonstrated that perturbations in iron status
and metabolism alter folate metabolism, the biochemical mechanisms
underlying these associations have yet to be identified. The effect of
altered ferritin expression on folate metabolism was determined in
human MCF-7 cells and SH-SY5Y neuroblastoma. Cells expressing rat heavy
chain ferritin (HCF) exhibited markedly increased expression of the
folate-dependent enzyme cytoplasmic serine
hydroxymethyltransferase (cSHMT). These effects were not seen when rat
light chain ferritin was expressed. Additionally, cSHMT expression was
not altered when HCF expression was induced in MCF-7 cells cultured
with supplemental ferric citrate. This indicates that cSHMT expression
is increased by elevated HCF concentrations, independent of increased
iron availability, suggesting that cSHMT expression may respond to
HCF-induced chelation of the regulatory iron pool. Increased HCF
expression did not alter cSHMT mRNA levels, but did increase
translation rates of cSHMT mRNA. The increase in translation was
mediated, at least in part, through the cSHMT 5'-untranslated region of
the transcript. MCF-7 cells with increased expression of cSHMT
displayed increased efficiency of de novo thymidylate
biosynthesis, indicating that thymidylate synthesis is normally limited
by cSHMT activity in MCF-7 cells. Our data suggest that the iron
regulatory pool may play an important role in regulating folate
metabolism and thereby thymidine biosynthesis.
Heavy Chain Ferritin Enhances Serine Hydroxymethyltransferase
Expression and de Novo Thymidine Biosynthesis*
*
This work was supported in part by United States Public
Health Service Grants HD35678 and DK49621 (to P. J. S.) and Training Grant DK07158-21 (to E. W. O.).
To whom correspondence should be addressed. Tel.:
607-255-9751; Fax: 607-255-9751; E-mail: pjs13@cornell.edu.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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