Heavy Chain Ferritin Enhances Serine Hydroxymethyltransferase Expression and de Novo Thymidine Biosynthesis

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.