The folate-coupled enzyme MTHFD2 is a nuclear protein and promotes cell proliferation
2015 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, 15029Article in journal (Refereed) Published
Folate metabolism is central to cell proliferation and a target of commonly used cancer chemotherapeutics. In particular, the mitochondrial folate-coupled metabolism is thought to be important for proliferating cancer cells. The enzyme MTHFD2 in this pathway is highly expressed in human tumors and broadly required for survival of cancer cells. Although the enzymatic activity of the MTHFD2 protein is well understood, little is known about its larger role in cancer cell biology. We here report that MTHFD2 is co-expressed with two distinct gene sets, representing amino acid metabolism and cell proliferation, respectively. Consistent with a role for MTHFD2 in cell proliferation, MTHFD2 expression was repressed in cells rendered quiescent by deprivation of growth signals (serum) and rapidly re-induced by serum stimulation. Overexpression of MTHFD2 alone was sufficient to promote cell proliferation independent of its dehydrogenase activity, even during growth restriction. In addition to its known mitochondrial localization, we found MTHFD2 to have a nuclear localization and co-localize with DNA replication sites. These findings suggest a previously unknown role for MTHFD2 in cancer cell proliferation, adding to its known function in mitochondrial folate metabolism.
Place, publisher, year, edition, pages
[Sheppard, Nina Gustafsson; Jarl, Lisa; Schmidt, Angelika; Tegner, Jesper; Nilsson, Roland] Karolinska Inst, Dept Med, Unit Computat Med, Stockholm, Sweden. [Sheppard, Nina Gustafsson; Jarl, Lisa; Schmidt, Angelika; Tegner, Jesper; Nilsson, Roland] Karolinska Inst, Ctr Mol Med, Stockholm, Sweden. [Sheppard, Nina Gustafsson] Karolinska Inst, Dept Med Biochem & Biophys, Div Translat Med & Chem Biol, Sci Life Lab, Stockholm, Sweden. [Mahadessian, Diana; Lundberg, Emma K.] Royal Inst Technol, Sci Life Lab, Solna, Sweden. [Strittmatter, Laura; Madhusudan, Nikhil] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Strittmatter, Laura; Madhusudan, Nikhil] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Asplund, Anna] Uppsala Univ, Sci Life Lab, Dept Immunol Genet & Pathol, Uppsala, Sweden. [Jain, Mohit] Univ Calif San Diego, Dept Med, Inst Metabol Med, San Diego, CA 92103 USA., 2015. Vol. 5, 15029
Cell Biology Cancer and Oncology
IdentifiersURN: urn:nbn:se:kth:diva-176336DOI: 10.1038/srep15029ISI: 000362641800003ScopusID: 2-s2.0-84944271150OAI: oai:DiVA.org:kth-176336DiVA: diva2:868046
QC 201511092015-11-092015-11-032015-11-09Bibliographically approved