title: The folate-coupled enzyme MTHFD2 is a nuclear protein and promotes cell proliferation.
abstract: 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.
authors.affiliation: Unit of Computational Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.|Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.|Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
authors.forename: Nina
authors.initials: N
authors.lastname: Gustafsson Sheppard
authors.affiliation: Unit of Computational Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.|Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Lisa
authors.initials: L
authors.lastname: Jarl
authors.affiliation: Science for Life Laboratory, Royal Institute of Technology, Solna, Sweden.
authors.forename: Diana
authors.initials: D
authors.lastname: Mahadessian
authors.affiliation: Department of Molecular Biology and the Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Strittmatter
authors.affiliation: Unit of Computational Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.|Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Angelika
authors.initials: A
authors.lastname: Schmidt
authors.affiliation: Department of Molecular Biology and the Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
authors.forename: Nikhil
authors.initials: N
authors.lastname: Madhusudan
authors.affiliation: Unit of Computational Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.|Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Jesper
authors.initials: J
authors.lastname: Tegnér
authors.affiliation: Science for Life Laboratory, Royal Institute of Technology, Solna, Sweden.
authors.forename: Emma K
authors.initials: EK
authors.lastname: Lundberg
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Asplund
authors.affiliation: Department of Medicine, Institute for Metabolomics Medicine, University of California, San Diego, USA.
authors.forename: Mohit
authors.initials: M
authors.lastname: Jain
authors.affiliation: Unit of Computational Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.|Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Roland
authors.initials: R
authors.lastname: Nilsson
mesh_terms: D051046:Amino-Acid N-Acetyltransferase / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000201:enzymology*; D049109:Cell Proliferation; D005492:Folic Acid / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP) / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000201:enzymology* / Q000473:pathology*; D009687:Nuclear Proteins / Q000378:metabolism; D051381:Rats; D013045:Species Specificity
chemical_list: D009687:Nuclear Proteins; D005492:Folic Acid; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP); D051046:Amino-Acid N-Acetyltransferase