The folate-coupled enzyme MTHFD2 is a nuclear protein and promotes cell proliferation

Scientific Reports

Volumn 5, Issue , 2015, Pages

  Gustafsson Sheppard, Nina ^a,b   Jarl, Lisa ^a   Mahadessian, Diana ^b   Strittmatter, Laura ^c   Schmidt, Angelika ^a   Madhusudan, Nikhil ^c   Tegnér, Jesper ^a   Lundberg, Emma K ^b   Asplund, Anna ^d   Jain, Mohit ^e   Nilsson, Roland ^a  

^a KAROLINSKA INSTITUTE   (Sweden)

^b SCIENCE FOR LIFE LABORATORY   (Sweden)

^c MASSACHUSETTS GENERAL HOSPITAL   (United States)

^d UPPSALA UNIVERSITY   (Sweden)

^e UNIVERSITY OF CALIFORNIA SAN DIEGO   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMINO ACID ACETYLTRANSFERASE; FOLIC ACID; METHYLENETETRAHYDROFOLATE DEHYDROGENASE; NUCLEAR PROTEIN;

ANIMAL; CELL NUCLEUS; CELL PROLIFERATION; ENZYMOLOGY; EXPERIMENTAL NEOPLASM; HELA CELL LINE; HUMAN; METABOLISM; MITOCHONDRION; MOUSE; PATHOLOGY; RAT; SPECIES DIFFERENCE; TUMOR CELL LINE;

AMINO-ACID N-ACETYLTRANSFERASE; ANIMALS; CELL LINE, TUMOR; CELL NUCLEUS; CELL PROLIFERATION; FOLIC ACID; HELA CELLS; HUMANS; METHYLENETETRAHYDROFOLATE DEHYDROGENASE (NADP); MICE; MITOCHONDRIA; NEOPLASMS, EXPERIMENTAL; NUCLEAR PROTEINS; RATS; SPECIES SPECIFICITY;

EID: 84944271150     PISSN: None     EISSN: 20452322     Source Type: Journal    
DOI: 10.1038/srep15029     Document Type: Article

References (32)

1. Cairns, R. A., Harris, I. S. & Mak, T. W. Regulation of cancer cell metabolism. Nat Rev Cancer 11, 85-95, doi: 10.1038/nrc2981 (2011).
2. Tibbetts, A. S. & Appling, D. R. Compartmentalization of Mammalian folate-mediated one-carbon metabolism. Annu Rev Nutr 30, 57-81, doi: 10.1146/annurev.nutr.012809.104810 (2010).
3. Stover, P. J. & Field, M. S. Trafficking of intracellular folates. Adv Nutr 2, 325-331, doi: 10.3945/ an.111.000596 10.3945/ an.111.000596 (2011).
4. Desler, C., Lykke, A. & Rasmussen, L. J. The effect of mitochondrial dysfunction on cytosolic nucleotide metabolism. J Nucleic Acids 2010, doi: 10.4061/2010/701518 (2010).
5. Barlowe, C. K. & Appling, D. R. In vitro evidence for the involvement of mitochondrial folate metabolism in the supply of cytoplasmic one-carbon units. Biofactors 1, 171-176 (1988).
6. Jain, M. et al. Metabolite profiling identifies a key role for glycine in rapid cancer cell proliferation. Science 336, 1040-1044, doi: 10.1126/science.1218595 (2012).
7. Nilsson, R. et al. Metabolic enzyme expression highlights a key role for MTHFD2 and the mitochondrial folate pathway in cancer. Nat Commun 5, 3128, doi: 10.1038/ncomms4128 (2014).
8. Lehtinen, L. et al. High-throughput RNAi screening for novel modulators of vimentin expression identifies MTHFD2 as a regulator of breast cancer cell migration and invasion. Oncotarget 4, 48-63 (2013).
9. Selcuklu, S. D. et al. MicroRNA-9 inhibition of cell proliferation and identification of novel miR-9 targets by transcriptome profiling in breast cancer cells. The Journal of biological chemistry 287, 29516-29528, doi: 10.1074/jbc.M111.335943 (2012).
10. Mejia, N. R. & MacKenzie, R. E. NAD-dependent methylenetetrahydrofolate dehydrogenase is expressed by immortal cells. The Journal of biological chemistry 260, 14616-14620 (1985).
11. Mejia, N. R. & MacKenzie, R. E. NAD-dependent methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase in transformed cells is a mitochondrial enzyme. Biochemical and biophysical research communications 155, 1-6 (1988).
12. Fan, J. et al. Quantitative flux analysis reveals folate-dependent NADPH production. Nature doi: 10.1038/nature13236 (2014).
13. Kilberg, M. S., Shan, J. & Su, N. ATF4-dependent transcription mediates signaling of amino acid limitation. Trends Endocrinol Metab 20, 436-443, doi: 10.1016/j.tem.2009.05.008 (2009).
14. Kilberg, M. S., Balasubramanian, M., Fu, L. & Shan, J. The transcription factor network associated with the amino acid response in mammalian cells. Adv Nutr 3, 295-306, doi: 10.3945/an.112.001891 (2012).
15. Voets, A. M. et al. Patient-derived fibroblasts indicate oxidative stress status and may justify antioxidant therapy in OXPHOS disorders. Biochim Biophys Acta 1817, 1971-1978, doi: 10.1016/j.bbabio.2012.07.001 (2012).
16. Rathi, A. V., Saenz Robles, M. T. & Pipas, J. M. Enterocyte proliferation and intestinal hyperplasia induced by simian virus 40 T antigen require a functional J domain. J Virol 81, 9481-9489, doi: 10.1128/JVI.00922-07 (2007).
17. Lund, R., Aittokallio, T., Nevalainen, O. & Lahesmaa, R. Identification of novel genes regulated by IL-12, IL-4, or TGF-beta during the early polarization of CD4+ lymphocytes. J Immunol 171, 5328-5336 (2003).
18. Christensen, K. E., Mirza, I. A., Berghuis, A. M. & Mackenzie, R. E. Magnesium and phosphate ions enable NAD binding to methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase. J Biol Chem 280, 34316-34323, doi: 10.1074/ jbc.M505210200 (2005).
19. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646-674, doi: 10.1016/j.cell.2011.02.013 (2011).
20. Kudo, N. et al. Leptomycin B inhibition of signal-mediated nuclear export by direct binding to CRM1. Exp Cell Res 242, 540-547, doi: 10.1006/excr.1998.4136 (1998).
21. Zink, D., Fischer, A. H. & Nickerson, J. A. Nuclear structure in cancer cells. Nat Rev Cancer 4, 677-687, doi: 10.1038/nrc1430 (2004).
22. Scotti, M., Stella, L., Shearer, E. J. & Stover, P. J. Modeling cellular compartmentation in one-carbon metabolism. Wiley interdisciplinary reviews. Systems biology and medicine 5, 343-365, doi: 10.1002/wsbm.1209 (2013).
23. Field, M. S. et al. Nuclear enrichment of folate cofactors and methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) protect de novo thymidylate biosynthesis during folate deficiency. The Journal of biological chemistry, doi: 10.1074/jbc.M114.599589 (2014).
24. Lincet, H. & Icard, P. How do glycolytic enzymes favour cancer cell proliferation by nonmetabolic functions? Oncogene 0, doi: 10.1038/onc.2014.320 (2014).
25. Bolusani, S. et al. Mammalian MTHFD2L encodes a mitochondrial methylenetetrahydrofolate dehydrogenase isozyme expressed in adult tissues. J Biol Chem 286, 5166-5174, doi: 10.1074/jbc.M110.196840 (2011).
26. Patel, H., Di Pietro, E., Mejia, N. & MacKenzie, R. E. NAD- and NADP-dependent mitochondrially targeted methylenetetrahydrofolate dehydrogenase-cyclohydrolases can rescue mthfd2 null fibroblasts. Arch Biochem Biophys 442, 133-139, doi: 10.1016/j.abb.2005.07.022 (2005).
27. Anderson, D. D., Quintero, C. M. & Stover, P. J. Identification of a de novo thymidylate biosynthesis pathway in mammalian mitochondria. Proc Natl Acad Sci USA 108, 15163-15168, doi: 10.1073/pnas.1103623108 (2011).
28. Field, M. S. et al. Nuclear enrichment of folate cofactors and methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) protect de novo thymidylate biosynthesis during folate deficiency. J Biol Chem 289, 29642-29650, doi: 10.1074/jbc.M114.599589 (2014).
29. Barrett, T. et al. NCBI GEO: archive for functional genomics data sets-update. Nucleic Acids Res 41, D991-995, doi: 10.1093/ nar/gks1193 (2013).
30. Blake, J. A. et al. The Mouse Genome Database: integration of and access to knowledge about the laboratory mouse. Nucleic Acids Res 42, D810-817, doi: 10.1093/nar/gkt1225 (2014).
31. Dignam, J. D., Lebovitz, R. M. & Roeder, R. G. Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res 11, 1475-1489 (1983).
32. Carpenter, A. E. et al. CellProfiler: image analysis software for identifying and quantifying cell phenotypes. Genome Biol 7, R100, doi: 10.1186/gb-2006-7-10-r100 (2006).