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Gene Review

Dhfr  -  dihydrofolate reductase

Mus musculus

Synonyms: 8430436I03Rik, AA607882, AI662710, AW555094, Dihydrofolate reductase
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Disease relevance of Dhfr


High impact information on Dhfr


Chemical compound and disease context of Dhfr


Biological context of Dhfr


Anatomical context of Dhfr

  • We demonstrate that this altered gene can be employed as a dominant selectable marker in cultured cells expressing normal levels of wild-type dihydrofolate reductase [16].
  • Microcells prepared from diploid mouse fibroblasts were fused with mutant hamster cells lacking the dihydrofolate reductase gene (Dhfr), and DHFR+ microcell hybrids were selected in medium lacking purines and pyrimidines [17].
  • Liver-cell homogenate from one patient had a previously undetectable level of dihydrofolate reductase restored to normal by high cation concentration in the assay [2].
  • Through analysis of transiently and stably transfected NIH 3T3 cells, we have now demonstrated that DHFR promoter sequences extending from -270 to +20 are sufficient to confer similar regulation on a reporter gene [18].
  • The ability of the tyr22-DHFR transgenic marrow to confer MTX-resistance to bone marrow transplant (BMT) recipients did not correlate with the level of mRNA expression or the number of transgene copies [19].

Associations of Dhfr with chemical compounds

  • Functional analysis of the E2F1 core domain demonstrated that replacement of phenylalanine residues 413, 425, and 429 with alanine reduces both transcriptional activation of the dhfr promoter and protein-protein interactions with CBP, transcription factor (TF) IIH, and TATA-binding protein (TBP) [20].
  • Aminopterin, an inhibitor of dihydrofolate reductase, has been demonstrated to allow HGPRT(-) cells to be negatively selected [21].
  • Such plasmids specify a protein that has enzymatic properties, immunological reactivity and molecular size characteristic of the mouse dihydrofolate reductase, and render host cells resistant to the antimetabolic drug trimethoprim [22].
  • The most active of these drugs, MGT-6a, was three orders of magnitude more effective than distamycin and inhibited complexes between E2F1 and the dihydrofolate reductase promoter by 50% at 0.00085 microM [23].
  • These boron-containing compounds were shown to inhibit DNA synthesis; such inhibition was caused primarily by reducing de novo purine biosynthesis via inhibition of PRPP amidotransferase, IMP dehydrogenase and dihydrofolate reductase activities [24].

Physical interactions of Dhfr


Regulatory relationships of Dhfr


Other interactions of Dhfr


Analytical, diagnostic and therapeutic context of Dhfr

  • We investigated the effect of substrate binding on the mechanical stability of mouse dihydrofolate reductase using single-molecule force spectroscopy by atomic force microscopy [32].
  • Transgenic mice expressing the tyr22 variant of murine DHFR: protection of transgenic marrow transplant recipients from lethal doses of methotrexate [19].
  • These results indicate that tyr22-DHFR is likely to be superior to arg22-DHFR in conferring MTX-resistance in BMT recipients, illustrating its usefulness for chemoprotection during MTX chemotherapy and also potentially for in vivo selection of transduced cells in gene therapy trials [19].
  • Molecular cloning, mapping, and DNA sequencing techniques have been used to characterize the functional human dihydrofolate reductase (DHFR) gene [33].
  • The L5178YR cell line synthesizes approximately 10-11% of its total soluble cell protein as DHFR regardless of growth phase, as measured by direct immunoprecipitation with a monospecific antiserum [34].


  1. Expression of the mouse dihydrofolate reductase cDNA in B. subtilis: a system to select mutant cDNAs coding for methotrexate resistant enzymes. Grange, T., Kunst, F., Thillet, J., Ribadeau-Dumas, B., Mousseron, S., Hung, A., Jami, J., Pictet, R. Nucleic Acids Res. (1984) [Pubmed]
  2. Dihydrofolate reductase deficiency causing megaloblastic anemia in two families. Tauro, G.P., Danks, D.M., Rowe, P.B., Van der Weyden, M.B., Schwarz, M.A., Collins, V.L., Neal, B.W. N. Engl. J. Med. (1976) [Pubmed]
  3. c-myc antisense transcripts accelerate differentiation and inhibit G1 progression in murine erythroleukemia cells. Prochownik, E.V., Kukowska, J., Rodgers, C. Mol. Cell. Biol. (1988) [Pubmed]
  4. The amino acid sequence of dihydrofolate reductase from the mouse lymphoma L1210. Stone, D., Paterson, S.J., Raper, J.H., Phillips, A.W. J. Biol. Chem. (1979) [Pubmed]
  5. Structure of amplified normal and variant dihydrofolate reductase genes in mouse sarcoma S180 cells. Crouse, G.F., Simonsen, C.C., McEwan, R.N., Schimke, R.T. J. Biol. Chem. (1982) [Pubmed]
  6. Linkage map of two HLA-SB beta and two HLA-SB alpha-related genes: an intron in one of the SB beta genes contains a processed pseudogene. Trowsdale, J., Kelly, A., Lee, J., Carson, S., Austin, P., Travers, P. Cell (1984) [Pubmed]
  7. SV40 T antigen binding site mutations that affect autoregulation. Rio, D.C., Tjian, R. Cell (1983) [Pubmed]
  8. Unstable amplification of an altered dihydrofolate reductase gene associated with double-minute chromosomes. Haber, D.A., Schimke, R.T. Cell (1981) [Pubmed]
  9. Toxicity of folic acid analogs in cultured human cells: a microtiter assay for the analysis of drug competition. Roos, D.S., Schimke, R.T. Proc. Natl. Acad. Sci. U.S.A. (1987) [Pubmed]
  10. Trimetrexate inhibits progression of the murine 32Dp210 model of chronic myeloid leukemia in animals expressing drug-resistant dihydrofolate reductase. Sweeney, C.L., Frandsen, J.L., Verfaillie, C.M., McIvor, R.S. Cancer Res. (2003) [Pubmed]
  11. Increased gene amplification in L5178Y mouse lymphoma cells with hydroxyurea-induced chromosomal aberrations. Hill, A.B., Schimke, R.T. Cancer Res. (1985) [Pubmed]
  12. Role of the cellular oxidation-reduction state in methotrexate binding to dihydrofolate reductase and dissociation induced by reduced folates. Matherly, L.H., Anderson, L.A., Goldman, I.D. Cancer Res. (1984) [Pubmed]
  13. Rate and extent of interconversion of tetrahydrofolate cofactors to dihydrofolate after cessation of dihydrofolate reductase activity in stationary versus log phase L1210 leukemia cells. Trent, D.F., Seither, R.L., Goldman, I.D. J. Biol. Chem. (1991) [Pubmed]
  14. Analysis of the mouse Dhfr/Rep-3 major promoter region by using linker-scanning and internal deletion mutations and DNase I footprinting. Smith, M.L., Mitchell, P.J., Crouse, G.F. Mol. Cell. Biol. (1990) [Pubmed]
  15. Characterization and chromosome location of the mouse link protein gene (Crtl1). Deák, F., Mátés, L., Krysan, K., Liu, Z., Szabó, P.E., Mann, J.R., Beier, D.R., Kiss, I. Cytogenet. Cell Genet. (1999) [Pubmed]
  16. Isolation and expression of an altered mouse dihydrofolate reductase cDNA. Simonsen, C.C., Levinson, A.D. Proc. Natl. Acad. Sci. U.S.A. (1983) [Pubmed]
  17. Assignment of genes encoding dihydrofolate reductase and hexosaminidase B to Mus musculus chromosome 13. Killary, A.M., Leach, R.J., Moran, R.G., Fournier, R.E. Somat. Cell Mol. Genet. (1986) [Pubmed]
  18. The HIP1 binding site is required for growth regulation of the dihydrofolate reductase gene promoter. Means, A.L., Slansky, J.E., McMahon, S.L., Knuth, M.W., Farnham, P.J. Mol. Cell. Biol. (1992) [Pubmed]
  19. Transgenic mice expressing the tyr22 variant of murine DHFR: protection of transgenic marrow transplant recipients from lethal doses of methotrexate. James, R.I., May, C., Vagt, M.D., Studebaker, R., McIvor, R.S. Exp. Hematol. (1997) [Pubmed]
  20. Activation of the murine dihydrofolate reductase promoter by E2F1. A requirement for CBP recruitment. Fry, C.J., Pearson, A., Malinowski, E., Bartley, S.M., Greenblatt, J., Farnham, P.J. J. Biol. Chem. (1999) [Pubmed]
  21. Requirement of de novo protein synthesis for aminopterin-induced apoptosis in a mouse myeloma cell line. Chung, Y.H., Youn, J., Choi, Y., Paik, D.J., Cho, Y.J. Immunol. Lett. (2001) [Pubmed]
  22. Phenotypic expression in E. coli of a DNA sequence coding for mouse dihydrofolate reductase. Chang, A.C., Nunberg, J.H., Kaufman, R.J., Erlich, H.A., Schimke, R.T., Cohen, S.N. Nature (1978) [Pubmed]
  23. Targeting E2F1-DNA complexes with microgonotropen DNA binding agents. Chiang, S.Y., Bruice, T.C., Azizkhan, J.C., Gawron, L., Beerman, T.A. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  24. Synthesis and pharmacological activities of amine-boranes. Burnham, B.S. Current medicinal chemistry. (2005) [Pubmed]
  25. Activation of the E2F transcription factor by cyclin D1 is blocked by p16INK4, the product of the putative tumor suppressor gene MTS1. Schulze, A., Zerfass, K., Spitkovsky, D., Henglein, B., Jansen-Dürr, P. Oncogene (1994) [Pubmed]
  26. A mechanism of resistance to methotrexate. NADPH but not NADH stimulation of methotrexate binding to dihydrofolate reductase. Kamen, B.A., Whyte-Bauer, W., Bertino, J.R. Biochem. Pharmacol. (1983) [Pubmed]
  27. Type 1 transforming growth factor beta: amplified expression and secretion of mature and precursor polypeptides in Chinese hamster ovary cells. Gentry, L.E., Webb, N.R., Lim, G.J., Brunner, A.M., Ranchalis, J.E., Twardzik, D.R., Lioubin, M.N., Marquardt, H., Purchio, A.F. Mol. Cell. Biol. (1987) [Pubmed]
  28. Effect of direct suppression of thymidylate synthase at the 5,10-methylenetetrahydrofolate binding site on the interconversion of tetrahydrofolate cofactors to dihydrofolate by antifolates. Influence of degree of dihydrofolate reductase inhibition. Seither, R.L., Trent, D.F., Mikulecky, D.C., Rape, T.J., Goldman, I.D. J. Biol. Chem. (1991) [Pubmed]
  29. C/EBPalpha inhibits cell growth via direct repression of E2F-DP-mediated transcription. Slomiany, B.A., D'Arigo, K.L., Kelly, M.M., Kurtz, D.T. Mol. Cell. Biol. (2000) [Pubmed]
  30. Isolation of extrachromosomal elements by histone immunoprecipitation. Kuschak, T.I., Kuschak, B.C., Smith, G.M., Wright, J.A., Mai, S. BioTechniques (2001) [Pubmed]
  31. Deficiency of retinoblastoma protein leads to inappropriate S-phase entry, activation of E2F-responsive genes, and apoptosis. Almasan, A., Yin, Y., Kelly, R.E., Lee, E.Y., Bradley, A., Li, W., Bertino, J.R., Wahl, G.M. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  32. Influence of substrate binding on the mechanical stability of mouse dihydrofolate reductase. Junker, J.P., Hell, K., Schlierf, M., Neupert, W., Rief, M. Biophys. J. (2005) [Pubmed]
  33. The functional human dihydrofolate reductase gene. Chen, M.J., Shimada, T., Moulton, A.D., Cline, A., Humphries, R.K., Maizel, J., Nienhuis, A.W. J. Biol. Chem. (1984) [Pubmed]
  34. Correlation of dihydrofolate reductase elevation with gene amplification in a homogeneously staining chromosomal region in L5178Y cells. Dolnick, B.J., Berenson, R.J., Bertino, J.R., Kaufman, R.J., Nunberg, J.H., Schimke, R.T. J. Cell Biol. (1979) [Pubmed]
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