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Gene Review

Tyms  -  thymidylate synthase

Mus musculus

Synonyms: TS, TSase, Thymidylate synthase
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Disease relevance of Tyms

  • Although the amino-end of the amplified TS was unblocked, that isolated from a FUdR-resistant rat hepatoma cell line contained mostly N-acetylmethionine on its N-terminal end, a finding that may have significant regulatory consequences, which are discussed [1].
  • Restriction enzyme mapping, subcloning, and DNA sequencing analysis of recombinant phage lambda and P1 clones revealed that exons encoding the 1.9-kb mouse TS mRNA are dispersed over >150 kb genomic DNA [2].
  • Mutants of human colon adenocarcinoma, selected for thymidylate synthase deficiency [3].
  • When the TS promoter was replaced by the simian virus 40 early promoter or by a TS promoter that retained only 60 nucleotides upstream of the first transcriptional start site, the minigene was expressed constitutively [4].
  • We found that the mouse TS promoter had about the same strength as the simian virus 40 early promoter but was significantly stronger than the herpes simplex virus thymidine kinase promoter [4].

High impact information on Tyms

  • Induction of apoptosis by LSFdn parallels the process known as thymineless death, which is induced by the TS inhibitor and chemotherapeutic drug 5-fluorodeoxyuridine [5].
  • Mutation of the LSF binding sites inhibits G(1)-S induction of mRNA derived from a TS minigene [5].
  • Inhibition of the mammalian transcription factor LSF induces S-phase-dependent apoptosis by downregulating thymidylate synthase expression [5].
  • The thymidylate synthase (TS) gene, which is induced at the G(1)-S transition in growth-stimulated cells, encodes an enzyme that is essential for DNA replication and cell survival [5].
  • Using nuclear run-on assays, we observed that the transcription rates for these genes, with the exception of TS, are essentially invariant not only throughout the cell cycle in proliferating cells, but also in noncycling (G0) cells [6].

Chemical compound and disease context of Tyms

  • GC3/c1 human colon adenocarcinoma cells were treated with the mutagen ethyl methanesulfonate, and three clones deficient in thymidylate synthase (5,10-methylenetetrahydrofolate:dUMP C-methyltransferase, EC 2.1.1. 45) activity were selected and characterized [3].
  • Influence of dose of [6RS]leucovorin on reduced folate pools and 5-fluorouracil-mediated thymidylate synthase inhibition in human colon adenocarcinoma xenografts [7].
  • In addition to studying toxicity, plasma deoxyuridine (UdR) elevations were measured as a marker of TS inhibition [8].
  • Enhanced antitumor activity for the thymidylate synthase inhibitor 1843U89 through decreased host toxicity with oral folic acid [9].
  • Using thymidylate synthase purified from colon adenocarcinoma HxVRC5, CH2-H4PteGlu5 (where the subscript digit attached to the glutamate portion equals the number of glutamate residues) stabilized the covalent ternary complex at greater than 200-fold lower concentration in comparison to CH2-H4PteGlu1 [10].

Biological context of Tyms


Anatomical context of Tyms


Associations of Tyms with chemical compounds


Physical interactions of Tyms

  • Furthermore, the binding of Sp1 to mutated Sp1-binding motifs in the promoter region of the human TS gene was correlated with the promoter activity, as measured by the CAT assay [19].

Regulatory relationships of Tyms


Other interactions of Tyms


Analytical, diagnostic and therapeutic context of Tyms


  1. Isolation and expression of rat thymidylate synthase cDNA: phylogenetic comparison with human and mouse thymidylate synthases. Cieśla, J., Weiner, K.X., Weiner, R.S., Reston, J.T., Maley, G.F., Maley, F. Biochim. Biophys. Acta (1995) [Pubmed]
  2. Genomic organization, chromosomal localization, and expression of the murine thromboxane synthase gene. Zhang, L., Xiao, H., Schultz, R.A., Shen, R.F. Genomics (1997) [Pubmed]
  3. Mutants of human colon adenocarcinoma, selected for thymidylate synthase deficiency. Houghton, P.J., Germain, G.S., Hazelton, B.J., Pennington, J.W., Houghton, J.A. Proc. Natl. Acad. Sci. U.S.A. (1989) [Pubmed]
  4. The 5'-flanking region of the mouse thymidylate synthase gene is necessary but not sufficient for normal regulation in growth-stimulated cells. Li, Y., Li, D., Osborn, K., Johnson, L.F. Mol. Cell. Biol. (1991) [Pubmed]
  5. Inhibition of the mammalian transcription factor LSF induces S-phase-dependent apoptosis by downregulating thymidylate synthase expression. Powell, C.M., Rudge, T.L., Zhu, Q., Johnson, L.F., Hansen, U. EMBO J. (2000) [Pubmed]
  6. A cell cycle analysis of growth-related genes expressed during T lymphocyte maturation. Feder, J.N., Guidos, C.J., Kusler, B., Carswell, C., Lewis, D., Schimke, R.T. J. Cell Biol. (1990) [Pubmed]
  7. Influence of dose of [6RS]leucovorin on reduced folate pools and 5-fluorouracil-mediated thymidylate synthase inhibition in human colon adenocarcinoma xenografts. Houghton, J.A., Williams, L.G., Cheshire, P.J., Wainer, I.W., Jadaud, P., Houghton, P.J. Cancer Res. (1990) [Pubmed]
  8. Preclinical and phase I clinical studies with the nonclassical antifolate thymidylate synthase inhibitor nolatrexed dihydrochloride given by prolonged administration in patients with solid tumors. Rafi, I., Boddy, A.V., Calvete, J.A., Taylor, G.A., Newell, D.R., Bailey, N.P., Lind, M.J., Green, M., Hines, J., Johnstone, A., Clendeninn, N., Calvert, A.H. J. Clin. Oncol. (1998) [Pubmed]
  9. Enhanced antitumor activity for the thymidylate synthase inhibitor 1843U89 through decreased host toxicity with oral folic acid. Smith, G.K., Amyx, H., Boytos, C.M., Duch, D.S., Ferone, R., Wilson, H.R. Cancer Res. (1995) [Pubmed]
  10. Characterization of the pools of 5,10-methylenetetrahydrofolates and tetrahydrofolates in xenografts of human colon adenocarcinoma. Houghton, J.A., Williams, L.G., Radparvar, S., Houghton, P.J. Cancer Res. (1988) [Pubmed]
  11. Fe65, a ligand of the Alzheimer's beta-amyloid precursor protein, blocks cell cycle progression by down-regulating thymidylate synthase expression. Bruni, P., Minopoli, G., Brancaccio, T., Napolitano, M., Faraonio, R., Zambrano, N., Hansen, U., Russo, T. J. Biol. Chem. (2002) [Pubmed]
  12. Sequence of a cDNA for mouse thymidylate synthase reveals striking similarity with the prokaryotic enzyme. Perryman, S.M., Rossana, C., Deng, T.L., Vanin, E.F., Johnson, L.F. Mol. Biol. Evol. (1986) [Pubmed]
  13. Synergistic activation of the TATA-less mouse thymidylate synthase promoter by the Ets transcription factor GABP and Sp1. Rudge, T.L., Johnson, L.F. Exp. Cell Res. (2002) [Pubmed]
  14. Mouse thymidylate synthase messenger RNA lacks a 3' untranslated region. Jenh, C.H., Deng, T.L., Li, D.W., DeWille, J., Johnson, L.F. Proc. Natl. Acad. Sci. U.S.A. (1986) [Pubmed]
  15. Splicing signals are required for S-phase regulation of the mouse thymidylate synthase gene. Ke, Y., Ash, J., Johnson, L.F. Mol. Cell. Biol. (1996) [Pubmed]
  16. Redistribution of nucleoside transporters to the cell membrane provides a novel approach for imaging thymidylate synthase inhibition by positron emission tomography. Perumal, M., Pillai, R.G., Barthel, H., Leyton, J., Latigo, J.R., Forster, M., Mitchell, F., Jackman, A.L., Aboagye, E.O. Cancer Res. (2006) [Pubmed]
  17. Molecular cloning of DNA sequences complementary to mouse thymidylate synthase messenger RNA. Geyer, P.K., Johnson, L.F. J. Biol. Chem. (1984) [Pubmed]
  18. Cloning and characterization of the promoter region of monkey thymidylate synthase gene. Horie, N., Wakabayashi, M., Katai, H., Takeishi, K. Biol. Pharm. Bull. (1998) [Pubmed]
  19. Identification of functional elements in the promoter region of the human gene for thymidylate synthase and nuclear factors that regulate the expression of the gene. Horie, N., Takeishi, K. J. Biol. Chem. (1997) [Pubmed]
  20. Introns are essential for growth-regulated expression of the mouse thymidylate synthase gene. Ash, J., Ke, Y., Korb, M., Johnson, L.F. Mol. Cell. Biol. (1993) [Pubmed]
  21. 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]
  22. Thymidylate synthase gene amplification in fluorodeoxyuridine-resistant mouse cell lines. Jenh, C.H., Geyer, P.K., Baskin, F., Johnson, L.F. Mol. Pharmacol. (1985) [Pubmed]
  23. Insulin-like growth factor I regulation of transcription and replicating enzyme induction necessary for DNA synthesis. Yang, H.C., Pardee, A.B. J. Cell. Physiol. (1986) [Pubmed]
  24. 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]
  25. In vivo evaluation of 5-[(18)F]fluoro-2'-deoxyuridine as tracer for positron emission tomography in a murine pancreatic cancer model. Seitz, U., Wagner, M., Vogg, A.T., Glatting, G., Neumaier, B., Greten, F.R., Schmid, R.M., Reske, S.N. Cancer Res. (2001) [Pubmed]
  26. A novel polypyrimidine antitumor agent FdUMP[10] induces thymineless death with topoisomerase I-DNA complexes. Liao, Z.Y., Sordet, O., Zhang, H.L., Kohlhagen, G., Antony, S., Gmeiner, W.H., Pommier, Y. Cancer Res. (2005) [Pubmed]
  27. Inhibition of mouse thymidylate synthase promoter activity by the wild-type p53 tumor suppressor protein. Lee, Y., Chen, Y., Chang, L.S., Johnson, L.F. Exp. Cell Res. (1997) [Pubmed]
  28. The mouse thymidylate synthase promoter: essential elements are in close proximity to the transcriptional initiation sites. Deng, T., Li, Y., Jolliff, K., Johnson, L.F. Mol. Cell. Biol. (1989) [Pubmed]
  29. Construction and expression of mouse thymidylate synthase minigenes. DeWille, J.W., Jenh, C.H., Deng, T., Harendza, C.J., Johnson, L.F. J. Biol. Chem. (1988) [Pubmed]
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