The world's first wiki where authorship really matters (Nature Genetics, 2008). Due credit and reputation for authors. Imagine a global collaborative knowledge base for original thoughts. Search thousands of articles and collaborate with scientists around the globe.

wikigene or wiki gene protein drug chemical gene disease author authorship tracking collaborative publishing evolutionary knowledge reputation system wiki2.0 global collaboration genes proteins drugs chemicals diseases compound
Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)



Gene Review

Tbxas1  -  thromboxane A synthase 1, platelet

Mus musculus

Synonyms: CYP5, CYP5A1, Cyp5, Cyp5a1, Cytochrome P450 5A1, ...
Welcome! If you are familiar with the subject of this article, you can contribute to this open access knowledge base by deleting incorrect information, restructuring or completely rewriting any text. Read more.

Disease relevance of Tbxas1

  • Besides its well-recognized role in hemostasis and thrombosis, thromboxane A(2) synthase (TXAS) is proposed to be involved in thrombopoiesis and lymphocyte differentiation [1].
  • AA infusion caused a progressive drop of mean arterial pressure (MAP), cardiac arrest, and death in wild-type (WT) mice but did not induce shock in TXAS(-/-) mice or in WT and TXAS(-/-) mice treated with antagonist to the thromboxane-prostanoid (TP) receptor [1].
  • Biological characterization of a human colon adenocarcinoma cell line deficient in thymidylate synthase (TS-) is described [2].
  • Steady state kinetic studies have indicated the Escherichia coli thymidylate synthase (ecTS) is intrinsically more resistant to several TS-directed inhibitors as compared with the human enzyme, suggesting that ecTS is suitable for use as a drug-resistant marker [3].
  • We studied the antitumor activity and toxicity of ZD1694 (tomudex), a specific inhibitor of thymidylate synthase (TS), in nude mice bearing human head and neck squamous cell carcinoma A253 and FaDu xenografts [4].

High impact information on Tbxas1

  • 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].
  • These data, and the structure of the TXS promoter and enhancer, suggest that TXS belongs to a distinct subgroup of genes involved in platelet formation and function [6].
  • Three of seven colonies chosen for initial study were shown to be thymidylate synthase deficient (TS-) by enzyme assay, thymidine auxotrophy, and their inability to incorporate labeled deoxyuridine into their DNA in vivo [7].
  • We conclude that TXAS is not essential for thrombopoiesis and lymphocyte differentiation [1].
  • The TXAS-deleted mice will be valuable for investigating the roles of arachidonate metabolic shunt in various pathophysiologic processes [1].

Chemical compound and disease context of Tbxas1


Biological context of Tbxas1

  • Ribonuclease protection and 5'-RACE assays identified at least five major transcription start sites clustered within 31 bp of the Tbxas1 promoter [12].
  • Transfection analyses indicated that the expression of Tbxas1 is controlled by a short (70-bp) positive regulatory sequence and several upstream repressive elements [12].
  • These observations suggested that the inverse gene expression of PGIS and TXS in macrophages contributes to immune responses by modulating the relative levels of prostacyclin and thromboxane A2 [13].
  • Taken together, these results suggest that the expression of human TS gene is modulated by multiple factors including cis-elements, trans-activator(s), and possibly genomic methylation [14].
  • A 9-fold transactivation of luciferase (luc) reporter gene expression had been detected when NF-E2 cDNA was co-expressed with a TS promoter/luc construct [14].

Anatomical context of Tbxas1


Associations of Tbxas1 with chemical compounds

  • Sequence comparison indicated that one of the two N-glycosylation sites, eight of the eleven cysteine residues, and a heme-binding domain are conserved in both murine and human TS sequences [15].
  • Plasma levels of folates and thymidine in mice are about 10-fold higher than in humans and may influence the therapeutic efficacy of thymidylate synthase (TS) inhibitors, such as 5-fluorouracil (5FU) and the antifolates pemetrexed (MTA) and raltitrexed (RTX) [16].
  • N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N- methylamino]-2-thenoyl)-L-glutamic acid (ICI D1694) is a water-soluble, folate-based thymidylate synthase (TS) inhibitor designed to be a less toxic and more potent analogue of the clinically tested N10-propargyl-5,8-dideazafolic acid [17].
  • PURPOSE: A phase I, multicenter trial of the thymidylate synthase (TS) inhibitor THYMITAQ (nolatrexed dihydrochloride; Agouron Pharmaceuticals, Inc, San Diego, CA) given by 5-day continuous infusion was performed to establish the maximum-tolerated dose (MTD) and to investigate pharmacokinetics, pharmacodynamics, and antitumor effects [18].
  • We report that the gene for thymidylate synthase (TS) is amplified in the mouse cell line L1210:C15 that was selectively grown in increasing concentrations of the competitive inhibitor of thymidylate synthase, CB3717 [19].

Other interactions of Tbxas1

  • In situ hybridization analysis showed that the expression of mRNAs for PGIS and TXS was ascribable not only to the alteration of the expression levels of both mRNAs in the each macrophage but also to the changes in subpopulations of the cells expressing these mRNAs [13].
  • However, when coincubated with activin A, retinoic acid specifically induced the synthesis of thromboxane-A-synthase-specific mRNA and induced an increase in enzyme activity with a synergistic effect on cyclooxygenase-1 protein and mRNA [20].

Analytical, diagnostic and therapeutic context of Tbxas1

  • To evaluate its various physiologic roles, we generated TXAS-deleted mice by gene targeting [1].
  • Thymidylate synthase (TS) is an important target for cancer chemotherapy [21].
  • To clarify the underlying mechanism by which the combination exerts the synergistic effects, the expression of thymidylate synthase (TS) was assessed by Western blot analysis in vitro and by immunohistochemical analysis in an animal model [22].
  • The thymidylate synthase (TS) inhibition rate, an index of inhibition of the de novo pathway, was significantly higher in the 5-FU and 5-FU plus AZT groups than in the control group (P<0.01), but it did not differ from the control in the AZT group [23].
  • Immunohistochemistry showed that the expression of TS was down-regulated in tumors treated by S-1 plus radiation [24].


  1. TXAS-deleted mice exhibit normal thrombopoiesis, defective hemostasis, and resistance to arachidonate-induced death. Yu, I.S., Lin, S.R., Huang, C.C., Tseng, H.Y., Huang, P.H., Shi, G.Y., Wu, H.L., Tang, C.L., Chu, P.H., Wang, L.H., Wu, K.K., Lin, S.W. Blood (2004) [Pubmed]
  2. Mutation(s) of the thymidylate synthase gene of human adenocarcinoma cells causes a thymidylate synthase-negative phenotype that can be attenuated by exogenous folates. Houghton, P.J., Rahman, A., Will, C.L., Dolnick, B.J., Houghton, J.A. Cancer Res. (1992) [Pubmed]
  3. Retroviral expression of Escherichia coli thymidylate synthase cDNA confers high-level antifolate resistance to hematopoietic cells. Shaw, D., Berger, F.G., Spencer, H.T. Hum. Gene Ther. (2001) [Pubmed]
  4. Antitumor activity of ZD1694 (tomudex) against human head and neck cancer in nude mouse models: role of dosing schedule and plasma thymidine. Cao, S., McGuire, J.J., Rustum, Y.M. Clin. Cancer Res. (1999) [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. p45 NF-E2 regulates expression of thromboxane synthase in megakaryocytes. Deveaux, S., Cohen-Kaminsky, S., Shivdasani, R.A., Andrews, N.C., Filipe, A., Kuzniak, I., Orkin, S.H., Roméo, P.H., Mignotte, V. EMBO J. (1997) [Pubmed]
  7. Thymidylate synthase-deficient Chinese hamster cells: a selection system for human chromosome 18 and experimental system for the study of thymidylate synthase regulation and fragile X expression. Nussbaum, R.L., Walmsley, R.M., Lesko, J.G., Airhart, S.D., Ledbetter, D.H. Am. J. Hum. Genet. (1985) [Pubmed]
  8. Structure-based design of lipophilic quinazoline inhibitors of thymidylate synthase. Jones, T.R., Varney, M.D., Webber, S.E., Lewis, K.K., Marzoni, G.P., Palmer, C.L., Kathardekar, V., Welsh, K.M., Webber, S., Matthews, D.A., Appelt, K., Smith, W.W., Janson, C.A., Villafranca, J.E., Bacquet, R.J., Howland, E.F., Booth, C.L., Herrmann, S.M., Ward, R.W., White, J., Moomaw, E.W., Bartlett, C.A., Morse, C.A. J. Med. Chem. (1996) [Pubmed]
  9. Structure-based design of substituted diphenyl sulfones and sulfoxides as lipophilic inhibitors of thymidylate synthase. Jones, T.R., Webber, S.E., Varney, M.D., Reddy, M.R., Lewis, K.K., Kathardekar, V., Mazdiyasni, H., Deal, J., Nguyen, D., Welsh, K.M., Webber, S., Johnston, A., Matthews, D.A., Smith, W.W., Janson, C.A., Bacquet, R.J., Howland, E.F., Booth, C.L., Herrmann, S.M., Ward, R.W., White, J., Bartlett, C.A., Morse, C.A. J. Med. Chem. (1997) [Pubmed]
  10. Gene expression in cells infected with gammaherpesvirus saimiri: properties of transcripts from two immediate-early genes. Nicholas, J., Smith, E.P., Coles, L., Honess, R. Virology (1990) [Pubmed]
  11. The ability of hypoxia to modify the gene expression of thymidylate synthase in tumour cells in vivo. Ehrnrooth, E., von der Maase, H., Sørensen, B.S., Poulsen, J.H., Horsman, M.R. Int. J. Radiat. Biol. (1999) [Pubmed]
  12. 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]
  13. Inverse gene expression of prostacyclin and thromboxane synthases in resident and activated peritoneal macrophages. Kuwamoto, S., Inoue, H., Tone, Y., Izumi, Y., Tanabe, T. FEBS Lett. (1997) [Pubmed]
  14. Multiple factors regulating the expression of human thromboxane synthase gene. Lee, K.D., Baek, S.J., Shen, R.F. Biochem. J. (1996) [Pubmed]
  15. Molecular cloning and expression of murine thromboxane synthase. Zhang, L., Chase, M.B., Shen, R.F. Biochem. Biophys. Res. Commun. (1993) [Pubmed]
  16. Modulation of both endogenous folates and thymidine enhance the therapeutic efficacy of thymidylate synthase inhibitors. van der Wilt, C.L., Backus, H.H., Smid, K., Comijn, L., Veerman, G., Wouters, D., Voorn, D.A., Priest, D.G., Bunni, M.A., Mitchell, F., Jackman, A.L., Jansen, G., Peters, G.J. Cancer Res. (2001) [Pubmed]
  17. ICI D1694, a quinazoline antifolate thymidylate synthase inhibitor that is a potent inhibitor of L1210 tumor cell growth in vitro and in vivo: a new agent for clinical study. Jackman, A.L., Taylor, G.A., Gibson, W., Kimbell, R., Brown, M., Calvert, A.H., Judson, I.R., Hughes, L.R. Cancer Res. (1991) [Pubmed]
  18. 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]
  19. Analysis of thymidylate synthase gene amplification and of mRNA levels in the cell cycle. Imam, A.M., Crossley, P.H., Jackman, A.L., Little, P.F. J. Biol. Chem. (1987) [Pubmed]
  20. Activin A and retinoic acid synergize in cyclooxygenase-1 and thromboxane synthase induction during differentiation of J774.1 macrophages. Nüsing, R.M., Mohr, S., Ullrich, V. Eur. J. Biochem. (1995) [Pubmed]
  21. Comparison of thymidylate synthase (TS) protein up-regulation after exposure to TS inhibitors in normal and tumor cell lines and tissues. Welsh, S.J., Titley, J., Brunton, L., Valenti, M., Monaghan, P., Jackman, A.L., Aherne, G.W. Clin. Cancer Res. (2000) [Pubmed]
  22. Schedule-dependent synergism of vinorelbine and 5-fluorouracil/UFT against non-small cell lung cancer. Matsumoto, S., Igishi, T., Hashimoto, K., Kodani, M., Shigeoka, Y., Nakanishi, H., Touge, H., Kurai, J., Makino, H., Takeda, K., Yasuda, K., Hitsuda, Y., Shimizu, E. Int. J. Oncol. (2004) [Pubmed]
  23. Experimental studies on potentiation of the antitumor activity of 5-fluorouracil with 3'-azido-3'-deoxythymidine for the gastric cancer cell line MKN28 in vivo. Yasuda, C., Kato, M., Kuroda, D., Ohyanagi, H. Jpn. J. Cancer Res. (1997) [Pubmed]
  24. S-1, an oral fluoropyrimidine, enhances radiation response of DLD-1/FU human colon cancer xenografts resistant to 5-FU. Nakata, E., Fukushima, M., Takai, Y., Nemoto, K., Ogawa, Y., Nomiya, T., Nakamura, Y., Milas, L., Yamada, S. Oncol. Rep. (2006) [Pubmed]
WikiGenes - Universities