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Gene Review

TK1  -  thymidine kinase 1, soluble

Homo sapiens

Synonyms: Thymidine kinase, cytosolic
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Disease relevance of TK1

  • The low levels of TK1 and dTMPK in lymphocytes from HIV-infected patients may be related to the anergy phenomenon observed as a result of HIV infection [1].
  • The levels of expression of all the examined genes in leukocytes from patients with either Graves' or Hashimoto's disease were significantly increased when compared to those in controls; above a twofold elevation of expression of TK1, ADA4, and ADA5 genes was observed [2].
  • We conclude that TK1 might be a more accurate marker than PCNA for estimation of cell proliferation and malignant potentials in breast carcinomas [3].
  • Single high dose rate irradiation of 4 Gy in SW-1573 cells, derived from non-small cell lung cancer, led to increased activities of deoxycytidine kinase (dCK) and thymidine kinase 1 and 2 (TK1 and 2) [4].
  • We have now determined the structures of the TK1 family, the human and Ureaplasma urealyticum enzymes, in complex with the feedback inhibitor dTTP [5].

High impact information on TK1

  • We now report the isolation of a complementary DNA that, on transfection into COS cells, encodes immunoreactive addressin that specifically binds the mucosal HEV-binding T-cell lymphoma TK1 [6].
  • These results have important implications for DNA damage signaling and CHK2-dependent tumor suppression, and they indicate that FHA domains play important and unsuspected roles in S/T kinase signaling mechanisms in prokaryotes and eukaryotes [7].
  • Mammals have four deoxyribonucleoside kinases, the cytoplasmic (TK1) and mitochondrial (TK2) thymidine kinases, and the deoxycytidine (dCK) and deoxyguanosine (dGK) kinases, which salvage the precursors for nucleic acids synthesis [8].
  • RESULTS: Total TK (TK1 plus TK2) levels in tumors were significantly (P < .001) elevated in patients who subsequently had recurrence compared with levels in those who did not [9].
  • With measurement of levels of TK, particularly TK1, in breast tumors and serum, it may be possible to predict recurrence of breast cancer [9].

Chemical compound and disease context of TK1


Biological context of TK1


Anatomical context of TK1


Associations of TK1 with chemical compounds

  • Study of cellular mechanisms responsible for cross-resistance to pyrimidine analogs in AZT-resistant H9 cells revealed decreased mRNA levels of thymidine kinase 1 (TK1) and lack of deoxycytidine kinase (dCK) mRNA expression [20].
  • The anti-HIV analogue zidovudine (AZT) is phosphorylated by cytosolic thymidine kinase 1 (TK1), thymidylate kinase (dTMPK), and nucleoside diphosphate kinase [1].
  • In conclusion, thymidine is not only a substrate of TK1 but also acts as its expression regulator by modulating its proteolytic control during mitotic exit, conferring a feed-forward regulation of dTTP formation [13].
  • Cytosolic thymidine kinase 1, TK1, is a well known cell-cycle-regulated enzyme of importance in nucleotide metabolism as well as an activator of antiviral and anticancer drugs such as 3'-azido-3'-deoxythymidine (AZT) [5].
  • With TK1, the Km values for 5-fluorodeoxyuridine (FdUrd), 3'-azido-2',3'-dideoxythymidine (AZT), and 3'-fluoro-2',3'-dideoxythymidine (FLT) were 2.2, 0.6, and 2.1 microM as compared to 0.5 microM for dThd and 9 microM for deoxyuridine (dUrd) [21].

Physical interactions of TK1

  • In contrast, mutant-type hTK1 protein defective in thymidine binding ability could still be polyubiquitinated by APC/C-Cdh1 in the presence of thymidine [13].

Enzymatic interactions of TK1

  • Tightly adsorbed fractions possessed high troponin T kinase and phosvitin kinase activities and phosphorylated only serine-1 of troponin T. The results suggest that standard preparations of phosphorylase kinase are contaminated by troponin T kinase, which can phosphorylate serine-1 of troponin T [22].

Regulatory relationships of TK1

  • Taken together, we concluded that activation of the APC/C-Cdh1 complex during mitotic exit controls timing of hTK1 destruction, thus effectively minimizing dTTP formation from the salvage pathway in the early G(1) phase of the cell cycle in mammalian cells [23].
  • In mammalian cells, salvage pathway phosphorylation of thymidine is catalyzed by two thymidine kinases: the cell-cycle regulated cytoplasmic TK1 and the constitutively expressed mitochondrial TK2 [10].
  • We demonstrated previously that overexpression of BCL-2 or BCL-x(L) enhanced the frequency of X-ray-induced TK1 mutations, including loss of heterozygosity events presumed to arise by mitotic recombination [24].

Other interactions of TK1

  • However, overexpression of TK1 overcame p21(Waf1)-mediated growth suppression and blocked the association of CDK2 with p21(Waf1), suggesting that TK1 interferes with the inhibitory function of p21(Waf1) [25].
  • Using the mAb 1E3, a significantly higher TK1 labeling index (LI) of AC patients was found (68%) compared to the LI of Ki-67 (36%) [26].
  • The TK1-labelling index (TK1-LI) and PCNA-labeling index (PCNA-LI) were significantly higher in malignant lesions than in nonmalignant lesions (p < 0.0001 and p < 0.0013, respectively) [3].
  • With TK1 and TK2, similar sugar-modified analogues of dU and dT were feeble substrates [27].
  • These results suggest that the status of thymidine binding to hTK1 protein determines its susceptibility to degradation due to APC/C targeting [13].

Analytical, diagnostic and therapeutic context of TK1

  • Differences in in vitro activation, as determined by flow cytometry, of the peripheral lymphocytes were not responsible for the decreased TK1 and dTMPK activities [1].
  • To explore the expression of cytosolic thymidine kinase 1 (TK1) as a cell proliferative marker in human breast cancers, immunohistochemistry was used to detect the expression of TK1 in 52 malignant breast lesions, 20 benign breast lesions, and 16 normal breast tissues [3].
  • We identified human thymidine kinase 1 (TK1), which is cell cycle regulatory gene and confirmed expression of TK1 mRNA by Northern blot analysis [15].
  • Tumor levels of TK1 protein and cofactor (ATP) were determined by Western blotting and bioluminescence, respectively [28].
  • CONCLUSION: The TK1 enzyme-labeled immunoassay uses a stable substrate, is precise, appears to be accurate, and is resistant to interferences [29].


  1. Decrease in thymidylate kinase activity in peripheral blood mononuclear cells from HIV-infected individuals. Jacobsson, B., Britton, S., Törnevik, Y., Eriksson, S. Biochem. Pharmacol. (1998) [Pubmed]
  2. Expression of genes for certain enzymes of pyrimidine and purine salvage pathway in peripheral blood leukocytes collected from patients with Graves' or Hashimoto's disease. Karbownik, M., Brzeziańska, E., Zasada, K., Lewiński, A. J. Cell. Biochem. (2003) [Pubmed]
  3. A comparative study: immunohistochemical detection of cytosolic thymidine kinase and proliferating cell nuclear antigen in breast cancer. Mao, Y., Wu, J., Wang, N., He, L., Wu, C., He, Q., Skog, S. Cancer Invest. (2002) [Pubmed]
  4. Time course of enhanced activity of deoxycytidine kinase and thymidine kinase 1 and 2 in cultured human squamous lung carcinoma cells, SW-1573, induced by gamma-irradiation. Haveman, J., Sigmond, J., van Bree, C., Franken, N.A., Koedooder, C., Peters, G.J. Oncol. Rep. (2006) [Pubmed]
  5. Structures of thymidine kinase 1 of human and mycoplasmic origin. Welin, M., Kosinska, U., Mikkelsen, N.E., Carnrot, C., Zhu, C., Wang, L., Eriksson, S., Munch-Petersen, B., Eklund, H. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  6. MAdCAM-1 has homology to immunoglobulin and mucin-like adhesion receptors and to IgA1. Briskin, M.J., McEvoy, L.M., Butcher, E.C. Nature (1993) [Pubmed]
  7. The molecular basis of FHA domain:phosphopeptide binding specificity and implications for phospho-dependent signaling mechanisms. Durocher, D., Taylor, I.A., Sarbassova, D., Haire, L.F., Westcott, S.L., Jackson, S.P., Smerdon, S.J., Yaffe, M.B. Mol. Cell (2000) [Pubmed]
  8. Deoxyribonucleoside kinases: two enzyme families catalyze the same reaction. Sandrini, M.P., Piskur, J. Trends Biochem. Sci. (2005) [Pubmed]
  9. Can thymidine kinase levels in breast tumors predict disease recurrence? O'Neill, K.L., Hoper, M., Odling-Smee, G.W. J. Natl. Cancer Inst. (1992) [Pubmed]
  10. Human thymidine kinase 1. Regulation in normal and malignant cells. Munch-Petersen, B., Cloos, L., Jensen, H.K., Tyrsted, G. Adv. Enzyme Regul. (1995) [Pubmed]
  11. A pseudoreceptor modelling study of the varicella-zoster virus and human thymidine kinase binding sites. Greenidge, P.A., Merz, A., Folkers, G. J. Comput. Aided Mol. Des. (1995) [Pubmed]
  12. Thymidine kinase in epithelial ovarian cancer: relationship with the other pyrimidine pathway enzymes. Fujiwaki, R., Hata, K., Nakayama, K., Moriyama, M., Iwanari, O., Katabuchi, H., Okamura, H., Sakai, E., Miyazaki, K. Int. J. Cancer (2002) [Pubmed]
  13. Hiding human thymidine kinase 1 from APC/C-mediated destruction by thymidine binding. Ke, P.Y., Hu, C.M., Chang, Y.C., Chang, Z.F. FASEB J. (2007) [Pubmed]
  14. Serine 13 is the site of mitotic phosphorylation of human thymidine kinase. Chang, Z.F., Huang, D.Y., Chi, L.M. J. Biol. Chem. (1998) [Pubmed]
  15. The modulation of radiation-induced cell death by genistein in K562 cells: activation of thymidine kinase 1. Jeong, M.H., Jin, Y.H., Kang, E.Y., Jo, W.S., Park, H.T., Lee, J.D., Yoo, Y.J., Jeong, S.J. Cell Res. (2004) [Pubmed]
  16. Increased expression of mRNA specific for thymidine kinase, deoxycytidine kinase or thymidine phosphorylase in human papillary thyroid carcinoma. Karbownik, M., Brzezianska, E., Lewinski, A. Cancer Lett. (2005) [Pubmed]
  17. Thymidine and 3'-azido-3'-deoxythymidine metabolism in human peripheral blood lymphocytes and monocyte-derived macrophages. A study of both anabolic and catabolic pathways. Arnér, E.S., Valentin, A., Eriksson, S. J. Biol. Chem. (1992) [Pubmed]
  18. Bromovinyl-deoxyuridine: A selective substrate for mitochondrial thymidine kinase in cell extracts. Franzolin, E., Rampazzo, C., Pérez-Pérez, M.J., Hernández, A.I., Balzarini, J., Bianchi, V. Biochem. Biophys. Res. Commun. (2006) [Pubmed]
  19. S-acyl-2-thioethyl (SATE) pronucleotides are potent inhibitors of HIV-1 replication in T-lymphoid cells cross-resistant to deoxycytidine and thymidine analogs. Gröschel, B., Cinatl, J., Périgaud, C., Gosselin, G., Imbach, J.L., Doerr, H.W., Cinatl, J. Antiviral Res. (2002) [Pubmed]
  20. 3'-Azido-2',3'-dideoxythymidine induced deficiency of thymidine kinases 1, 2 and deoxycytidine kinase in H9 T-lymphoid cells. Gröschel, B., Kaufmann, A., Höver, G., Cinatl, J., Doerr, H.W., Noordhuis, P., Loves, W.J., Peters, G.J., Cinatl, J. Biochem. Pharmacol. (2002) [Pubmed]
  21. Diverging substrate specificity of pure human thymidine kinases 1 and 2 against antiviral dideoxynucleosides. Munch-Petersen, B., Cloos, L., Tyrsted, G., Eriksson, S. J. Biol. Chem. (1991) [Pubmed]
  22. Phosphorylase kinase phosphorylation of skeletal-muscle troponin T. Risnik, V.V., Dobrovolskii, A.B., Gusev, N.B., Severin, S.E. Biochem. J. (1980) [Pubmed]
  23. Mitotic degradation of human thymidine kinase 1 is dependent on the anaphase-promoting complex/cyclosome-CDH1-mediated pathway. Ke, P.Y., Chang, Z.F. Mol. Cell. Biol. (2004) [Pubmed]
  24. Gene conversion is strongly induced in human cells by double-strand breaks and is modulated by the expression of BCL-x(L). Wiese, C., Pierce, A.J., Gauny, S.S., Jasin, M., Kronenberg, A. Cancer Res. (2002) [Pubmed]
  25. Interaction of human thymidine kinase 1 with p21(Waf1). Huang, D.Y., Chang, Z.F. Biochem. J. (2001) [Pubmed]
  26. Expression of cell proliferating genes in patients with non-small cell lung cancer by immunohistochemistry and cDNA profiling. Mao, Y., Wu, J., Skog, S., Eriksson, S., Zhao, Y., Zhou, J., He, Q. Oncol. Rep. (2005) [Pubmed]
  27. Substrate/inhibitor specificities of human deoxycytidine kinase (dCK) and thymidine kinases (TK1 and TK2). Kierdaszuk, B., Krawiec, K., Kazimierczuk, Z., Jacobsson, U., Johansson, N.G., Munch-Petersen, B., Eriksson, S., Shugar, D. Adv. Exp. Med. Biol. (1998) [Pubmed]
  28. 3'-deoxy-3'-[18F]fluorothymidine as a new marker for monitoring tumor response to antiproliferative therapy in vivo with positron emission tomography. Barthel, H., Cleij, M.C., Collingridge, D.R., Hutchinson, O.C., Osman, S., He, Q., Luthra, S.K., Brady, F., Price, P.M., Aboagye, E.O. Cancer Res. (2003) [Pubmed]
  29. Sensitive nonradiometric method for determining thymidine kinase 1 activity. Ohrvik, A., Lindh, M., Einarsson, R., Grassi, J., Eriksson, S. Clin. Chem. (2004) [Pubmed]
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