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

• To study the ATP effect on the molecular level, an IPTG inducible T7 RNA polymerase-dependent expression system for the entire human TK1 polypeptide in E. coli was established [10].
• A representative range of pyrimidine nucleoside analogues that are known to inhibit herpes simplex virus (HSV) replication have been used to construct receptor binding site models for the varicella-zoster virus (VZV) thymidine kinase (TK) and human TK1 [11].

Biological context of TK1

• Patients with high-TK1 gene expression had a significantly poorer survival than those with low TK1 gene expression [12].
• The increase in activity of both dCK, and TK1 and 2 might be involved in an adaptive response of the cells to radiation by facilitation of DNA repair [4].
• Moreover, exposure of mitotic-arrested K562 cells to thymidine (100 microM) stabilized endogenous TK1, causing nucleotide imbalance in the early G1 phase and an increase of S phase accumulation [13].
• Thus, Cdc2 or related kinase(s) is probably involved in mitotic phosphorylation on Ser13 of the hTK1 polypeptide [14].
• These results suggest that the activation of TK1 may be critical to modulate the radiation-induced cell death and cell cycle progression in irradiated K562 cells [15].

Anatomical context of TK1

• It is concluded that an increased expression of mRNA, specific for TK1, dCK and dThdPase, may be involved in carcinogenic processes in the human thyroid [16].
• The fact that TK2 and not TK1 phosphorylates AZT in macrophages should have important implications for combination chemotherapy [17].
• When cultured human fibroblasts passed from proliferation to quiescence TK2 activity increased by 3-fold, stressing the importance of TK2 function in the absence of TK1 [18].
• Surprisingly, we did not observe any effect of ATP on TK1 purified from bone-marrow cells from a patient with acute monocytic leukemia (AMOL) [10].
• In this cell line, expression of deoxycytidine kinase (dCK) and thymidine kinase 1 (TK1) was decreased in comparison to parental cells (3.8 and 2.9-fold, respectively) [19].

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].

References