Overexpression of human thymidine kinase mRNA without corresponding enzymatic activity in patients with chronic lymphatic leukemia

Kristensen, Tina; Jensen, Helle Kock; Munch‐Petersen, Birgitte

doi:10.1016/0145-2126(94)90168-6

Cited by 16 publications

(10 citation statements)

References 25 publications

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“…It was indeed shown that CLL cells displayed RNA processing abnormalities (54,55). Strikingly, thymidine kinase mRNA is 100-fold higher in CLL than in normal lymphocytes without the corresponding enzymatic activity (56). These results are relevant to what we observed in CD5 ϩ cells, which may help our understanding of how the lack of ribosomal and mRNA processing and trafficking leading to the accumulation of abnormal RNAs in the nucleus might disturb the cell's normal feedback systems or generate abnormal proteins, thereby favoring the development of malignant conditions.…”

Section: Discussionmentioning

confidence: 99%

Natural Phosphorylation of CD5 in Chronic Lymphocytic Leukemia B Cells and Analysis of CD5-Regulated Genes in a B Cell Line Suggest a Role for CD5 in Malignant Phenotype

Gary-Gouy

Sainz-Perez

Marteau

et al. 2007

The Journal of Immunology

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Section: Discussionmentioning

confidence: 99%

Natural Phosphorylation of CD5 in Chronic Lymphocytic Leukemia B Cells and Analysis of CD5-Regulated Genes in a B Cell Line Suggest a Role for CD5 in Malignant Phenotype

Gary-Gouy

Sainz-Perez

Marteau

et al. 2007

The Journal of Immunology

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“…TK is a cellular enzyme involved in a DNA synthesis salvage pathway, and its levels are directly correlated with tumor cell proliferation [4,7]. Both IL2R and TK1 genes are overexpressed in several human leukemia cases [2,9]; however, there are no reports available for bovine leukosis. In the present case, these 2 genes showed increased expression compared to control cattle.…”

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confidence: 99%

Calf Form Bovine Leukosis with Lameness in a Holstein Heifer

Tawfeeq

Miura

Nakanishi

et al. 2012

The Journal of Veterinary Medical Science

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ABSTRACT. A 12-month-old Holstein heifer with anorexia, lameness, and enlargement of peripheral lymph nodes was suspected of having bovine leukosis. Although lymphocytosis was not observed, cytology of fine needle aspirate from a superficial cervical node, and increased serum lactate dehydrogenase and thymidine kinase activities, strongly suggested lymphosarcoma. Increased numbers of mononuclear cells as well as mitotic cells were observed in synovial fluid collected from swollen joints. Pathological examination confirmed B-cell calf form bovine leukosis and joint swelling related to neoplastic cell infiltration. Both interleukin-2 receptor and thymidine kinase 1 genes were highly expressed in cells from superficial cervical lymph node aspirate. KEY WORDS: calf form bovine leukosis, gene expression, joint infiltration.doi: 10.1292/jvms.12-0090; J. Vet. Med. Sci. 74(9): 1225-1228, 2012 Bovine leukosis is one of the most common neoplasms detected in dairy cattle and is generally divided into 2 types: enzootic bovine leukosis caused by bovine leukemia virus (BLV) and sporadic bovine leukosis, which has not known cause and does not appear to have any association with BLV [1]. The sporadic form of bovine leukosis can be further subdivided into calf, juvenile/thymic, and cutaneous forms [3,15]. Thymic and calf forms of leukosis can affect calves and heifers from birth up to 18 months of age [15]. Younger cattle are generally affected by the B-cell calf form [15,17]. The most obvious clinical sign of the calf form is diffuse lymphadenopathy that results in obvious and palpable enlargement of peripheral lymph nodes [3]. Tumor cells often infiltrate many organs, including the thymus, lymph nodes, liver, spleen, lung, bone marrow, mammary gland, salivary gland, gall bladder, adrenal gland, and pancreas [11]. Ataxia is another common clinical sign of the calf form, because tumor cells often invade the central nervous system [11,14]. However, tumor cell infiltration into the musculoskeletal system, such as muscles and joints, is not common in the calf form. In this report, we describe a clinical case of calf form bovine leukosis with lameness and joint swelling related to neoplastic cell infiltration in a Holstein heifer. Additionally, we evaluated enzymatic activity and gene expression related to leukosis as biomarker candidates for the onset of bovine leukosis.A 12-month-old Holstein heifer presented with anorexia and lameness. At initial examination, the heifer had a body temperature of 38.8°C and heart rate of 108 beats/min (bpm). Diffuse lymphadenopathy was noted. Despite treatment with antibiotics and dexamethasone, the general condition of the heifer did not improve. The heifer was taken to the Veterinary Teaching Hospital at Obihiro University of Agriculture and Veterinary Medicine on day 9. Upon admission, emaciation, depression, lameness, abdominal posture − standing under, and swollen carpal and tarsal joints were noted (Fig. 1). Rectal temperature was 39.9°C, heart rate was 120 bpm, and respiratory rate was 56 b...

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“…Its activity fluctuates with DNA synthesis, being high in dividing and malignant cells and low in quiescent cells (4,5). The expression of TK1 is meticulously controlled on the transcriptional and post-transcriptional level (6,7).…”

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Valine, Not Methionine, Is Amino Acid 106 in Human Cytosolic Thymidine Kinase (TK1)

Berenstein

Christensen

Kristensen

et al. 2000

Journal of Biological Chemistry

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(t1 ⁄2 at 15°C is 41 and 392 min, respectively). Because valine with high probability is the naturally occurring amino acid at position 106 in human TK1 and because this position has high impact on the enzyme properties, the Val-106 form should be used in future investigations of recombinant human TK1.The human cytosolic thymidine kinase, TK1 (EC 2.7.1.21), is a key enzyme in the salvage synthesis of TMP from thymidine. Intracellular TMP is quickly phosphorylated to TDP and TTP. Because TTP is an allosteric effector of ribonucleotide reductase, imbalances in the TTP pool disturb the supply of both purines and pyrimidines for DNA synthesis and repair. In turn, imbalanced deoxynucleoside triphosphate (dNTP) pools increase the mutation rate and probability of carcinogenesis (1-3).TK1 is a cell cycle-regulated enzyme. Its activity fluctuates with DNA synthesis, being high in dividing and malignant cells and low in quiescent cells (4, 5). The expression of TK1 is meticulously controlled on the transcriptional and post-transcriptional level (6, 7). At the enzymatic level, ATP, besides being a cosubstrate, has been shown to be a regulator of the catalytic activity of TK1 (8). Thus, exposure to ATP induces a reversible enzyme concentration-dependent transition from a low thymidine affinity dimer of about 50 kDa (K m ϭ 15 M) to a high affinity tetramer (K m ϭ 0.7 M). To further investigate the effect of ATP, we constructed a pET3a-TK1 plasmid (9) containing the amino acid coding region of TK1 cDNA from the pTK11 plasmid of Bradshaw and Deininger (10), who had used SV40 transformed human fibroblasts as the mRNA source. We expressed the resulting recombinant TK1 (rTFi-TK1) in Escherichia coli, and purified and characterized the enzyme. To our surprise we found that the enzymatic properties of rTFi-TK1 differed markedly from those of the endogenous Ly-TK1 with respect to the regulatory effect of ATP (9). Irrespective of preexposure to ATP, the recombinant rTFi-TK1 was a permanent tetramer of about 100 kDa with high affinity to thymidine with a K m value about 0.4 M (9). At that time, we assumed that the amino acid sequences of rTFi-TK1 and Ly-TK1 were identical and explained the divergent properties of rTFi-TK1 by the absence of post-translational modification of TK1 when expressed in E. coli (9). Because the pET3a-TK1 expression system was not satisfactory in terms of amount of TK1 protein produced, we constructed another expression plasmid, pGEX-2T-LyTK1. Here, the amino acid coding region of TK1 from normal human lymphocytes was cloned into the pGEX-2T vector, and the recombinant TK1 was expressed as an isopropyl-1-thio-␤-D-galactopyranoside-inducible glutathione S-transferase fusion protein. In contrast to the findings with rTFi-TK1, our preliminary kinetic experiments showed that the recombinant lymphocyte TK1 (rLy-TK1) 1 behaved essentially as the endogenous lymphocyte enzyme, Ly-TK1, regarding kinetic and oligomerization properties. Therefore, absence of posttranslational modification of rTFi-TK1 in E. coli cannot ex...

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Overexpression of human thymidine kinase mRNA without corresponding enzymatic activity in patients with chronic lymphatic leukemia

Cited by 16 publications

References 25 publications

Natural Phosphorylation of CD5 in Chronic Lymphocytic Leukemia B Cells and Analysis of CD5-Regulated Genes in a B Cell Line Suggest a Role for CD5 in Malignant Phenotype

Natural Phosphorylation of CD5 in Chronic Lymphocytic Leukemia B Cells and Analysis of CD5-Regulated Genes in a B Cell Line Suggest a Role for CD5 in Malignant Phenotype

Calf Form Bovine Leukosis with Lameness in a Holstein Heifer

Valine, Not Methionine, Is Amino Acid 106 in Human Cytosolic Thymidine Kinase (TK1)

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