Deoxycytidine kinase is constitutively expressed in human lymphocytes: Consequences for compartmentation effects, unscheduled dna synthesis, and viral replication in resting cells

Arnér, Elias S.J.; Flygar, Martin; Bohman, Christina; Wallström, Birgitta; Eriksson, Staffan

doi:10.1016/0014-4827(88)90403-x

Cited by 58 publications

(13 citation statements)

References 21 publications

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“…Although E2F may play a role in basal dCK expression, there is no evidence to support the cell cycle-specific regulation of dCK transcription. Arner et al have shown that dCK specific activity is constitutively high and does not increase by more than twofold during the cell cycle using resting and activated peripheral blood lymphocytes or elutriated CEM T lymphoblasts (15,48 ( 19,20). Double mutations of the E2F sites in cellular genes abolish GI /S regulation either by preventing GI/ S induction (51)(52)(53) or by making the promoter constitutively active (54)(55)(56)(57).…”

Section: Resultsmentioning

confidence: 99%

Characterization of the deoxycytidine kinase promoter in human lymphoblast cell lines.

Chen¹,

Johnson²,

Vetter³

et al. 1995

J. Clin. Invest.

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Deoxycytidine kinase (dCK) phosphorylates 2'-deoxycytidine, as well as the purine deoxyribonucleosides and a number of nucleoside analogues that are important in the chemotherapy of leukemias. The enzyme is highly expressed in the thymus relative to other tissues and may play an important role in the T cell depletion associated with adenosine deaminase and purine nucleoside phosphorylase deficiencies. To characterize the dCK promoter region and to determine whether it mediates higher levels of gene expression in T lymphoblasts, we have analyzed a 700-bp genomic fragment encompassing 548 bp of 5' flanking region for functional activity and for transcription factor binding using T and B lymphoblast cell lines and nuclear extracts. The regions of the promoter that were defined as important to its function include a 5'GC box, an E box, a 3'GC box, and an E2F site. The transcription factor Spl binds to both GC boxes, activating at the 5' site but repressing at the 3' site. MLTF/ USF activates transcription through the E box, whereas E2F activates through the E2F site, but binds weakly to this site in vitro and does not appear to mediate cell cycle-specific expression of dCK in vivo. No significant differences in promoter activity or transcription factor binding were observed between Jurkat T and Raji B lymphoblasts. The promoter of the dCK gene is thus regulated by a number of ubiquitously expressed transcription factors. DCK expression in cultured lymphoblast cell lines is not solely a function of the T or B lineage derivation. (J. Clin. Invest. 1995. '95:1660-1668

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Section: Resultsmentioning

confidence: 99%

Characterization of the deoxycytidine kinase promoter in human lymphoblast cell lines.

Chen¹,

Johnson²,

Vetter³

et al. 1995

J. Clin. Invest.

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“…One important physiological function of dCK is considered to be in providing cells with deoxyribonucleotides for DNA repair (24). The role of dGK would be to provide deoxyribonucleotides for mitochondrial DNA synthesis together with the other mitochondrial nucleoside kinase; thymidine kinase 2.…”

Section: Discussionmentioning

confidence: 99%

Cloning and expression of human deoxyguanosine kinase cDNA.

Johansson

Karlsson

1996

Proc. Natl. Acad. Sci. U.S.A.

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A human cDNA sequence homologous to human deoxycytidine kinase (dCK; EC 2.7.1.74) was identified in the GenBank sequence data base. The longest open reading frame encoded a protein that was 48% identical to dCK at the amino acid level. The cDNA was expressed in Escherichia coli and shown to encode a protein with the same substrate specificity as described for the mitochondrial deoxyguanosine kinase (dGK; EC 2.7.1.113). The N terminus of the deduced amino acid sequence had properties characteristic for a mitochondrial translocation signal, and cleavage at a putative mitochondrial peptidase cleavage site would give a mature protein size of 28 kDa. Northern blot analysis determined the length of dGK mRNA to 1.3 kbp with no cross-hybridization to the 2.8-kbp dCK mRNA. dGK mRNA was detected in all tissues investigated with the highest expression levels in muscle, brain, liver, and lymphoid tissues. Alignment of the dGK and herpes simplex virus type 1 thymidine kinase amino acid sequences showed that five regions, including the substrate-binding pocket and the ATP-binding glycine loop, were also conserved in dGK. To our knowledge, this is the first report of a cloned mitochondrial nucleoside kinase and the first demonstration of a general sequence homology between two mammalian deoxyribonucleoside kinases. Our findings suggest that dCK and dGK are evolutionarily related, as well as related to the family of herpes virus thymidine kinases.

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“…[99][100][101] The dCK activity is high in quiescent cells in which it phosphorylates nucleosides necessary for DNA repair and, depending on the cell type, may increase several-fold when the cells enter the S-phase of the cell cycle. [102][103][104][105] Deoxycytidine kinase activity has been shown to be decreased or absent in different cell lines resistant to NA. [106][107][108][109] Transfection of the dCK gene in dCK-deficient tumor cell lines restores in vitro sensitivity to ara-C. 110,111 Moreover, in vitro models have shown crossresistance between 2-CdA, gemcitabine, fludarabine and ara-C with reduced dCK activity as the underlying determinant of resistance.…”

Section: Deoxycytidine Kinasementioning

confidence: 99%