Activation of deoxycytidine kinase by protein kinase inhibitors and okadaic acid in leukemic cells
| Autor: | Georges Van den Berghe, Sabine Cardoen, Anne Delacauw, Eric Van Den Neste, Caroline Smal, Françoise Bontemps, Luc Bertrand, Augustin Ferrant |
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| Rok vydání: | 2004 |
| Předmět: |
MAPK/ERK pathway
Antineoplastic Agents Protein Serine-Threonine Kinases Biology Biochemistry Protein Phosphatase 1 Deoxycytidine Kinase Okadaic Acid Phosphoprotein Phosphatases Tumor Cells Cultured medicine Humans Staurosporine Protein Phosphatase 2 Protein kinase A Nucleotide salvage Protein kinase C Pharmacology Leukemia Kinase Intracellular Signaling Peptides and Proteins Protein phosphatase 1 Deoxycytidine kinase Protein-Tyrosine Kinases Enzyme Activation Cancer research Cladribine Mitogen-Activated Protein Kinases Carrier Proteins medicine.drug |
| Zdroj: | Biochemical Pharmacology. 68:95-103 |
| ISSN: | 0006-2952 |
| Popis: | Deoxycytidine kinase (dCK) is a key enzyme in the deoxynucleoside salvage pathway and in the activation of numerous nucleoside analogues used in cancer and antiviral chemotherapy. Recent studies indicate that dCK activity might be regulated through reversible phosphorylation. Here, we report the effects of a large panel of protein kinase inhibitors on dCK activity in the B-leukemia cell line EHEB, both in basal conditions and in the presence of the nucleoside analogue 2-chloro-2'-deoxyadenosine (CdA) which induces activation of dCK. Except staurosporine and H-7 that significantly reduced the activation of dCK by CdA, no specific protein kinase inhibitor diminished basal dCK activity or its activation by CdA. In contrast, genistein, a general protein tyrosine kinase inhibitor, and AG-490, an inhibitor of JAK2 and JAK3, increased basal dCK activity more than two-fold. Two specific inhibitors of the MAPK/ERK pathway, PD-98059 and U-0126, also enhanced dCK activity. These data suggest that the JAK/MAPK pathway could be involved in the regulation of dCK. Moreover, we show that the activity of dCK, raised by CdA, can return to its initial level by treatment with protein phosphatase-2A (PP2A). Accordingly, dCK activity in intact cells increased upon incubation with okadaic acid (OA) at concentrations that should inhibit PP2A, but not protein phosphatase-1. Activation of dCK by protein kinase inhibitors and OA was also observed in CCRF-CEM cells and in chronic lymphocytic leukemia B-lymphocytes, suggesting a general mechanism of post-translational regulation of dCK, which could be exploited to enhance the activation of antileukemic nucleoside analogues. |
| Databáze: | OpenAIRE |
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