Selective increase of dATP pools upon activation of deoxycytidine kinase in lymphocytes: implications in apoptosis.
Stimulation of the activity of deoxycytidine kinase (dCK), the principal deoxynucleoside salvage enzyme, has been recently considered as a protective cellular response to a wide range of agents interfering with DNA repair and apoptosis. In light of this, the potential contribution of dCK activation to apoptosis induction--presumably by supplying dATP or its analogues for the apoptosome formation--deserves consideration. Two-hour exposure of human tonsillar lymphocytes to 2-chloro-deoxyadenosine (CdA) led to a two-fold activation of dCK. This activation process was inhibited by pifithrin-alpha, a potent inhibitor of p53. When the dNTP pools were determined, both deoxypyrimidine triphosphate and dGTP pools were reduced after the treatments, while dATP levels elevated by 62%, 77% and 50% in the CdA, aphidicolin and etoposide-treated cells, respectively. We assume that dCK activation elicited by cellular damage might be a proapoptotic factor in terms of generating dATP well before the release of cytochrome c and deoxyguanosine kinase from mitochondria.
Keszler
Gergely
G
Institute of Medical Chemistry, Molecular Biology and Pathobiochemistry, Semmelweis University, Budapest, Hungary.
Spasokoukotskaja
Tatjana
T
Csapo
Zsolt
Z
Virga
Szula
S
Staub
Maria
M
Sasvari-Szekely
Maria
M
D000255:Adenosine Triphosphate / Q000737:chemistry* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D052160:Benzothiazoles; D002478:Cells, Cultured; D017338:Cladribine / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004260:DNA Repair; D003842:Deoxycytidine Kinase / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D006801:Humans; D008214:Lymphocytes / Q000201:enzymology* / Q000473:pathology; D008954:Models, Biological; D014066:Palatine Tonsil / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D013844:Thiazoles / Q000378:metabolism; D014050:Toluene / Q000031:analogs & derivatives* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000970:Antineoplastic Agents; D052160:Benzothiazoles; D013844:Thiazoles; D016159:Tumor Suppressor Protein p53; D014050:Toluene; D017338:Cladribine; D000255:Adenosine Triphosphate; D045304:Cytochromes c; C121565:pifithrin; D017853:Phosphotransferases (Alcohol Group Acceptor); C019165:deoxyguanosine kinase; D003842:Deoxycytidine Kinase