Inhibition of deoxynucleoside kinases in human thymocytes prevents dATP accumulation and induction of apoptosis.
Thymocytes lacking adenosine deaminase (ADA) activity, a purine metabolism enzyme, accumulate intracellular dATP and consequently undergo apoptosis during development. We have analyzed the effect of ADA enzyme inhibition in human thymocyte suspension cultures with regard to accumulation of intracellular dATP and induction of apoptosis. We demonstrate that while inhibition of deoxycytidine kinase will prevent the accumulation of dATP and induction of apoptosis to a large degree, inhibition of both deoxycytidine kinase and adenosine kinase completely abrogates the accumulation of dATP and significantly reduces the induction of apoptosis. Thus, both deoxynucleoside kinases are involved in this model of ADA deficiency.
Joachims
Michelle L
ML
Department of Immunobiology and Cancer, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104, USA. Michelle-Joachims@omrf.org
Marble
Patrick
P
Knott-Craig
Christopher
C
Pastuszko
Peter
P
Blackburn
Michael R
MR
Thompson
Linda F
LF
D000243:Adenosine Deaminase / Q000172:deficiency / Q000378:metabolism; D058892:Adenosine Deaminase Inhibitors; D000248:Adenosine Kinase / Q000037:antagonists & inhibitors*; D018952:Antigens, CD34 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D003838:Deoxyadenine Nucleotides / Q000378:metabolism*; D003842:Deoxycytidine Kinase / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007223:Infant; D054504:Precursor Cells, T-Lymphoid / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology* / Q000187:drug effects / Q000254:growth & development
D058892:Adenosine Deaminase Inhibitors; D018952:Antigens, CD34; D003838:Deoxyadenine Nucleotides; D004791:Enzyme Inhibitors; D000248:Adenosine Kinase; D003842:Deoxycytidine Kinase; D000243:Adenosine Deaminase; C026600:2'-deoxyadenosine triphosphate