title: Overexpression of a heterologous thymidine kinase delays apoptosis induced by factor deprivation and inhibitors of deoxynucleotide metabolism.
abstract: Perturbing deoxyribonucleoside triphosphate (dNTP) metabolism with inhibitors of the de novo synthesis of dNTP causes apoptosis in the interleukin-3 (IL-3)-dependent pre-B cell line BAF3. Under these conditions apoptosis is prevented when deoxyribonucleosides for dNTP synthesis are supplied in the culture medium. On the other hand, removal of IL-3 from cultures of BAF3 cells resulted in down-regulation of thymidine kinase activity, rapid imbalance in dNTP levels, and apoptosis. In this study we show that overexpression of a heterologous thymidine kinase, herpes simplex virus thymidine kinase (TK), in BAF3 cells protects these cells from apoptosis induced by either inhibitors of dNTP synthesis or IL-3 deprivation. This protection against apoptosis is abrogated by 9-(4-hydroxybutyl)-N2-phenylguanine, a specific inhibitor of herpes simplex virus-1 TK. These results suggest that deoxyribonucleoside kinases, particularly TK, may be important in the regulation of apoptosis in hemopoietic cells.
authors.affiliation: Instituto de Parasitología y Biomedicina, Consejo Superior de Investigaciones Científicas, 18001 Granada, Spain.
authors.forename: F J
authors.initials: FJ
authors.lastname: Oliver
authors.forename: M K
authors.initials: MK
authors.lastname: Collins
authors.forename: A
authors.initials: A
authors.lastname: López-Rivas
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D017077:Culture Media, Conditioned; D003854:Deoxyribonucleotides / Q000378:metabolism / Q000494:pharmacology; D005467:Floxuridine / Q000494:pharmacology; D018259:Herpesvirus 1, Human / Q000201:enzymology; D006918:Hydroxyurea / Q000494:pharmacology; D007377:Interleukin-3 / Q000494:pharmacology*; D007700:Kinetics; D008727:Methotrexate / Q000494:pharmacology; D051379:Mice; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000378:metabolism; D013937:Thymidine Kinase / Q000096:biosynthesis* / Q000378:metabolism; D014162:Transfection
chemical_list: D017077:Culture Media, Conditioned; D003854:Deoxyribonucleotides; D007377:Interleukin-3; D019384:Nucleic Acid Synthesis Inhibitors; D011994:Recombinant Proteins; D005467:Floxuridine; D013937:Thymidine Kinase; D006918:Hydroxyurea; D008727:Methotrexate