Abstract
NB4 cells are the only bona fide in vitro model of human acute promyelocytic leukemia. We have examined cytidine and guanosine transport in this cell line and characterized a novel guanosine-specific transporter. Cytidine transport occurred predominately by equilibrative nitrobenzylthioinosine (NBMPR)-sensitive (es) transport. In the presence of Na+, guanosine at various concentrations accumulated at least 6-fold above equilibrium. The initial rate of guanosine transport in Na+ buffer decreased by 75% with the addition of 1 microM NBMPR and the IC50 for NBMPR inhibition was 0.7 +/- 0.1 nM. Replacement of Na+ with choline also resulted in a 75% decrease in total guanosine transport. The potent inhibition of guanosine transport by NBMPR and the loss of transport in choline suggested that a Na+-dependent NBMPR-sensitive transporter was responsible for the majority of guanosine uptake. This concentrative, sensitive transporter is Na+ dependent with a stoichiometric coupling ratio of 1:1. This novel transporter, referred to as csg, is guanosine-specific with total guanosine transport inhibited by only 50% in the presence of 1 mM competing nucleosides. HL-60, acute myelocytic leukemia cells, do not exhibit csg activity while L1210, murine acute lymphocytic leukemia cells, exhibit csg transport. The presence of the csg transporter suggests an important role for guanosine in particular forms of leukemia and may provide a new target for cytotoxic therapy.
Highlights
Purine and pyrimidine nucleotides, and their related metabolic products, participate in numerous biological processes
Concentrative nucleoside transport processes have been identified in numerous specialized mammalian cells [6]
We describe the complete characterization of an NBMPR-sensitive, Na1-dependent guanosine-specific transporter, the first to be described in eukaryotic cells
Summary
Their related metabolic products, participate in numerous biological processes. There are two discrete equilibrative transporters, NBMPR-sensitive (es) and -insensitive (ei), that have similar kinetic properties, but differ markedly in sensitivity to NBMPR (10 –12) Both equilibrative transporters are inhibited by low concentrations of dipyridamole and dilazep [9]. Concentrative nucleoside transport processes have been identified in numerous specialized mammalian cells [6] These transporters are insensitive to NBMPR and dipyridamole at concentrations up to 10 mM [9, 15]. The fourth ci transporter exhibits broad permeant selectivity and is referred to as cib [6, 20, 21] Both adenosine and uridine are substrates for all four ci transporter types [2]. Some cell types such as human erythrocytes express only a singe NT system, es [24], whereas, both es and ei
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