TY - JOUR
T1 - Biochemical phenotype of 5-fluorouracil-resistant murine T-lymphoblasts with genetically altered CTP synthetase activity
AU - Aronow, B.
AU - Watts, T.
AU - Lassetter, J.
AU - Washtien, W.
AU - Ullman, B.
N1 - Copyright:
Copyright 2012 Elsevier B.V., All rights reserved.
PY - 1984
Y1 - 1984
N2 - From wild type mouse lymphoma cells, a clone, (FURT-1A) was isolated by virtue of its resistance to 1 μM 5-fluorouracil and 10 μM thymidine. In comparative growth rate experiments, FURT-1A cells were also less sensitive than parental cells to the growth inhibitory effects of thymidine, deoxyguanosine, 5-fluorouridine, and arabinosylcytosine. The altered growth sensitivity of FURT-1A cells to cytotoxic nucleosides was directly related to their decreased ability to accumulate the corresponding triphosphate from exogenous nucleoside. FURT-1A cells contained elevated cytidylate nucleotide pools which prevented normal growth sensitivity and interfered with the salvage of nucleosides by inhibiting nucleoside kinase activities, by stimulating nucleotide dephosphorylating activities, and by overcoming certain allosteric inhibitions imposed on ribonucleotide reductase. Metabolic flux experiments with [3H]uridine in situ indicated that FURT-1A cells had a 2-fold enhanced rate of conversion of UTP to CTP. Kinetic analyses indicated that the CTP synthetase activity in extracts of FURT-1A cells was refractory to inhibition by CTP. The genetic loss of normal allosteric inhibition of the CTP synthetase activity in FURT-1A cells could account for the unusual phenotypic properties of these cells and conferred a high spontaneous mutator phenotype to cells possessing this mutation.
AB - From wild type mouse lymphoma cells, a clone, (FURT-1A) was isolated by virtue of its resistance to 1 μM 5-fluorouracil and 10 μM thymidine. In comparative growth rate experiments, FURT-1A cells were also less sensitive than parental cells to the growth inhibitory effects of thymidine, deoxyguanosine, 5-fluorouridine, and arabinosylcytosine. The altered growth sensitivity of FURT-1A cells to cytotoxic nucleosides was directly related to their decreased ability to accumulate the corresponding triphosphate from exogenous nucleoside. FURT-1A cells contained elevated cytidylate nucleotide pools which prevented normal growth sensitivity and interfered with the salvage of nucleosides by inhibiting nucleoside kinase activities, by stimulating nucleotide dephosphorylating activities, and by overcoming certain allosteric inhibitions imposed on ribonucleotide reductase. Metabolic flux experiments with [3H]uridine in situ indicated that FURT-1A cells had a 2-fold enhanced rate of conversion of UTP to CTP. Kinetic analyses indicated that the CTP synthetase activity in extracts of FURT-1A cells was refractory to inhibition by CTP. The genetic loss of normal allosteric inhibition of the CTP synthetase activity in FURT-1A cells could account for the unusual phenotypic properties of these cells and conferred a high spontaneous mutator phenotype to cells possessing this mutation.
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M3 - Article
C2 - 6611336
AN - SCOPUS:0021215808
SN - 0021-9258
VL - 259
SP - 9035
EP - 9043
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 14
ER -