A reduced folate carrier mutation produces substrate-dependent alterations in carrier mobility in murine leukemia cells and methotrexate resistance with conservation of growth in 5-formyltetrahydrofolate.

The Journal of Biological Chemistry
R ZhaoI D Goldman

Abstract

With 5-formyltetrahydrofolate (5-CHO-THF) as the folate source a methotrexate (MTX) transport-deficient murine leukemia cell line, L1210-G1a, was isolated after chemical mutagenesis and MTX selection. This cell line was 10-fold resistant to MTX in comparison to parental L1210 cells, yet the EC50 for 5-CHO-THF was increased by a factor of only 2. The initial uptake of MTX, at a concentration of 1 microM, was decreased by a factor of 40, whereas influx of 5-CHO-THF dropped by a factor of only 8. This difference in initial uptake rates was attributed solely to changes in influx Vmax without a significant change in Km. Whereas the RFC1 mRNA level in L1210-G1a cells was indistinguishable from that of parental L1210 cells, a serine to asparagine substitution was identified at amino acid 46 within the first predicted transmembrane domain. This was a result of a homozygous mutation of G-->A in the genome. Transfection of the mutated RFC1 cDNA into MTXrA cells, which lack functional endogenous carrier, resulted in a clonal derivative MTXrA-S46N. The increase in influx of 5-CHO-THF and 5-CH3THF was 5 and 13 times greater than that for MTX in the transfectant, consistent with the influx ratio in the L1210-G1a line. The functional expressi...Continue Reading

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Citations

Mar 6, 2007·Cancer Metastasis Reviews·Larry H MatherlyYijun Deng
Mar 3, 2007·Cancer Metastasis Reviews·Yehuda G Assaraf
May 15, 2002·Biochemical Pharmacology·Iraida G SharinaI David Goldman
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