Acute effect of 5-fluorouracil on cytoplasmic and nuclear dihydrofolate reductase messenger RNA metabolism

Studies were completed in C3-L5178Y cells, in which the DNA-coding region for dihydrofolate reductase messenger RNA (DHFR-mRNA) is amplified, to determine the acute effect of 5-fluorouracil (FUra) on DHFR-mRNA metabolism. There was minimal to no effect of 100 microM FUra on total cytoplasmic DHFR-mR...

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Bibliographic Details
Published in:The Journal of biological chemistry 1986-06, Vol.261 (16), p.7366-7371
Main Authors: Armstrong, R D, Lewis, M, Stern, S G, Cadman, E C
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Cell metabolism, cell oxidation
Cell Nucleus - metabolism
Cell physiology
Cells, Cultured
Cytidine - metabolism
Cytoplasm - metabolism
Dose-Response Relationship, Drug
Fluorouracil - pharmacology
Fundamental and applied biological sciences. Psychology
Gene Expression Regulation
Leukemia, Experimental - pathology
Mice
Molecular and cellular biology
RNA - analysis
RNA, Messenger - metabolism
Tetrahydrofolate Dehydrogenase - genetics
Tritium
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Summary:Studies were completed in C3-L5178Y cells, in which the DNA-coding region for dihydrofolate reductase messenger RNA (DHFR-mRNA) is amplified, to determine the acute effect of 5-fluorouracil (FUra) on DHFR-mRNA metabolism. There was minimal to no effect of 100 microM FUra on total cytoplasmic DHFR-mRNA levels by 6 and 12 h and only a 25% reduction by 24 h. These results contrasted with the nuclear DHFR-mRNA levels which by 6 h following exposure to FUra increased by 80% in a dose-dependent manner. Furthermore, some of the increased nuclear DHFR-mRNA was found to be in a non-polyadenylated form. Under conditions to examine only RNA synthesized during the drug exposure, FUra was found to markedly enhance the level of newly synthesized nuclear DHFR-mRNA in a dose-dependent manner, while also producing an apparent dose-dependent reduction in the cytoplasmic DHFR-mRNA. RNA fractionated by 1.5% agarose-urea gel electrophoresis revealed two major cytoplasmic DHFR-mRNA species approximately 1.8 and 0.8 kilobases in size. Following a 24-h FUra exposure, a dose-dependent loss of the 0.8-kilobase DHFR-mRNA was observed. The combined results of these experiments indicate that FUra treatment reduces the ability of nascent DHFR-mRNA to relocate to the cytoplasm, suggesting either an inhibition of mRNA processing or nuclear-cytoplasmic transport.
ISSN:0021-9258
1083-351X
DOI:10.1016/S0021-9258(17)38400-4