Article
Full Access
Methionine metabolism in BHK cells: Preliminary characterization of the physiological effects of cycloleucine, an inhibitor of S-adenosylmethionine biosynthesis
Dr. Michel Caboche,
Jacques Hatzfeld,
Corresponding Author
Dr. Michel Caboche
Laboratoire de Génétique Cellulaire, Institut National de la Recherche Agronomique, BP 12, 31320 Castanet Tolosan, France
Lab. biologiè Cellulaire, CNRA, 78000 Versailles, FranceSearch for more papers by this authorJacques Hatzfeld
Institut de Biologie Moléculaire, Université Paris 7, 2 Place Jussieu, 75221 Paris Cedex 05, France
Search for more papers by this authorDr. Michel Caboche,
Jacques Hatzfeld,
Corresponding Author
Dr. Michel Caboche
Laboratoire de Génétique Cellulaire, Institut National de la Recherche Agronomique, BP 12, 31320 Castanet Tolosan, France
Lab. biologiè Cellulaire, CNRA, 78000 Versailles, FranceSearch for more papers by this authorJacques Hatzfeld
Institut de Biologie Moléculaire, Université Paris 7, 2 Place Jussieu, 75221 Paris Cedex 05, France
Search for more papers by this authorAbstract
Cycloleucine is in vitro a competitive inhibitor of methionine adenosyltransferase, an enzyme involved in S-adenosylmethionine biosynthesis. The physiological effects of this drug on baby hamster kidney cells have been studied. When cells are grown in a medium containing 10 μM methionine, cycloleucine is an inhibitor of cell proliferation; high concentrations of methionine are able to withdraw this inhibition suggesting that cycloleucine toxicity is related to methionine metabolism. The drug does not primarily affect methionine uptake and its subsequent use for protein biosynthesis. Cycloleucine toxicity is correlated with a block of SAM biosynthesis and nucleic acids methylations. The actions of cycloleucine on progression in the cell cycle and DNA, RNA and protein biosynthesis are studied. The implications of these results are discussed.
Literature Cited
- Abshire, J. C., and R. Pineau 1967 Reversal of toxicity of 1-aminocyclopentane carboxylic acid by valine in Escherichia Coli. Can. J. Biochem., 45: 1637–1640.
- Adams, R. P. 1971 The relationship between synthesis and methylation of DNA in mouse fibroblasts. Biochim. Biophys. Acta, 254: 205–212.
- Amalric, F., J. P., Bachellerie and M. Caboche 1977 RNA methylation and control of eukaryotic RNA biosynthesis: Processing and utilization of undermethylated t RNAs in CHO cells. Nucleic Acid Res., 4: 4357–4370.
- Arber, W. 1974 DNA modification and restriction. Progr. Nuc. Ac. Res. Mol. Biol., 14: 1–34.
- Bjork, G. R., and L. A. Isaksson 1970 Isolation of mutants of Escherichia coli lacking 5-methyluracil in transferribonucleic acid or 1-methylguanine in ribosomal RNA. J. Mol. Biol., 51: 83–100.
- Boynton, A. L., J. F., Whitfield and R. J. Isaacs 1976 A possible involvement of polyamine in the initiation of DNA synthesis by human W I-38 and mouse BALB/3T3 cells. J. Cell. Physiol., 89: 481–488.
- Burdon, R. M., and R. P. Adams 1969 The in vivo methylation of DNA in mouse fibroblasts. Biochim. Biophys. Acta, 174: 322–329.
- Caboche, M. 1974 Comparison of the frequencies of spontaneous and chemically induced 5-bromodeoxyuridine-resistance mutations in wild type and revertant BHK 21/13 cells. Genetics, 77: 309–322.
- Caboche, M. 1976 Methionine metabolism in BHK cells: Selection and characterization of ethionine resistant clones. J. Cell. Physiol., 87: 321–336.
- Caboche, M. 1977 Methionine metabolism in BHK cells: the regulation of methionine adenosyltransferase. J. Cell. Physiol., 92: 407–424.
- Caboche, M., and J. P. Bachellerie 1977 RNA methylation and control of eukaryotic RNA biosynthesis. Effects of cycloleucine, a specific inhibitor of methylation, on ribosomal RNA maturation. Eur. J. Biochem., 74: 19–28.
- Centrella, M., K., Muirhead and A. I. Meisler 1976 How does intracellular methionine regulate cytoplasmic ribosome content. J. Cell. Biol., 70: 343a.
- Clark, J. L., and J. L. Fuller 1975 Regulation of ornithine decarboxylase in 3T3 cells by putrescine and spermidine: indirect evidence for translational control. Biochemistry, 14: 4403–4409.
- Crissman, H. A., and J. A. Steinkamp 1973 Rapid, simultaneous measurement of DNA, protein, and cell volume in single cells from large mammalian cell populations. J. Cell. Biol., 59: 766–771.
- Evans, H. M., J. E., Evans and S. Littman 1973 Methylation of parental and progeny DNA strands in Physarum polycephalum. J. Mol. Biol., 74: 563–572.
- Fillingane, R. H., and D. R. Morris 1973 Polyamine accumulation during lymphocyte transformation and its relation to the synthesis, processing and accumulation of ribonucleic acid. Biochemistry, 12: 4479–4487.
- Gregory, F. J., S. F., Flint, H. W. Ruelius and G. M. Warren 1969 Reversal of antileukemic action and toxicity of 1-aminocyclopentane carboxylic acid in mice by L-valine. Cancer Res., 29: 728–729.
- Hildesheim, J., R., Hildesheim, P. Blanchard, G. Farrugia and R. Michelot 1973 Studies on synthetic inhibitors of t RNA methyltransferases: analogs of s-adenosyl homocysteine. Biochimie, 55: 541–546.
- Hobson, A. C. 1976 The synthesis of S-adenosylmethionine by mutants with defects in S-adenosylmethionine synthetase. Molec. gen. Genet., 144: 87–95.
- Jacquemont, B., and J. Huppert 1977 Inhibition of viral RNA methylation in Herpes Simplex virus type 1-in fected cells by 5′ S isobutyl-adenosine. J. Virol., 22 160–167.
- Johnson, L. F., H. T., Abelson, H. Green and S. Penman 1974 Changes in RNA in relation to growth of the fibroblast. 1. Amounts of m RNA, r RNA, and t RNA in resting and growing cells. Cell. 1: 95–100.
- Krokan, H., and A. Eriksen 1977 DNA synthesis in Held cells and isolated nuclei after treatment with an inhibitor of spermidine synthesis, methylglyoxal-bis-guanylhydrazone. Eur. J. Biochem., 72: 501–508.
- Ley, K. D., and R. A. Tobey 1970 Regulation of the initiation of DNA synthesis in chinese hamster cells. 2. Induction of DNA synthesis and cell division by isoleucine and glutamine in G1-arrested cells in suspension culture. J. Cell. Biol., 47: 453–459.
- Lombardini, J. B., A. W., Coulter and P. Talalay 1970 Analogues of methionine as substrates and inhibitors of the methionine adenosyltransferase reaction. Molec. Pharmacol., 6: 481–499.
- Marinus, M. G., and N. R. Morris 1974 Biological function for 6-methyladenine residues in the DNA of Escherichia coli K12. J. Mol. Biol., 85: 309–322.
- Newton, N. E., and M. M. Abdel-Monem 1977 Inhibitors polyamine biosynthesis: 4. Effects of α-methyl-ornithine and methylglyoxal-bis-guanylhydrazone on growth and polyamine content of L. 1210 leukemic cells of mice. J. Med. Chem., 20: 249–253.
- Perry, R. P., and D. E. Kelley 1974 Existence of methylated messenger RNA in mouse L cells. Cell, 1: 37–42.
- Robert-Gero, M., F., Lawrence and P. Vigier 1975 Reversable inhibition by methioninyl adenylate of protein synthesis and growth in chick embryo fibroblasts. Biochem. Biophys. Res. Commun., 63: 594–600.
- Schepartz, B. 1973 Regulation of aminoacids metabolism in mammals. W. B. Saunders, ed. Philadelphia, pp. 36–50.
- Stambrook, P. J., and J. E. Sisken 1972 The relationship between rates of (3H) uridine and (3H) adenine incorpration into RNA and the measured rates of RNA synthesis during the cell cycle. Biochim. Biophys. Acta, 281: 45–54.
- Vaughan, M. H., R., Soeiro, J. R. Warner and J. E. Darnell 1967 The effect of methionine deprivation on ribosome synthesis in HELA cells. Proc. Natl. Acad. Sci. (U.S.A.), 58: 1527–1534.
Citing Literature
