Abstract
The processing pathway of G-proteins and Ras family proteins includes the isoprenylation of the cysteine residue, followed by proteolysis of three terminal residues and α-carboxyl methyl esterification of the cysteine residue. Farnesylcysteine methyltransferase (FCMT) activity is responsible for the methylation reaction which play a role in the membrane attachment of a variety of cellular proteins. Four kinds of Ras protein (c-Ha-ras, c-N-Ras, c-Ki-Ras, pan-Ras) expression were detected in adenocarcinoma of human tissue by immunohistochemical method, and hematoxylin and eosin staining. The level of Ras protein in human stomach tumor tissues was much higher than in normal and peritumoral regions of the same biopsy samples. The FCMT activities of each cellular fractions were high in mitochondrial fraction followed by microsomal fraction, whole homogenate and cytosolic fraction. The inhibitory effect on FCMT activity on stomach tumor tissue was determined after treatment with 0.25 μM of S-adenosyl-l-homocysteine. S-adenosyl-l-homocysteine inhibited FCMT activity from 11.2% to 30.5%. These results suggested that FCMT might be involved in Ras proteins activity.
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References Cited
Bos, J. L., The ras gene family and human carcinogenesis.Mutat. Res., 195, 255–271 (1988).
Casey, P. J., Solski, P. A., Der, C. J. and Buss, J., p 21ras is modified by a farnesyl isoprenoid.Proc. Natl. Acad. Sci. USA, 86, 1167–1177 (1989).
Chiva, V. A. and Mato, J. M., Inhibition of phospholipid methylation by a cytosolic factor.Biochem. J., 218, 637–639 (1984).
Clarke, S., Vogel, J. P., Deschenes, R. J. and Stock, J., Posttranslational modification of the Ha-ras oncogene protein: Evidence for a third class of protein carboxylmethyltransferases.Proc. Natl. Acad. Sci. USA, 85, 4643–4647 (1988).
Deng, G., Eh, Z., Xu, Y. and Lu, Y., Activation of oncogene c-Ha-ras in gastric cancer of Chinese patients.Sem. Surgi. Oncol., 10, 83–87 (1994).
Gutierrez, L., Magee, A. I., Marshall, C. J. and Hancock, J. F., Posttranslational processing of p21ras is two-step and involves carboxyl-methylation and carboxy-terminal proteolysis.EMBO J., 8, 1093–1098 (1989).
Hancock, J. F., Magee, A. I., Childs, J. E. and Marshall, C. J., All ras proteins are polyisoprenylated but only some are palmitoylated.Cell, 57, 1167–1177 (1989).
Hancock, J. F., Cadwallader, K. and Marshall, C. J., Methylation and proteolysis are essential for efficient membrane binding of prenylated p21K-ras(B).EMBO J., 10, 641–646 (1991).
Hong, S. Y., Lee, H. W., Desi, S., Kim, S. and Paik, W. K., Studies on naturally occurring proteinous inhibitor for transmethylation reactions.Eur. J. Biochem., 156, 79–84 (1986).
Hsu, S.-M., Raine, L. and Fanger, H., Use of avidinbiotin-peroxidase complex (ABC) in immunoperoxidase techniques: a comparison between ABC and unlabeled antibody (PAP) procedures.J. Histochem. Cytochem., 29, 577–580 (1981).
Kim, S. and Paik, W. K., Natural inhibitor for protein methylase II.Biochim. Biophys. Acta, 252, 526–532 (1971).
Klein, Z., Baruch, G. B., Marciano, D., Solomon, R., Altaras, M. and Kloog, Y., Characterization of the prenylated protein methyltransferase in human endometrial carcinoma.Biochim. Biophys. Acta, 1226, 330–336 (1994).
Lederer, E. D., Jacobs, A. A., Hoffman, J. L., Harding, G. B., Robishaw, J. D. and McLeish, K. R., Role of carboxylmethylation in chemoattractant receptor-stimulated G protein activation and functional responses.Biochem. Biophys. Res. Commun., 200, 1604–1614 (1994).
Krontiris, T. G., Devlin, B., Karp, D. D., Robert, N. J. and Risch, N., An association between the risk of cancer and mutations in the Hras1 minisatellite locus.N. Eng. J. of Med., 329, 517–523 (1993).
Motojima, K., Furui, J., Kohara, N., Izawa, K., Kanematsu, T. and Shiku, H., Expression of Kirsten-ras p 21 in gastric cancer correlates with tumor progression and is prognostic.Diagno. Mol. Pathol., 3, 184–191 (1994).
Munoz, N., Correa, P., Cuello, C. and Duque, E., Histologic types of gastric carcinoma in high- and low-risk areas.Int. J. Cancer, 3, 809–818 (1968).
Ota, I. M. and Clarke, S., Enzymatic methylation of 23–29kDa bovine retinal rod outer segment membrane proteins. Evidence for methyl ester formation at carboxyl-terminal cysteinyl residues.J. Biol. Chem., 264, 13806–13813 (1989).
Park, K. S., Choi, S. Y., Park, K. H. and Kim, S., Studies on mammalian brain protein farnesylcysteine carboxyl-methyltransferase,Kor. J. Biochem, 26, 47–57 (1994).
Portier, M., Moles, J. P., Mazars, G. R., Jeanteur, P., Bataille, R., Klein, B. and Theillet, C., p53 and ras gene mutations in multiple myeloma.Oncogene, 7, 2539–2543 (1992).
Rodenhuis, S., and Slebos, R. J. C., The ras oncogenes in human lung cancer.Am. Rev. Resir. Dis., 142, S27-S30 (1990).
Rodenhuis, S. and Slebos, R. J. C., Clinical significance of ras oncogene activation in human lung cancer.Cancer Res., 52, 2665s-2669s (1992).
Sinn, E., Muller, W., Pattengale, P., Tepler, I., Wallace, R. and Leder, P., Coexpression of MMTV/v-Ha-ras and MMTV/c-myc genes in transgenic mice: Synergistic action of oncogenesin vivo.Cell, 49, 465–475 (1987).
Tahara, E., Yasui, W., Taniyama, K., Ochiai, A., Yamamoto, T., Nakajo, S. and Yamamoto, M., Haras oncogene product in human gastric carcinoma: Correlation with invasiveness.Jpn. J. Cancer Res., 77, 517–522 (1986).
Tan, E. W., Perez-Sala, D., Canada, F. J. and Rando, R. R., Identifying the recognition unit for G protein methylation.J. Biol. Chem., 266, 10719–10722 (1991).
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Han, ES., Oh, HY., Ha, KW. et al. Farnesylcysteine methyltransferase activity and Ras protein expression in human stomach tumor tissue. Arch. Pharm. Res. 21, 378–384 (1998). https://doi.org/10.1007/BF02974630
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DOI: https://doi.org/10.1007/BF02974630