It has been found that incubation of UDP-galactose with GTP, Mn ions and extracts of transformed cells results in the formation of several rapidly migrating products. Two of these products are dominant, """"""""Fast Peak 2"""""""" (FP2) and """"""""Fast Peak 4"""""""" (FP4). The reaction is catalyzed by extracts of transformed cells with mutated or elevated levels of ras oncogene product (K-ras, H-ras and N-ras). Activity is also seen in human tumor cell lines (breast, lung, bladder), SV40-transformed cells and chemically transformed liver cells. The reaction is not detected in a variety of control cells, polyoma and Rous virus-transformed cells and some malignant cells. Preliminary experiments indicate that the reaction catalyzed by an extract of KMSV-transformed mouse fibroblasts can be inhibited by an anti-ras monoclonal antibody.
Our aim i s to: (a) obtain sufficient material to establish the structures of FP2 and FP4; (b) study their effects on cells and reactions related to growth control in order to establish their role in malignant (and normal) cells, i.e., whether the FP derivatives are involved in normal control of growth and differentiation; (c) fractionate the enzymes and factors involved in the synthesis of FP; (d) determine the nature of the reaction and the metabolic relation of FP2 and FP4; (e) establish that the ras gene product is a part of the mechanism and determine the action of the ras protein in normal and malignant cells; and (f) determine the distribution of the FP synthesizing enzymes in control and malignant tissues. We also plan to complete our studies in progress on: 1) the degradation of CMPNAN to form a putative CMPpyruvate. 2) comparison of glycopeptides of control and transformed cells. 3) the influence of environment and drugs on the carbohydrate component of IgG produced by hybridomas and the consequences of altered carbohydrate structure.

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National Cancer Institute (NCI)
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Cellular Biology and Physiology Subcommittee 1 (CBY)
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Wistar Institute
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Warren, L; Malarska, A; Jardillier, J C (1995) The structure of P-glycoprotein and the secretion of lysosomal enzymes in multidrug-resistant cells. Cancer Chemother Pharmacol 35:267-9
Warren, L; Jardillier, J C; Malarska, A et al. (1992) Increased accumulation of drugs in multidrug-resistant cells induced by liposomes. Cancer Res 52:3241-5
Warren, L; Jardillier, J C; Ordentlich, P (1991) Secretion of lysosomal enzymes by drug-sensitive and multiple drug-resistant cells. Cancer Res 51:1996-2001
Warren, L (1990) Stimulation of lysosomal enzyme secretion by growth factors. Exp Cell Res 190:133-6
Rothman, R J; Perussia, B; Herlyn, D et al. (1989) Antibody-dependent cytotoxicity mediated by natural killer cells is enhanced by castanospermine-induced alterations of IgG glycosylation. Mol Immunol 26:1113-23
Rothman, R J; Warren, L; Vliegenthart, J F et al. (1989) Clonal analysis of the glycosylation of immunoglobulin G secreted by murine hybridomas. Biochemistry 28:1377-84
Warren, L (1989) Stimulated secretion of lysosomal enzymes by cells in culture. J Biol Chem 264:8835-42
Rothman, R J; Warren, L (1988) Analysis of IgG glycopeptides by alkaline borate gel filtration chromatography. Biochim Biophys Acta 955:143-53
Warren, L (1986) Sialic acid lyase in human promyelocytic leukemic cells (HL-60) during phorbol-ester-induced differentiation. Biochim Biophys Acta 888:278-81
Cossu, G; Cortesi, E; Warren, L (1985) Increased sialylation of complex glycopeptides during differentiation of mouse embryonal carcinoma cells. Differentiation 29:63-7

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