Ganglioside GM1 activates the mitogen-activated protein kinase Erk2 and p70 S6 kinase in U-1242 MG human glioma cells.
Gangliosides are implicated in the regulation of cellular proliferation as evidenced by differences in ganglioside composition associated with malignant transformation and density of cells in culture, as well as their inhibitory effects when added to cells growing in culture. Exogenously added gangliosides have a bimodal effect on proliferation in U-1242 MG glioma cells, inhibiting DNA synthesis in growing cells and stimulating it in quiescent cells. We investigated the mechanisms involved in stimulation of DNA synthesis using [3H]thymidine incorporation and immune complex kinase assays to identify responsible signal transduction pathways. Treatment of quiescent U-1242 MG cells with GM1 caused activation of the mitogen-activated protein (MAP) kinase isoform Erk2. Pretreatment with the specific MAP kinase kinase inhibitor PD98059 prevented the GM1-stimulated Erk2 activation and GM1-stimulated DNA synthesis. GM1 treatment stimulated another distinct signaling pathway leading to activation of p70 S6 kinase (p70s6k), and this was prevented by pretreatment with rapamycin. Rapamycin also inhibited GM1-stimulated DNA synthesis. Activation of both pathways and stimulation of DNA synthesis were inhibited by forskolin treatment; however, GM1 had no effect on cyclic AMP levels. Platelet-derived growth factor also activated both Erk2 and p70s6k but did not cause DNA synthesis, suggesting that GM1 may stimulate additional cascades, which also contribute to GM1-mediated DNA synthesis.
Van Brocklyn
J R
JR
Department of Pathology (Division of Neuropathology), Ohio State University, Columbus 43210, U.S.A.
Vandenheede
J R
JR
Fertel
R
R
Yates
A J
AJ
Rampersaud
A A
AA
D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000494:pharmacology; D004247:DNA / Q000096:biosynthesis; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D005677:G(M1) Ganglioside / Q000378:metabolism / Q000494:pharmacology*; D005910:Glioma; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases; D008934:Mitogens / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011090:Polyenes / Q000494:pharmacology; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D019893:Ribosomal Protein S6 Kinases; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology; D020123:Sirolimus; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D005419:Flavonoids; D007166:Immunosuppressive Agents; D008934:Mitogens; D010982:Platelet-Derived Growth Factor; D011090:Polyenes; D047428:Protein Kinase Inhibitors; D005576:Colforsin; D005677:G(M1) Ganglioside; D004247:DNA; D000242:Cyclic AMP; D017346:Protein Serine-Threonine Kinases; D019893:Ribosomal Protein S6 Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D020123:Sirolimus