title: Molecular mechanism for transcriptional activation of ganglioside GM3 synthase and its function in differentiation of HL-60 cells.
abstract: Previous studies have demonstrated that the activity of GM3 synthase and GM3 content are increased during the differentiation of human promyelocytic leukemia HL-60 cells into the monocyte/macrophage lineage after phorbol 12-myristate 13-acetate (PMA) treatment. However, the molecular mechanisms involved in transcriptional activation of GM3 synthase during differentiation of PMA-induced HL-60 cells are not well understood. As evidenced by western blot analysis, PMA induced the marked activation of protein kinase C (PKC)/extracellular regulated kinases (ERKs) signal transduction pathway during the differentiation of HL-60 cells. In addition, PKC/ERKs activation induced by PMA in HL-60 cells led to the phosphorylation of cAMP-responsive element binding protein (CREB) as a transcription factor. In PMA-stimulated HL-60 cells, the PKC/ERKs-dependent CREB activation regulated expression of GM3 synthase, inducing a synthesis of ganglioside GM3 product. On the other hand, although ganglioside GM3 was shown to be able to induce the differentiation of HL-60 cells into the monocyte/macrophage lineage, effect of ganglioside GM3 on expression of CD11b as a differentiation marker in HL-60 cells has been not reported yet. Interestingly, the increased ganglioside GM3 through PKC/ERKs/CREB-dependent pathway by PMA resulted in an increase of CD11b surface antigen expression and induction of HL-60 cells adherence. Treatment with L-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP), glucosylceramide synthase inhibitor, decreased induction of not only CD11b expression but also cellular adherence by reduction of PMA-induced ganglioside GM3. Furthermore, treatment of HL-60 cells with exogenous ganglioside GM3 induced CD11b expression. These results show that the enhanced expression of GM3 synthase through PKC/ERKs-dependent CREB activation by PMA is associated with the differentiation of HL-60 cells by inducing expression of CD11b known as a monocyte/macrophage differentiation maker.
authors.affiliation: National Research Laboratory for Glycobiology, MOST, Korea.
authors.forename: Tae-Wook
authors.initials: TW
authors.lastname: Chung
authors.forename: Hee-Jung
authors.initials: HJ
authors.lastname: Choi
authors.forename: Young-Choon
authors.initials: YC
authors.lastname: Lee
authors.forename: Cheorl-Ho
authors.initials: CH
authors.lastname: Kim
mesh_terms: D039481:CD11b Antigen / Q000378:metabolism; D002448:Cell Adhesion; D002454:Cell Differentiation / Q000187:drug effects; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D012799:Sialyltransferases / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D015533:Transcriptional Activation / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D039481:CD11b Antigen; D017362:Cyclic AMP Response Element-Binding Protein; D012799:Sialyltransferases; C021343:haematoside synthetase; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D013755:Tetradecanoylphorbol Acetate