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: Tae-Wook Chung, Hee-Jung Choi, Young-Choon Lee, Cheorl-Ho Kim
• Journal: Glycobiology (Glycobiology) Vol. 15 Issue 3 Pg. 233-44 (Mar 2005) ISSN: 0959-6658 [Print] England
• PMID: 15385432 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CD11b Antigen
• Cyclic AMP Response Element-Binding Protein
• Sialyltransferases
• haematoside synthetase
• Phosphatidylinositol 3-Kinases
• Protein Kinase C
• Extracellular Signal-Regulated MAP Kinases
• JNK Mitogen-Activated Protein Kinases
• p38 Mitogen-Activated Protein Kinases
• Tetradecanoylphorbol Acetate

Topics

• CD11b Antigen (metabolism)
• Cell Adhesion
• Cell Differentiation (drug effects)
• Cyclic AMP Response Element-Binding Protein (metabolism)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• HL-60 Cells
• Humans
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Protein Kinase C (metabolism)
• Sialyltransferases (genetics)
• Signal Transduction (drug effects)
• Tetradecanoylphorbol Acetate (pharmacology)
• Transcriptional Activation (drug effects)
• p38 Mitogen-Activated Protein Kinases (metabolism)