Mannosylerythritol lipid induces characteristics of neuronal differentiation in PC12 cells through an ERK-related signal cascade

Rat pheochromocytoma PC12 cells undergo neuronal differentiation in respons e to nerve growth factor (NGF). The differentiation involves protein kinase cascades that include the kinases MEK and ERK, as well as activation of th e transcription factors c-Jun and c-Fos. We show here, that exposure of PC1 2 cells to mannosylerythritol lipid (MEL), a yeast extracellular glycolipid , enhances the activity of acetylcholinesterase and interrupts the cell cyc le at the G1 phase, with resulting outgrowth of neurites and partial cellul ar differentiation. Treatment with MEL stimulates the phosphorylation of ER K to a similar extent as treatment with NGF, although, the appearance of ph osphorylated ERK is somewhat delayed. Both the MEL-induced outgrowth of neu rites and the increase in the activity of acetylcholinesterase are prevente d by PD98059, a specific inhibitor of MEK. Northern blotting analysis of c- jun transcripts and analysis of transcription in PC12 cells of a c-jun/CAT reporter construct demonstrated a significant increase in the rate of trans cription of the c-jun gene upon treatment with MEL. The sequence elements r equired for the MEL-mediated activation of transcription of the c-jun gene are located between nucleotides -126 and -79 in the 5' flanking region. Our results suggest that MEL induces characteristics of neuronal differentiati on in PC12 cells, with transactivation of the c-jun gene, via an ERK-relate d signal cascade that is partially overlapping the pathways activated in re sponse to NGF. These results might provide the groundwork for the use of mi crobial extracellular glycolipids as novel reagents for the treatment of ca ncer cells.