Opposing effects of ERK and p38-JNK MAP kinase pathways on formation of prions in GT1-1 cells.
Brain-derived neurotrophic factor, which activates the extracellular regulated kinase (ERK) pathway, increases formation of prions in scrapie-infected gonadotropin-releasing hormone (GT1-1) cells. This indicates that conversion of the cellular prion protein PrP(C) to its pathogenic isoform, PrP(Sc), can be regulated by physiological stimuli acting on specific signal transduction pathways. In the present study, we examined the involvement of different mitogen-activated protein (MAP) kinase cascades and the cAMP-PKA pathway in formation of proteinase K-resistant PrP(Sc) (rPrP(Sc)). Long-term depolarization of GT1-1 cells infected with the Rocky Mountain Laboratory strain of scrapie increased the formation of rPrP(Sc). This effect was associated to ERK activation and was blocked by the MAPK/ERK kinase (MEK) inhibitor U0126. Treatment with forskolin caused a similar increase in rPrP(Sc) formation that was prevented by the protein kinase A (PKA) inhibitor H89. Both depolarization and forskolin treatment were accompanied by increased phosphorylation of the S6 ribosomal protein, while phosphorylation of histone H3 occurred only after forskolin treatment. Inhibitors of p38- and c-Jun NH(2)-terminal kinase (JNK) promoted the formation of rPrP(Sc), in contrast to the clearance of rPrP(Sc) produced by inhibitors of the ERK pathway. Thus, the ERK and the p38-JNK MAP kinase pathways appear to exert opposing effects on rPrP(Sc) formation, suggesting that balances between these intracellular signaling cascades may regulate replication of prions.
Nordström
Elin
E
Department of Neuroscience, Retzius väg 8, Karolinska Institutet, Stockholm, SE-171 77 Sweden. elin.nordstrom@ki.se
Fisone
Gilberto
G
Kristensson
Krister
K
D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D005576:Colforsin / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D011189:Potassium Chloride / Q000494:pharmacology; D011328:Prions / Q000096:biosynthesis*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D011328:Prions; D047428:Protein Kinase Inhibitors; D005576:Colforsin; D011189:Potassium Chloride; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases