Militarinone A induces differentiation in PC12 cells via MAP and Akt kinase signal transduction pathways.
The fungal metabolite militarinone A (MILI A) promotes neurite outgrowth in PC12 cells. This study was conducted to investigate the signaling pathways involved in the cellular differentiation processes induced by the compound, with a focus on cascades implicated with nerve growth factor (NGF)-mediated neuritogenesis. MILI A possessed pronounced amphiphilic properties. The compound rapidly accumulated in the cell membrane and was slowly released into the cytoplasma. In primed PC12 cells, an early activation of protein kinase B (Akt), representing a downstream target of phosphoinositol 3 (PI3) kinase, and a delayed phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), and of transcription factor cAMP responsive element binding protein (CREB) was found. The NGF-dependent activation of c-Jun amino terminal kinase (SAPK/JNK1) was potentiated. Morphological differentiation of cells and the phosphorylation of specific signal molecules were blocked by the MAP kinase (MEK1) inhibitor PD098059, the PI3-kinase (PI3K) inhibitor wortmannin and the adenylyl cyclase inhibitor 9-cyclopentyladenine.
Riese
Ulrike
U
Institute of Pharmacy, Friedrich-Schiller-University Jena, Semmelweisstrasse 10, D-07743 Jena, Germany.
Ziegler
Elke
E
Hamburger
Matthias
M
D000262:Adenylyl Cyclases / Q000187:drug effects; D000470:Alkaloids / Q000737:chemistry / Q000494:pharmacology*; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D050882:CREB-Binding Protein; D002454:Cell Differentiation / Q000187:drug effects*; D002462:Cell Membrane / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007700:Kinetics; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D015394:Molecular Structure; D020932:Nerve Growth Factor / Q000494:pharmacology; D016501:Neurites / Q000187:drug effects / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D016716:PC12 Cells; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D011728:Pyridones / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D015398:Signal Transduction; D013347:Subcellular Fractions; D015534:Trans-Activators / Q000378:metabolism; D000077191:Wortmannin
D000262:Adenylyl Cyclases; D000470:Alkaloids; D000730:Androstadienes; D050882:CREB-Binding Protein; D004791:Enzyme Inhibitors; D005419:Flavonoids; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D020932:Nerve Growth Factor; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011728:Pyridones; D015534:Trans-Activators; D000077191:Wortmannin; C449040:militarinone A; C494365:Crebbp protein, rat; C494920:Akt1 protein, rat; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one