Activation of stress-activated protein kinases correlates with neurite outgrowth induced by protease inhibition in PC12 cells.
PC12 cells are well characterized for their ability to differentiate into neuronal-like cells when challenged with nerve growth factor. It has been reported that the calpain and proteasome inhibitor N-acetyl-Leu-Leu-norleucinal (CI) is also able to induce neurite outgrowth in PC12 cells. In this study, we report that the inhibitor of proteasomal chymotrypsin-like activity, carbobenzoxy-Ile-Glu-(O-tert-butyl)-Ala-Leu-aldehyde (PSI), can also induce differentiation of PC12 cells. Induction of neurite outgrowth with PSI, CI, or its close analogue, carbobenzoxy-Leu-Leu-leucinal (MG132), was associated with stress-activated protein kinase (SAPK) activation. Neurite formation induced by protease inhibition was independent of mitogen-activated protein kinase/extracellular signal-regulated kinase, p38/reactivating kinase, or phosphatidylinositol 3-kinase activities. The exact mechanism by which protease inhibition activates SAPKs remains to be elucidated; however, our results suggest that the SAPK signal transduction cascade may be an alternative and/or parallel pathway in the regulation of neuronal differentiation.
Giasson
B I
BI
Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
Bruening
W
W
Durham
H D
HD
Mushynski
W E
WE
D000818:Animals; D015153:Blotting, Western; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D004591:Electrophoresis, Polyacrylamide Gel; D004789:Enzyme Activation / Q000502:physiology; D007976:Leupeptins / Q000494:pharmacology; D048291:Mitogen-Activated Protein Kinase 12; D020928:Mitogen-Activated Protein Kinases; D016501:Neurites / Q000187:drug effects* / Q000201:enzymology; D016716:PC12 Cells; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011233:Precipitin Tests; D011480:Protease Inhibitors / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases
D007976:Leupeptins; D011480:Protease Inhibitors; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D048291:Mitogen-Activated Protein Kinase 12; D019869:Phosphatidylinositol 3-Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde