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 n euronal-like cells when challenged with nerve growth factor. It has been re ported that the calpain and proteasome inhibitor N-acetyl-Leu-Leu-norleucin al (CI) is also able to induce neurite outgrowth in PC12 cells. In this stu dy, we report that the inhibitor of proteasomal chymotrypsin-like activity, carbobenzoxylle-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-leucinaI (MG132), was associa ted with stress-activated protein kinase (SAPK) activation. Neurite formati on induced by protease inhibition was independent of mitogen-activated prot ein kinase/extracellular signal-regulated kinase, p38/reactivating kinase, or phosphatidylinositol 3-kinase activities. The exact mechanism by which p rotease inhibition activates SAPKs remains to be elucidated; however, our r esults suggest that the SAPK signal transduction cascade may be an alternat ive and/or parallel pathway in the regulation of neuronal differentiation.