title: Activation of Rac1-dependent redox signaling is critically involved in staurosporine-induced neurite outgrowth in PC12 cells.
abstract: Staurosporine, a non-specific protein kinase inhibitor, has been shown to induce neurite outgrowth in PC12 cells, but the mechanism by which staurosporine induces neurite outgrowth is still obscure. In the present study, we investigated whether the activation of Rac1 was responsible for the neurite outgrowth triggered by staurosporine. Staurosporine caused rapid neurite outgrowth independent of the ERK signaling pathways. In contrast, neurite outgrowth in response to staurosporine was accompanied by activation of Rac1, and the Rac1 inhibitor NSC23766 attenuated the staurosporine-induced neurite outgrowth in a concentration-dependent manner. In addition, suppression of Rac1 activity by expression of the dominant negative mutant Rac1N17 also blocked the staurosporine-induced morphological differentiation of PC12 cells. Staurosporine caused an activation of NADPH oxidase and increased the production of reactive oxygen species (ROS), which was prevented by NSC23766 and diphenyleneiodonium (DPI), an NADPH oxidase inhibitor. Staurosporine-induced neurite outgrowth was attenuated by pretreatment with DPI and exogenous addition of sublethal concentration of H2O2 accelerated neurite outgrowth triggered by staurosporine. These results indicate that activation of Rac1, which leads to ROS generation, is required for neurite outgrowth induced by staurosporine in PC12 cells.
authors.affiliation: Department of Oral Biology, BK 21 Project for Yonsei Dental Sciences, Yonsei University College of Dentistry, Seoul, Korea.
authors.forename: Du Sik
authors.initials: du S
authors.lastname: Kim
authors.forename: Jeong Mi
authors.initials: JM
authors.lastname: An
authors.forename: Han Gil
authors.initials: HG
authors.lastname: Lee
authors.forename: Su Ryeon
authors.initials: SR
authors.lastname: Seo
authors.forename: Seon Sook
authors.initials: SS
authors.lastname: Kim
authors.forename: Ju Yeon
authors.initials: JY
authors.lastname: Kim
authors.forename: Jeong Wan
authors.initials: JW
authors.lastname: Kang
authors.forename: Yun Soo
authors.initials: YS
authors.lastname: Bae
authors.forename: Jeong Taeg
authors.initials: JT
authors.lastname: Seo
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology; D009154:Mutation; D019255:NADPH Oxidases / Q000378:metabolism; D016501:Neurites / Q000187:drug effects / Q000502:physiology*; D009861:Onium Compounds / Q000494:pharmacology; D010084:Oxidation-Reduction; D016716:PC12 Cells; D047428:Protein Kinase Inhibitors / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D019311:Staurosporine / Q000494:pharmacology*; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000634:Aminoquinolines; D004791:Enzyme Inhibitors; C487513:NSC 23766; D009861:Onium Compounds; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D017382:Reactive Oxygen Species; C007517:diphenyleneiodonium; D006861:Hydrogen Peroxide; D019255:NADPH Oxidases; D048049:Extracellular Signal-Regulated MAP Kinases; C499134:Rac1 protein, rat; D020830:rac1 GTP-Binding Protein; D019311:Staurosporine