title: Indirubin-3'-oxime inhibits c-Jun NH2-terminal kinase: anti-apoptotic effect in cerebellar granule neurons.
abstract: Previous studies have demonstrated that c-Jun NH2-terminal protein kinase (JNK) plays a crucial role in neuronal apoptosis. Here, we report that indirubin-3'-oxime, a known effective inhibitor of cyclin-dependent kinases (CDKs) and glycogen synthase kinase 3-beta (GSK-3beta), has a significant inhibitory effect on JNK. Kinase assay showed that indirubin-3'-oxime directly inhibited the activity of all three isoforms of JNK (JNK1, and JNK3) in vitro, with half inhibition dose (IC50) of 0.8 microM, 1.4 microM, and 1.0 microM, respectively. In cerebellar granule neurons (CGNs), indirubin-3'-oxime blocked c-Jun phosphorylation induced by potassium withdrawal and prevented CGNs from apoptosis in a dose dependent manner. However, inhibitors of CDKs and GSK-3beta were ineffective in reducing c-Jun phosphorylation both in vitro and in vivo, suggesting that indirubin-3'-oxime prevents c-Jun phosphorylation independent of its inhibition on CDKs and GSK-3beta. Our studies give further supports for JNK-targeting strategy in preventing neuronal apoptosis.
authors.affiliation: Department of Pharmacology, Zhongshan Medical College, SUN Yat-sen University, No 74, Zhongshan Rd 2, Guangzhou 510080, China.
authors.forename: Yuanbin
authors.initials: Y
authors.lastname: Xie
authors.forename: Yanling
authors.initials: Y
authors.lastname: Liu
authors.forename: Chi
authors.initials: C
authors.lastname: Ma
authors.forename: Zhongmin
authors.initials: Z
authors.lastname: Yuan
authors.forename: Wenya
authors.initials: W
authors.lastname: Wang
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Zhu
authors.forename: Guoquan
authors.initials: G
authors.lastname: Gao
authors.forename: Xianguo
authors.initials: X
authors.lastname: Liu
authors.forename: Hengxin
authors.initials: H
authors.lastname: Yuan
authors.forename: Ruzhu
authors.initials: R
authors.lastname: Chen
authors.forename: Shoujian
authors.initials: S
authors.lastname: Huang
authors.forename: Xuelan
authors.initials: X
authors.lastname: Wang
authors.forename: Xiaonan
authors.initials: X
authors.lastname: Zhu
authors.forename: Xuemin
authors.initials: X
authors.lastname: Wang
authors.forename: Zixu
authors.initials: Z
authors.lastname: Mao
authors.forename: Mingtao
authors.initials: M
authors.lastname: Li
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000873:Anthracenes / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western / Q000379:methods; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology; D010091:Oximes / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011188:Potassium / Q000633:toxicity; D051381:Rats
chemical_list: D000873:Anthracenes; D004791:Enzyme Inhibitors; D007211:Indoles; D010091:Oximes; C474021:indirubin-3'-monoxime; C432165:pyrazolanthrone; D048031:JNK Mitogen-Activated Protein Kinases; D011188:Potassium