GSK‐3 inhibition by adenoviral FRAT1 overexpression is neuroprotective and induces Tau dephosphorylation and β‐catenin stabilisation without elevation of glycogen synthase activity

FEBS Letters

Cross, Darren A.E.⁴  Culbert, Ainsley A.⁴  Reith, Alastair D.¹  Frame, Sheelagh²  Hagen, Thilo¹  Brown, Murray J.¹  Bax, Benjamin³ 

[1] Systems Research, GlaxoSmithKline Pharmaceuticals, Harlow, Essex CM19 5AD, UK;Division of Signal Transduction Therapy, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK;Department of Structural Biology, GlaxoSmithKline Pharmaceuticals, Harlow, Essex CM19 5AD, UK;Neurology Centre of Excellence in Drug Discovery, GlaxoSmithKline Pharmaceuticals, Harlow, Essex CM19 5AD, UK

关键词: Glycogen synthase kinase-3;    FRAT1;    Neuroprotection;    Tau;    β-Catenin;    PC12 cell;   

DOI  :  10.1016/S0014-5793(01)02990-8

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

Glycogen synthase kinase 3 (GSK-3) has previously been shown to play an important role in the regulation of apoptosis. However, the nature of GSK-3 effector pathways that are relevant to neuroprotection remains poorly defined. Here, we have compared neuroprotection resulting from modulation of GSK-3 activity in PC12 cells using either selective small molecule ATP-competitive GSK-3 inhibitors (SB-216763 and SB-415286), or adenovirus overexpressing requently earranged in dvanced -cell lymphomas 1 (FRAT1), a protein proposed as a negative regulator of GSK-3 activity towards Axin and β-catenin. Our data demonstrate that cellular overexpression of FRAT1 is sufficient to confer neuroprotection and correlates with inhibition of GSK-3 activity towards Tau and β-catenin, but not modulation of glycogen synthase (GS) activity. By comparison, treatment with SB-216763 and SB-415286 proved more potent in terms of neuroprotection, and correlated with inhibition of GSK-3 activity towards GS in addition to Tau and β-catenin.

【 授权许可】

Unknown