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GSK‐3 inhibition by adenoviral FRAT1 overexpression is neuroprotective and induces Tau dephosphorylation and β‐catenin stabilisation without elevation of glycogen synthase activity
Author(s) -
Culbert Ainsley A.,
Brown Murray J.,
Frame Sheelagh,
Hagen Thilo,
Cross Darren A.E.,
Bax Benjamin,
Reith Alastair D.
Publication year - 2001
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/s0014-5793(01)02990-8
Subject(s) - gsk 3 , neuroprotection , gsk3b , glycogen synthase , dephosphorylation , chemistry , microbiology and biotechnology , catenin , phosphorylation , atp synthase , cancer research , signal transduction , biology , biochemistry , neuroscience , enzyme , phosphatase , wnt signaling pathway
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.