GSK-3 inhibition by adenoviral FRAT1 overexpression is neuroprotective and induces Tau dephosphorylation and beta-catenin stabilisation without elevation of glycogen synthase activity.
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 frequently rearranged in advanced T-cell lymphomas 1 (FRAT1), a protein proposed as a negative regulator of GSK-3 activity towards Axin and beta-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 beta-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 beta-catenin.
Culbert
A A
AA
Neurology Centre of Excellence in Drug Discovery, GlaxoSmithKline Pharmaceuticals, Essex, UK.
Brown
M J
MJ
Frame
S
S
Hagen
T
T
Cross
D A
DA
Bax
B
B
Reith
A D
AD
D048868:Adaptor Proteins, Signal Transducing; D000256:Adenoviridae / Q000235:genetics; D000627:Aminophenols / Q000494:pharmacology; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002352:Carrier Proteins; D003593:Cytoplasm / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D007211:Indoles / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D009363:Neoplasm Proteins; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents; D016716:PC12 Cells; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D015534:Trans-Activators; D051176:beta Catenin; D016875:tau Proteins / Q000378:metabolism*
C417520:3-(3-chloro-4-hydroxyphenylamino)-4-(4-nitrophenyl)-1H-pyrrole-2,5-dione; D048868:Adaptor Proteins, Signal Transducing; D000627:Aminophenols; D002352:Carrier Proteins; C495268:Ctnnb1 protein, rat; D003598:Cytoskeletal Proteins; D004791:Enzyme Inhibitors; C491818:Frat1 protein, mouse; D007211:Indoles; D008301:Maleimides; D009363:Neoplasm Proteins; D018696:Neuroprotective Agents; D011518:Proto-Oncogene Proteins; C417521:SB 216763; D015534:Trans-Activators; D051176:beta Catenin; D016875:tau Proteins; D038341:Glycogen Synthase Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3