Selective small-molecule inhibitors of glycogen synthase kinase-3 activity protect primary neurones from death

被引:259
作者
Cross, DAE [1 ]
Culbert, AA [1 ]
Chalmers, KA [1 ]
Facci, L [1 ]
Skaper, SD [1 ]
Reith, AD [1 ]
机构
[1] GlaxoSmithKline Pharmaceut, Neurol Ctr Excellence Drug Discovery, Harlow CM19 5AW, Essex, England
关键词
glycogen synthase kinase-3; kinase inhibitors; neuronal survival; protein kinase B; tau; beta-catenin;
D O I
10.1046/j.1471-4159.2001.00251.x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The phosphatidylinositol 3-kinase (PI 3-kinase)/protein kinase B (PKB; also known as AM) signalling pathway is recognized as playing a central role in the survival of diverse cell types. Glycogen synthase kinase-3 (GSK-3) isa ubiquitously expressed serine/threonine protein kinase that is one of several known substrates of PKB. PKB phosphorylates; GSK-3 in response to insulin and growth factors, which inhibits GSK-3 activity and leads to the modulation of multiple GSK-3 regulated cellular processes. We show that the novel potent and selective small-molecule inhibitors of GSK-3; SB-415286 and SB-216763, protect both central and peripheral nervous system neurones in culture from death induced by reduced PI 3-kinase pathway activity. The inhibition of neuronal death mediated by these compounds correlated with inhibition of GSK-3 activity and modulation of GSK-3 substrates tau and beta -catenin. Thus, in addition to the previously assigned roles of GSK-3, our data provide clear pharmacological and biochemical evidence that selective inhibition of the endogenous pool of GSK-3 activity in primary neurones is sufficient to prevent death, implicating GSK-3 as a physiologically relevant principal regulatory target of the PI 3-kinase/PKB neuronal survival pathway.
引用
收藏
页码:94 / 102
页数:9
相关论文
共 46 条
[1]   Mechanism of activation and function of protein kinase B [J].
Alessi, DR ;
Cohen, P .
CURRENT OPINION IN GENETICS & DEVELOPMENT, 1998, 8 (01) :55-62
[2]  
Baldessarini RJ, 1999, J CLIN PSYCHIAT, V60, P77
[3]   NEURAL AND DEVELOPMENTAL ACTIONS OF LITHIUM - A UNIFYING HYPOTHESIS [J].
BERRIDGE, MJ ;
DOWNES, CP ;
HANLEY, MR .
CELL, 1989, 59 (03) :411-419
[4]   Regulation and localization of tyrosine216 phosphorylation of glycogen synthase kinase-3β in cellular and animal models of neuronal degeneration [J].
Bhat, RV ;
Shanley, J ;
Correll, MP ;
Fieles, WE ;
Keith, RA ;
Scott, CW ;
Lee, CM .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2000, 97 (20) :11074-11079
[5]   Regulation of cell death protease caspase-9 by phosphorylation [J].
Cardone, MH ;
Roy, N ;
Stennicke, HR ;
Salvesen, GS ;
Franke, TF ;
Stanbridge, E ;
Frisch, S ;
Reed, JC .
SCIENCE, 1998, 282 (5392) :1318-1321
[6]   Lithium activates the serine/threonine kinase Akt-1 and suppresses glutamate-induced inhibition of Akt-1 activity in neurons [J].
Chalecka-Franaszek, E ;
Chuang, DM .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (15) :8745-8750
[7]   Selective small molecule inhibitors of glycogen synthase kinase-3 modulate glycogen metabolism and gene transcription [J].
Coghlan, MP ;
Culbert, AA ;
Cross, DAE ;
Corcoran, SL ;
Yates, JW ;
Pearce, NJ ;
Rausch, OL ;
Murphy, GJ ;
Carter, PS ;
Cox, LR ;
Mills, D ;
Brown, MJ ;
Haigh, D ;
Ward, RW ;
Smith, DG ;
Murray, KJ ;
Reith, AD ;
Holder, JC .
CHEMISTRY & BIOLOGY, 2000, 7 (10) :793-803
[8]   The development and therapeutic potential of protein kinase inhibitors [J].
Cohen, P .
CURRENT OPINION IN CHEMICAL BIOLOGY, 1999, 3 (04) :459-465
[9]   INHIBITION OF GLYCOGEN-SYNTHASE KINASE-3 BY INSULIN-MEDIATED BY PROTEIN-KINASE-B [J].
CROSS, DAE ;
ALESSI, DR ;
COHEN, P ;
ANDJELKOVICH, M ;
HEMMINGS, BA .
NATURE, 1995, 378 (6559) :785-789
[10]   Glycogen synthase kinase-3β activity is critical for neuronal death caused by inhibiting phosphatidylinositol 3-kinase or Akt but not for death caused by nerve growth factor withdrawal [J].
Crowder, RJ ;
Freeman, RS .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (44) :34266-34271