A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
The Wnt pool of glycogen synthase kinase 3 beta is critical for trophic-deprivation-induced neuronal death
Tekijät: Hongisto V, Vainio JC, Thompson R, Courtney MJ, Coffey ET
Kustantaja: AMER SOC MICROBIOLOGY
Julkaisuvuosi: 2008
Journal: Molecular and Cellular Biology
Tietokannassa oleva lehden nimi: MOLECULAR AND CELLULAR BIOLOGY
Lehden akronyymi: MOL CELL BIOL
Vuosikerta: 28
Numero: 5
Aloitussivu: 1515
Lopetussivu: 1527
Sivujen määrä: 13
ISSN: 0270-7306
DOI: https://doi.org/10.1128/MCB.02227-06
Tiivistelmä
Glycogen synthase kinase 3 (GSK-3) is implicated in neuronal death through a causal role, and precise mechanisms have not been unambiguously defined. We show that short hairpin RNA (shRNA) knockdown of GSK-3 beta, but not GSK-3 alpha, protects cerebellar granule neurons from trophic-deprivation-induced death. Using compartment-targeted inhibitors of the Wnt-regulated GSK-3 pool, NLS-FRAT1, NES-FRAT1, and axin-GSK-3-interacting domain (axin-GID), we locate proapoptotic GSK-3 action to the cytosol and regulation of Bim protein turnover despite constitutive cycling of GSK-3 between the cytosol and nucleus, revealed by leptomycin B. We examine the importance of Ser21/9 (GSK-3 alpha/beta) phosphorylation on proapoptotic GSK-3 function. Neurons isolated from GSK-3 alpha/beta(S21A/S9A) knock-in mice survive normally and are fully sensitive to trophic-deprivation-induced death. Nonetheless, inhibition of GSK-3 catalytic activity with lithium or SB216763 protects GSK-3 alpha/beta(S21A/S9A) neurons from death. This indicates that dephosphorylation of GSK-3 beta/Ser9 and GSK-3 alpha/Ser21 is insufficient for GSK-3 proapoptotic function and that another level of regulation is required. Gel filtration reveals a stress-induced loss of neuronal GSK-3 beta from a high-molecular-mass complex with a concomitant decrease in axin-bound GSK-3 beta. These data imply that Wnt-regulated GSK-3 beta plays a nonredundant role in trophic-deprivation-induced death of neurons.
Glycogen synthase kinase 3 (GSK-3) is implicated in neuronal death through a causal role, and precise mechanisms have not been unambiguously defined. We show that short hairpin RNA (shRNA) knockdown of GSK-3 beta, but not GSK-3 alpha, protects cerebellar granule neurons from trophic-deprivation-induced death. Using compartment-targeted inhibitors of the Wnt-regulated GSK-3 pool, NLS-FRAT1, NES-FRAT1, and axin-GSK-3-interacting domain (axin-GID), we locate proapoptotic GSK-3 action to the cytosol and regulation of Bim protein turnover despite constitutive cycling of GSK-3 between the cytosol and nucleus, revealed by leptomycin B. We examine the importance of Ser21/9 (GSK-3 alpha/beta) phosphorylation on proapoptotic GSK-3 function. Neurons isolated from GSK-3 alpha/beta(S21A/S9A) knock-in mice survive normally and are fully sensitive to trophic-deprivation-induced death. Nonetheless, inhibition of GSK-3 catalytic activity with lithium or SB216763 protects GSK-3 alpha/beta(S21A/S9A) neurons from death. This indicates that dephosphorylation of GSK-3 beta/Ser9 and GSK-3 alpha/Ser21 is insufficient for GSK-3 proapoptotic function and that another level of regulation is required. Gel filtration reveals a stress-induced loss of neuronal GSK-3 beta from a high-molecular-mass complex with a concomitant decrease in axin-bound GSK-3 beta. These data imply that Wnt-regulated GSK-3 beta plays a nonredundant role in trophic-deprivation-induced death of neurons.
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