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The Wnt pool of glycogen synthase kinase 3beta is critical for trophic-deprivation-induced neuronal death.
Mol Cell Biol. 2008 Mar; 28(5):1515-27.MC

Abstract

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-3beta, but not GSK-3alpha, 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-3alpha/beta) phosphorylation on proapoptotic GSK-3 function. Neurons isolated from GSK-3alpha/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-3alpha/beta(S21A/S9A) neurons from death. This indicates that dephosphorylation of GSK-3beta/Ser9 and GSK-3alpha/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-3beta from a high-molecular-mass complex with a concomitant decrease in axin-bound GSK-3beta. These data imply that Wnt-regulated GSK-3beta plays a nonredundant role in trophic-deprivation-induced death of neurons.

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Authors+Show Affiliations

Hongisto V
Turku Centre for Biotechnology, Turku University and Abo Akademi University, BioCity, Tykistokatu 6, Turku FIN-20521, Finland.
Vainio JC
No affiliation info available
Thompson R
No affiliation info available
Courtney MJ
No affiliation info available
Coffey ET
No affiliation info available

MeSH

AlanineAmino Acid SubstitutionAnimalsCell DeathCell LineEnzyme InhibitorsFatty Acids, UnsaturatedGene Expression RegulationGlutathione TransferaseGlycogen Synthase Kinase 3Glycogen Synthase Kinase 3 betaHomozygoteHumansIndolesKidneyLithiumMaleimidesMiceNeuronsPhosphorylationRNA, Small InterferingRatsRats, Sprague-DawleyRecombinant ProteinsTime FactorsTransfectionWnt Proteins

Pub Type(s)

Comparative Study
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18195042

Citation

Hongisto, Vesa, et al. "The Wnt Pool of Glycogen Synthase Kinase 3beta Is Critical for Trophic-deprivation-induced Neuronal Death." Molecular and Cellular Biology, vol. 28, no. 5, 2008, pp. 1515-27.
Hongisto V, Vainio JC, Thompson R, et al. The Wnt pool of glycogen synthase kinase 3beta is critical for trophic-deprivation-induced neuronal death. Mol Cell Biol. 2008;28(5):1515-27.
Hongisto, V., Vainio, J. C., Thompson, R., Courtney, M. J., & Coffey, E. T. (2008). The Wnt pool of glycogen synthase kinase 3beta is critical for trophic-deprivation-induced neuronal death. Molecular and Cellular Biology, 28(5), 1515-27. https://doi.org/10.1128/MCB.02227-06
Hongisto V, et al. The Wnt Pool of Glycogen Synthase Kinase 3beta Is Critical for Trophic-deprivation-induced Neuronal Death. Mol Cell Biol. 2008;28(5):1515-27. PubMed PMID: 18195042.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The Wnt pool of glycogen synthase kinase 3beta is critical for trophic-deprivation-induced neuronal death. AU - Hongisto,Vesa, AU - Vainio,Jenni C, AU - Thompson,Róisín, AU - Courtney,Michael J, AU - Coffey,Eleanor T, Y1 - 2008/01/14/ PY - 2008/1/16/pubmed PY - 2008/3/18/medline PY - 2008/1/16/entrez SP - 1515 EP - 27 JF - Molecular and cellular biology JO - Mol Cell Biol VL - 28 IS - 5 N2 - 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-3beta, but not GSK-3alpha, 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-3alpha/beta) phosphorylation on proapoptotic GSK-3 function. Neurons isolated from GSK-3alpha/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-3alpha/beta(S21A/S9A) neurons from death. This indicates that dephosphorylation of GSK-3beta/Ser9 and GSK-3alpha/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-3beta from a high-molecular-mass complex with a concomitant decrease in axin-bound GSK-3beta. These data imply that Wnt-regulated GSK-3beta plays a nonredundant role in trophic-deprivation-induced death of neurons. SN - 1098-5549 UR - https://www.unboundmedicine.com/medline/citation/18195042/The_Wnt_pool_of_glycogen_synthase_kinase_3beta_is_critical_for_trophic_deprivation_induced_neuronal_death_ DB - PRIME DP - Unbound Medicine ER -