Central role of glycogen synthase kinase-3β in endoplasmic reticulum stress-induced caspase-3 activation

Ling Song, Patrizia De Sarno, Richard S Jope

Research output: Contribution to journalArticle

227 Citations (Scopus)

Abstract

Stress of the endoplasmic reticulum (ER), which is associated with many neurodegenerative conditions, can lead to the elimination of affected cells by apoptosis through only partially understood mechanisms. Thapsigargin, which causes ER stress by inhibiting the ER Ca2+-ATPase, was found to not only activate the apoptosis effector caspase-3 but also to cause a large and prolonged increase in the activity of glycogen synthase kinase-3β (GSK3β). Activation of GSK3β was obligatory for thapsigargin-induced activation of caspase-3, because inhibition of GSK3β by expression of dominant-negative GSK3β or by the GSK3β inhibitor lithium blocked caspase-3 activation. Thapsigargin treatment activated GSK3β by inducing dephosphorylation of phospho-Ser-9 of GSK3β, a phosphorylation that normally maintains GSK3β inactivated. Caspase-3 activation induced by thapsigargin was blocked by increasing the phosphorylation of Ser-9-GSK3β with insulin-like growth factor-1 or with the phosphatase inhibitors okadaic acid and calyculin A, but the calcineurin inhibitors FK506 and cyclosporin A were ineffective. Insulin-like growth factor-1, okadaic acid, calyculin A, and lithium also protected cells from two other inducers of ER stress, tunicamycin and brefeldin A. Thus, ER stress activates GSK3β through dephosphorylation of phospho-Ser-9, a prerequisite for caspase-3 activation, and this process is amenable to pharmacological intervention.

Original languageEnglish
Pages (from-to)44701-44708
Number of pages8
JournalJournal of Biological Chemistry
Volume277
Issue number47
DOIs
StatePublished - Nov 22 2002
Externally publishedYes

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Glycogen Synthase Kinase 3
Endoplasmic Reticulum Stress
Caspase 3
Chemical activation
Thapsigargin
Okadaic Acid
Phosphorylation
Somatomedins
Lithium
Effector Caspases
Apoptosis
Brefeldin A
Tunicamycin
Calcium-Transporting ATPases
Tacrolimus
Phosphoric Monoester Hydrolases
Endoplasmic Reticulum
Cyclosporine
Pharmacology

ASJC Scopus subject areas

  • Biochemistry

Cite this

Central role of glycogen synthase kinase-3β in endoplasmic reticulum stress-induced caspase-3 activation. / Song, Ling; De Sarno, Patrizia; Jope, Richard S.

In: Journal of Biological Chemistry, Vol. 277, No. 47, 22.11.2002, p. 44701-44708.

Research output: Contribution to journalArticle

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