Glycogen synthase kinase-3β facilitates staurosporine- and heat shock- induced apoptosis. Protection by lithium

Gautam N. Bijur, Patrizia De Sarno, Richard S. Jope

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Abstract

The potential role of glycogen synthase kinase-3β in modulating apoptosis was examined in human SH-SY5Y neuroblastoma cells. Staurosporine treatment caused time- and concentration-dependent increases in the activities of caspase-3 and caspase-9 but not caspase-1, increased proteolysis of poly(ADP-ribose) polymerase, and induced morphological changes consistent with apoptosis. Overexpression of glycogen synthase kinase-3β to levels 3.5 times that in control cells did not alter basal indices of apoptosis but potentiated staurosporine-induced activation of caspase-3, caspase-9, proteolysis of poly(ADP-ribose) polymerase, and morphological changes indicative of apoptosis. Inhibition of glycogen synthase kinase-3β by lithium attenuated the enhanced staurosporine-induced activation of caspase-3 in cells overexpressing glycogen synthase kinase-3β. In cells subjected to heat shock, caspase-3 activity was more than three times greater in glycogen synthase kinase-3β-transfected than control cells, and this potentiated response was inhibited by lithium treatment. Thus, glycogen synthase kinase-3β facilitated apoptosis induced by two experimental paradigms. These findings indicate that glycogen synthase kinase-3β may contribute to proapoptotic-signaling activity, that inhibition of glycogen synthase kinase-3β can contribute to anti-apoptotic-signaling mechanisms, and that the neuroprotective actions of lithium may be due in part to its inhibitory modulation of glycogen synthase kinase-3β.

Original languageEnglish (US)
Pages (from-to)7583-7590
Number of pages8
JournalJournal of Biological Chemistry
Volume275
Issue number11
DOIs
StatePublished - Mar 17 2000
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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