Neural precursor cells are protected from apoptosis induced by trophic factor withdrawal or genotoxic stress by inhibitors of glycogen synthase kinase 3

Tae Yeon Eom, Kevin A. Roth, Richard S. Jope

Research output: Contribution to journalArticle

47 Scopus citations

Abstract

Mechanisms controlling the survival of neural precursor cells (NPCs) are critical during brain development, in adults for neuron replenishment, and after transplantation for neuron replacement. This investigation found that glycogen synthase kinase 3 (GSK3) promotes apoptotic signaling in cultured NPCs derived from embryonic mouse brain subjected to two common apoptotic conditions, trophic factor withdrawal and genotoxic stress. Trophic factor withdrawal activated GSK3 and the key apoptosis mediators Bax and caspase-3. Pharmacological inhibition of GSK3 activity produced dramatic reductions in the activation of Bax and caspase-3 and NPC death after trophic factor withdrawal. Trophic factor withdrawal-induced apoptosis was delayed in Bax knock-out NPCs, but GSK3 inhibitors provided additional protection. Genotoxic stress induced by camptothecin treatment of NPCs stabilized p53, which formed a complex with GSK3β and activated Bax and caspase-3. Camptothecin-induced activation of caspase-3 was reduced by GSK3 inhibitors in both bax+/+ and bax -/- NPCs. Thus, NPCs are sensitive to loss of trophic factors and genotoxic stress, and inhibitors of GSK3 are capable of enhancing NPC survival.

Original languageEnglish (US)
Pages (from-to)22856-22864
Number of pages9
JournalJournal of Biological Chemistry
Volume282
Issue number31
DOIs
StatePublished - Aug 3 2007
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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