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Updated: Jun 14, 2026

Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death
09:18

Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death

Published on: December 27, 2016

Glycogen synthase kinase-3 plays a central role in mediating glucocorticoid-induced apoptosis

Rachel Spokoini1, Shlomit Kfir-Erenfeld, Eitan Yefenof

  • 1The Lautenberg Center of Immunology, Institute of Medical Research, Faculty of Medicine, Hebrew University, Jerusalem, Israel.

Molecular Endocrinology (Baltimore, Md.)
|April 8, 2010
PubMed

Insights

Glucocorticoids (GCs) induce T cell death via glycogen synthase kinase 3 (GSK3). Inhibiting GSK3 or the Akt pathway can overcome GC resistance in lymphoma, improving therapy outcomes.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Glucocorticoids (GCs) are crucial for thymocyte apoptosis and T lymphoma treatment.
  • GC resistance in lymphoma cells limits therapeutic efficacy, necessitating new strategies.
  • The precise molecular mechanisms of GC-induced apoptosis remain incompletely understood.

Purpose of the Study:

  • To elucidate the signal transduction pathways mediating GC-induced apoptosis in thymocytes and T lymphoma.
  • To identify key kinases involved in GC sensitivity and resistance.
  • To explore novel therapeutic targets for overcoming GC resistance.

Main Methods:

  • Kinome-wide screening to identify signaling pathways.
  • Biochemical assays to study protein-protein interactions (GSK3, GR, Bim).
  • Pharmacological inhibition of GSK3 and the PI3K-Akt pathway.
  • Genetic manipulation using dominant-negative GSK3 mutants.
  • Analysis of Notch1 signaling in T acute lymphoblastic leukemia.

Main Results:

  • Glycogen synthase kinase 3 (GSK3) is identified as a central mediator of GC-induced apoptosis.
  • GSK3alpha interacts with the glucocorticoid receptor (GR) in the absence of ligand and dissociates upon GC exposure.
  • GSK3 activation leads to the proapoptotic protein Bim, crucial for GC-induced cell death.
  • Inhibition of GSK3 or the phosphatidylinositol-3 kinase-Akt pathway restores GC sensitivity.
  • Notch1 activation confers GC resistance by activating Akt, which inactivates GSK3.

Conclusions:

  • GSK3 is a critical downstream effector of GR signaling in GC-induced apoptosis.
  • Targeting GSK3 or the Akt pathway presents a promising strategy to enhance GC therapy for T lymphoma.
  • Understanding the interplay between GR, GSK3, Bim, and Akt/Notch1 pathways offers new avenues for overcoming GC resistance.

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