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Updated: Aug 15, 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

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A TRAIL receptor-dependent synthetic lethal relationship between MYC activation and GSK3beta/FBW7 loss of function

Sabine Rottmann1, Yan Wang, Marc Nasoff

  • 1Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA.

Proceedings of the National Academy of Sciences of the United States of America
|October 8, 2005
PubMed

Insights

Inactivating glycogen synthase kinase 3beta (GSK3beta) promotes cancer cell death in MYC-overexpressing cancers. This pathway stabilizes MYC, enhancing apoptosis and suggesting novel therapeutic strategies for MYC-driven tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • The MYC protooncogene is frequently deregulated in human cancers, driving tumor growth and progression.
  • Understanding pathways that regulate MYC stability and function is crucial for developing targeted cancer therapies.

Purpose of the Study:

  • To identify novel regulators of MYC-dependent apoptosis.
  • To investigate the role of glycogen synthase kinase 3beta (GSK3beta) in MYC-overexpressing cancer cells.

Main Methods:

  • Screening of a kinase-directed small inhibitory RNA library.
  • Analysis of apoptosis induction via TNF-related apoptosis-inducing ligand (TRAIL) death receptor pathway.
  • Investigation of MYC phosphorylation, ubiquitination, and stabilization.
  • In vitro and in vivo apoptosis assays.

Main Results:

  • GSK3beta inactivation potentiates TRAIL-mediated apoptosis specifically in MYC-overexpressing cells.
  • GSK3beta inhibition prevents MYC phosphorylation at T58, blocking FBW7-mediated degradation.
  • Attenuating the GSK3beta-FBW7 axis stabilizes MYC and up-regulates death receptor 5 (DR5) surface levels.
  • Enhanced DR5-induced apoptosis was observed both in vitro and in vivo.

Conclusions:

  • GSK3beta and FBW7 are potential cancer therapeutic targets.
  • MYC is a critical substrate in the GSK3beta survival-signaling pathway.
  • MYC-expressing tumors may be treatable with drug combinations that paradoxically increase MYC oncoprotein function.

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