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GSK3β inactivation induces apoptosis of leukemia cells by repressing the function of c-Myb

Fangfang Zhou1, Long Zhang, Theo van Laar

  • 1Department of Molecular Cell Biology and Centre for Biomedical Genetics, Leiden University Medical Center, 2300 RC Leiden, Netherlands.

Molecular Biology of the Cell
|July 29, 2011
PubMed

Insights

Glycogen synthase kinase 3β (GSK3β) inhibition triggers apoptosis in leukemia cells by degrading transcription factor c-Myb. This blocks antiapoptotic genes, revealing a novel GSK3β role in cancer cell survival.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Glycogen synthase kinase 3β (GSK3β) is a key regulator of numerous cellular processes.
  • GSK3β kinase activity is implicated in various cancers, but its precise role in leukemia survival is unclear.

Purpose of the Study:

  • To elucidate the mechanism by which GSK3β regulates leukemia cell survival.
  • To identify the key molecular targets of GSK3β in leukemia.

Main Methods:

  • GSK3β kinase inhibition assays in leukemia cell lines.
  • Western blotting to assess protein levels and degradation.
  • Coimmunoprecipitation and chromatin immunoprecipitation assays.
  • Reporter assays and gene knockdown studies.

Main Results:

  • GSK3β inhibition induces apoptosis and proliferation defects in leukemia cells.
  • Transcription factor c-Myb is identified as a primary target of GSK3β.
  • GSK3β inactivation promotes c-Myb degradation via ubiquitination.
  • Reduced c-Myb expression leads to decreased Bcl2 and survivin antiapoptotic gene expression.
  • c-Myb cooperates with transcription factor LEF-1 to activate Bcl2 and survivin.

Conclusions:

  • GSK3β controls leukemia cell survival through the c-Myb/LEF-1 transcriptional complex.
  • Targeting GSK3β represents a potential therapeutic strategy for leukemia by disrupting this survival pathway.

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