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The v-Jun point mutation allows c-Jun to escape GSK3-dependent recognition and destruction by the Fbw7 ubiquitin

Wenyi Wei1, Jianping Jin, Susanne Schlisio

  • 1Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

Cancer Cell
|July 19, 2005
PubMed

Insights

Glycogen synthase kinase 3 (GSK3) phosphorylation targets c-Jun for degradation by the F-box and WD repeat domain-containing 7 (Fbw7) E3 ligase. This GSK3-Fbw7 pathway regulates c-Jun stability and oncogenic activity.

Area of Science:

  • Molecular Biology
  • Oncology
  • Cellular Biology

Background:

  • c-Jun and c-Myc are oncogenic transcription factors known for their instability.
  • Protein instability is often mediated by polyubiquitination and subsequent proteasomal degradation.

Purpose of the Study:

  • To investigate the regulatory mechanism of c-Jun protein stability.
  • To elucidate the role of GSK3 and Fbw7 in c-Jun degradation.
  • To compare the stability and oncogenicity of c-Jun and v-Jun.

Main Methods:

  • Phosphorylation assays to determine GSK3 activity on c-Jun.
  • Ubiquitination assays to assess polyubiquitination.
  • Western blotting to measure protein levels.
  • Cell cycle analysis in mammalian cells.

Main Results:

  • GSK3-mediated phosphorylation of c-Jun creates a binding site for the E3 ligase Fbw7.
  • Fbw7 targets phosphorylated c-Jun for polyubiquitination and proteasomal degradation.
  • c-Jun protein levels inversely correlate with GSK3 activity in cycling cells.
  • A priming phosphorylation at Ser-243 is essential for GSK3 action.
  • Mutation of Ser-243 to phenylalanine in v-Jun confers resistance to Fbw7-mediated degradation.

Conclusions:

  • GSK3 and Fbw7 act in concert to regulate c-Jun stability, similar to their known role in c-Myc regulation.
  • The phosphorylation status of c-Jun at Ser-243 dictates its susceptibility to Fbw7-mediated degradation.
  • Enhanced stability and oncogenicity of v-Jun are attributed to its escape from GSK3/Fbw7-mediated degradation.

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