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AXIN is an essential co-activator for the promyelocytic leukemia protein in p53 activation

Q Li1, Y He, L Wei

  • 1Key Laboratory of Ministry of Education for Cell Biology and Tumor Cell Engineering, Fujian Laboratory for Cancer Biology, School of Life Sciences, Xiamen University, Fujian, China.

Oncogene
|November 9, 2010
PubMed

Insights

The tumor suppressors AXIN and PML (promyelocytic leukemia protein) form a complex to activate p53 and induce apoptosis after DNA damage. This interaction is crucial for their tumor suppressor functions.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Cellular Signaling

Background:

  • The promyelocytic leukemia (PML) protein is a known tumor suppressor, particularly in acute promyelocytic leukemia.
  • Both PML and AXIN (a Wnt signaling regulator) are involved in p53-dependent apoptosis following DNA damage.
  • The coordinated mechanism between PML and AXIN in tumor suppression remained unclear.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which PML and AXIN cooperate in tumor suppression.
  • To identify the components and interactions involved in PML-induced apoptosis.
  • To understand how these two major tumor suppressors coordinate their functions.

Main Methods:

  • In vivo protein interaction studies (co-immunoprecipitation).
  • Formation of ternary complex analysis (AXIN, PML, p53).
  • Cellular localization studies upon genotoxic stress (UV, doxorubicin).
  • Domain-mapping for AXIN-PML interaction.
  • Gene knockdown experiments (siRNA) and analysis of p53 activation and apoptosis.
  • Use of dominant-negative mutants and assessment of PML sumoylation.

Main Results:

  • AXIN and PML interact in vivo and form a ternary complex with p53.
  • Genotoxic stress induces nuclear translocation and co-localization of AXIN with PML in nuclear bodies.
  • The C-terminal region of AXIN mediates interaction with PML.
  • AXIN and PML are mutually dependent for p53 activation (p53-Ser-46 phosphorylation) and apoptosis induction.
  • AXIN promotes PML sumoylation, a key modification for PML function.

Conclusions:

  • AXIN and PML form a functional complex that is essential for p53 activation and apoptosis in response to DNA damage.
  • AXIN's nuclear import and PML sumoylation are critical steps in this tumor suppressor pathway.
  • This study reveals a novel mechanism for PML-mediated tumor suppression, highlighting the coordinated action of AXIN and PML.

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