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Yeast As a Chassis for Developing Functional Assays to Study Human P53
14:57

Yeast As a Chassis for Developing Functional Assays to Study Human P53

Published on: August 4, 2019

A cytoplasmic PML mutant inhibits p53 function

Cristian Bellodi1, Karin Kindle, Francesca Bernassola

  • 1MRC Toxicology Unit, Leicester, UK.

Cell Cycle (Georgetown, Tex.)
|December 19, 2006
PubMed

Insights

Cytoplasmic promyelocytic leukaemia (PML) proteins, previously uncharacterized, relocate nuclear PML, disrupt PML nuclear bodies, and inhibit p53 functions, impacting cell survival in aggressive acute promyelocytic leukaemia (APL).

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Cancer Genetics

Background:

  • The promyelocytic leukaemia gene (Pml) acts as a tumor suppressor, notably in acute promyelocytic leukaemia (APL) through its fusion with RAR alpha.
  • While nuclear PML (nPML) is well-studied for its role in PML nuclear bodies (PML-NBs) and p53 regulation, cytoplasmic PML isoforms are less understood.
  • Mutations leading to truncated cytoplasmic PML proteins (Mut PML) are found in aggressive APL cases.

Purpose of the Study:

  • To investigate the role and impact of cytoplasmic PML proteins on nuclear PML functions and cellular regulation.
  • To elucidate the mechanism by which cytoplasmic PML affects PML nuclear bodies and p53 activity.
  • To understand the implications of cytoplasmic PML expression in aggressive APL.

Main Methods:

  • Characterization of cytoplasmic PML protein localization and its effect on PML nuclear bodies.
  • Assessment of p53 transcriptional, growth suppressive, and apoptotic functions in the presence of cytoplasmic PML.
  • Analysis of missense mutations leading to truncated cytoplasmic PML proteins.

Main Results:

  • Cytoplasmic PML induces the relocation of nPML from PML nuclear bodies to the cytoplasm, reducing PML-NB numbers.
  • Mut PML significantly inhibits p53's transcriptional, growth suppressive, and apoptotic activities.
  • Cytoplasmic expression of PML demonstrates a survival advantage through p53 inhibition.

Conclusions:

  • Cytoplasmic PML proteins play a critical role in regulating nuclear PML functions and cellular fate.
  • The aberrant cytoplasmic expression of PML, particularly Mut PML, contributes to oncogenesis by inactivating the tumor suppressor p53.
  • These findings highlight cytoplasmic PML as a potential therapeutic target in APL and other cancers.

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