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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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PP2A inactivation is a crucial step in triggering apoptin-induced tumor-selective cell killing

R Zimmerman1, D J Peng, H Lanz

  • 1Department of Molecular Genetics, Leiden Institute for Chemistry, Leiden University, Leiden, The Netherlands.

Cell Death & Disease
|April 6, 2012
PubMed

Insights

Apoptin phosphorylation, crucial for tumor cell death, is triggered by inactivation of protein phosphatase 2A (PP2A) subunits. This discovery offers insights into developing safer, effective anticancer agents targeting tumor cells specifically.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Apoptin, an apoptosis-inducing protein, exhibits tumor-selective properties, suggesting its potential as a safe anticancer agent.
  • Apoptin phosphorylation is essential for inducing apoptosis in tumor cells, but not in normal cells.

Purpose of the Study:

  • To investigate the minimal cellular factors required for apoptin activation using an in vitro oncogenic transformation assay.
  • To elucidate the role of SV40 antigens and associated cellular pathways in regulating apoptin phosphorylation and subsequent apoptosis.

Main Methods:

  • Introduction of Flag-apoptin into normal fibroblasts with SV40 large T and small t antigens.
  • Utilizing mutational analysis to assess the impact of SV40 small t antigen binding to protein phosphatase 2A (PP2A) on apoptin phosphorylation.
  • Employing knockdown of PP2A subunits (B56γ and B56δ) and modulation of protein kinase A (PKA) activity to study their effects on apoptin phosphorylation.

Main Results:

  • Nuclear expression of SV40 small t antigen in normal cells induced apoptin phosphorylation.
  • Disruption of SV40 small t antigen binding to PP2A counteracted this phosphorylation.
  • Knockdown of PP2A-B56γ or PP2A-B56δ subunits mimicked SV40 small t antigen effects, inducing apoptin phosphorylation.
  • Inhibition of PKA increased apoptin phosphorylation in tumor cells, while PKA activation reduced it.

Conclusions:

  • Inactivation of PP2A, particularly its B56γ and B56δ subunits, is a critical step in initiating apoptin-induced tumor-selective cell death.
  • The interplay between PP2A, PKA, and SV40 antigens regulates apoptin activation, highlighting a potential therapeutic target for cancer treatment.

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