Inhibitors of protein phosphatases 1 and 2A differentially prevent intrinsic and extrinsic apoptosis pathways

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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

Published on: December 27, 2016

Kathryn Chatfield1, Alan Eastman

  • 1Norris Cotton Cancer Center, Dartmouth Medical School, Lebanon, NH 03756, USA.

Biochemical and Biophysical Research Communications
|September 29, 2004
PubMed

Insights

Serine/threonine protein phosphatase inhibitors block apoptosis. Protein phosphatase 2A (PP2A) inhibition protected against mitochondrial apoptosis, while Protein phosphatase 1 (PP1) inhibition protected against death receptor apoptosis.

Area of Science:

  • Cell Biology
  • Biochemistry
  • Molecular Biology

Background:

  • Apoptosis, or programmed cell death, is a critical cellular process.
  • Serine/threonine protein phosphatases play a role in regulating apoptosis.
  • Understanding the specific roles of different phosphatases is crucial for therapeutic development.

Purpose of the Study:

  • To investigate the specific roles of Protein phosphatase 1 (PP1) and Protein phosphatase 2A (PP2A) in apoptosis.
  • To determine which phosphatases are critical for inhibiting apoptosis induced by different pathways.

Main Methods:

  • Utilized three serine/threonine protein phosphatase inhibitors: calyculin A, okadaic acid, and tautomycin.
  • Assessed apoptosis inhibition in leukemia cell models.
  • Measured protein phosphorylation to determine effective inhibitor concentrations.
  • Investigated effects on mitochondrial pathways (Bax translocation) and death receptor pathways (Fas receptor, FADD, caspase 8).

Main Results:

  • All inhibitors prevented anisomycin-induced apoptosis, correlating with PP2A inhibition.
  • Inhibitors prevented Bax translocation to mitochondria, indicating upstream mitochondrial pathway regulation.
  • Tautomycin and calyculin A, but not okadaic acid, prevented CD95/Fas death receptor-induced apoptosis, correlating with PP1 inhibition.
  • Inhibition of Fas receptor oligomerization, FADD recruitment, and caspase 8 activation was observed.

Conclusions:

  • PP2A is critical for protecting against mitochondrial-mediated apoptosis.
  • PP1 is critical for protecting against death receptor-mediated apoptosis.
  • These findings highlight the distinct roles of PP1 and PP2A in regulating apoptosis pathways.

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