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08:47

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Published on: March 5, 2018

Blockade of tumor necrosis factor-induced Bid cleavage by caspase-resistant Rb

XiaoDong Huang1, Anja Masselli, Steven M Frisch

  • 1Division of Biological Sciences, Department of Medicine, University of California, San Diego, La Jolla, California 92093-0820, USA.

The Journal of Biological Chemistry
|August 10, 2007
PubMed

Insights

Tumor necrosis factor-alpha (TNF) triggers apoptosis via caspase-8. This study reveals retinoblastoma protein (Rb) cleavage is crucial for TNF-induced type-2 apoptosis, a process V-ATPase inhibition can restore.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Apoptosis Research

Background:

  • Tumor necrosis factor-alpha (TNF) initiates apoptosis through caspase-8 activation, leading to type-1 or type-2 cell death pathways.
  • Type-2 apoptosis involves Bid cleavage, a critical step in the TNF signaling cascade.

Purpose of the Study:

  • To investigate the role of retinoblastoma protein (Rb) cleavage in TNF-induced type-2 apoptosis.
  • To explore the impact of V-ATPase inhibition on apoptosis pathways in Rb-mutated cells.

Main Methods:

  • Utilized fibroblasts from Rb(MI/MI) mice with a mutated caspase cleavage site.
  • Assessed Bid cleavage and apoptosis induction in response to TNF.
  • Investigated the effect of V-ATPase inhibition on these processes.

Main Results:

  • TNF induces caspase-8-dependent Rb cleavage.
  • Rb(MI/MI) fibroblasts show defective Bid cleavage upon TNF stimulation.
  • Inhibition of V-ATPase restores Bid cleavage in Rb(MI/MI) cells and sensitizes them to TNF-induced apoptosis.
  • V-ATPase inhibition also stimulates colonic apoptosis in Rb(MI/MI) mice.

Conclusions:

  • Rb cleavage is essential for Bid cleavage in TNF-induced type-2 apoptosis.
  • V-ATPase inhibition can bypass the requirement for Rb cleavage, restoring type-2 apoptosis.
  • These findings offer insights into regulating TNF-mediated cell death pathways.

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