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Wild-type, mitochondrial and ER-restricted Bcl-2 inhibit DNA damage-induced apoptosis but do not affect death

J Rudner1, A Lepple-Wienhues, W Budach

  • 1Department of Radiation Oncology, University of Tübingen, Hoppe-Seyler Str. 3, D-72076 Tübingen, Germany.

Journal of Cell Science
|December 12, 2001
PubMed

Insights

Bcl-2 protein localized to mitochondria or endoplasmic reticulum protects cells from radiation-induced apoptosis. This suggests crosstalk between organelles in cell death pathways, but Bcl-2 did not affect death receptor-induced apoptosis.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • The proto-oncogene Bcl-2 confers resistance to apoptosis but its precise function in distinct cellular organelles is unclear.
  • Bcl-2 is typically found in mitochondrial and endoplasmic reticulum membranes.

Purpose of the Study:

  • To investigate the role of Bcl-2 in specific subcellular compartments during apoptosis.
  • To determine if Bcl-2 localization influences its anti-apoptotic function.

Main Methods:

  • Engineered Jurkat cells expressing Bcl-2 targeted to mitochondria (Bcl-2/MT) or endoplasmic reticulum (Bcl-2/ER).
  • Utilized wild-type Bcl-2 (Bcl-2/WT) and a mutant lacking a transmembrane domain (Bcl-2/DeltaTM).
  • Assessed apoptosis, mitochondrial membrane potential (ΔΨm), and caspase activation following ionizing radiation, CD95L, or TRAIL treatment.

Main Results:

  • Bcl-2/WT and Bcl-2/MT significantly inhibited radiation-induced apoptosis and caspase activation.
  • Bcl-2/ER also protected against radiation-induced apoptosis and mitochondrial damage, similar to Bcl-2/MT.
  • Bcl-2/DeltaTM lost all anti-apoptotic effects.
  • ER-localized Bcl-2 impacted mitochondrial membrane potential and caspase-9 activation, indicating organelle crosstalk.
  • Bcl-2 localization did not affect CD95- or TRAIL-mediated apoptosis.

Conclusions:

  • Mitochondrial or ER localization of Bcl-2 is crucial for its anti-apoptotic function against radiation.
  • A crosstalk mechanism exists between the endoplasmic reticulum and mitochondria in radiation-induced apoptosis.
  • Bcl-2's role in death receptor-mediated apoptosis differs from its role in radiation-induced apoptosis.

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