Cleavage of BID During Cytotoxic Drug and UV Radiation-Induced Apoptosis Occurs Downstream of the Point of Bcl-2 Action and Is Catalysed by caspase-3: A Potential Feedback Loop for Amplification of Apoptosis-Associated Mitochondrial Cytochrome C Release

Cell Death Differ. 2000 Jun;7(6):556-65. doi: 10.1038/sj.cdd.4400689.

Abstract

BID, a pro-apoptotic Bcl-2 family member, promotes cytochrome c release during apoptosis initiated by CD95L or TNF. Activation of caspase-8 in the latter pathways results in cleavage of BID, translocation of activated BID to mitochondria, followed by redistribution of cytochrome c to the cytosol. However, it is unclear whether BID participates in cytochrome c release in other (non-death receptor) cell death pathways. Here, we show that BID is cleaved in response to multiple death-inducing stimuli (staurosporine, UV radiation, cycloheximide, etoposide). However BID cleavage in these contexts was blocked by Bcl-2, suggesting that proteolysis of BID occurred distal to cytochrome c release. Furthermore, addition of cytochrome c to Jurkat post-nuclear extracts triggered breakdown of BID at Asp-59 which was catalysed by caspase-3 rather than caspase-8. We provide evidence that caspase-3 catalysed cleavage of BID represents a feedback loop for the amplification of mitochondrial cytochrome c release during cytotoxic drug and UV radiation-induced apoptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis* / drug effects
  • Apoptosis* / radiation effects
  • Aspartic Acid / metabolism
  • BH3 Interacting Domain Death Agonist Protein
  • Carrier Proteins / metabolism*
  • Caspase 3
  • Caspases / metabolism*
  • Catalysis
  • Cell-Free System
  • Cycloheximide / pharmacology
  • Cytochrome c Group / metabolism*
  • Enzyme Inhibitors / pharmacology
  • Etoposide / pharmacology
  • Humans
  • Jurkat Cells
  • Mice
  • Mitochondria, Liver / drug effects
  • Mitochondria, Liver / metabolism*
  • Nucleic Acid Synthesis Inhibitors / pharmacology
  • Protein Synthesis Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Staurosporine / pharmacology
  • Tumor Cells, Cultured
  • Ultraviolet Rays

Substances

  • BH3 Interacting Domain Death Agonist Protein
  • BID protein, human
  • Bid protein, mouse
  • Carrier Proteins
  • Cytochrome c Group
  • Enzyme Inhibitors
  • Nucleic Acid Synthesis Inhibitors
  • Protein Synthesis Inhibitors
  • Proto-Oncogene Proteins c-bcl-2
  • Aspartic Acid
  • Etoposide
  • Cycloheximide
  • CASP3 protein, human
  • Casp3 protein, mouse
  • Caspase 3
  • Caspases
  • Staurosporine