Bcl-2 Expression Prevents Activation of the ICE Protease Cascade

Oncogene. 1996 Jun 6;12(11):2251-7.

Abstract

The Bcl-2 family and the ICE family of cysteine proteases play important roles in regulating cell death. We show here that induction of cell death by a Ca2+ ionophore or hypoxia results in increased levels and activity of active ICE(-like) proteases and the subsequent activation of CPP32/Yama(-like) proteases, and that inhibition of these protease activities reduces the extent of cell death. Overexpression of the anti-apoptotic proteins Bcl-2 or Bcl-xL inhibits the cell death and the activation of ICE(-like) and CPP32/Yama(-like) proteases, indicating that Bcl-2 and Bcl-xL act upstream of these proteases. We also show that specific inhibition of ICE(-like) proteases in vivo prevents activation of CPP32/Yama(-like) proteases, whereas inhibition of CPP32/Yama(-like) proteases does not prevent activation of ICE(-like) proteases, suggesting the existence of a protease cascade in vivo that requires ICE(-like) proteases for activation of CPP32/Yama(-like) proteases. Induction of necrotic cell death by KCN also induces activation of ICE(-like) proteases but not of CPP32/Yama(-like) proteases, and Bcl-2 and Bcl-xL inhibit the activation and the cell death, suggesting that the functional site of Bcl-2 and Bcl-xL is also upstream of ICE(-like) proteases in at least some forms of necrosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenal Gland Neoplasms / metabolism
  • Adrenal Gland Neoplasms / pathology
  • Animals
  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Calcimycin / pharmacology
  • Caspase 1
  • Caspase 3
  • Caspases*
  • Cysteine Endopeptidases / physiology*
  • Cysteine Proteinase Inhibitors / pharmacology
  • Enzyme Activation / drug effects
  • Humans
  • Hypoxia
  • Ionophores / pharmacology
  • Oligopeptides / pharmacology
  • Pheochromocytoma / metabolism
  • Pheochromocytoma / pathology
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins / physiology*
  • Proto-Oncogene Proteins c-bcl-2
  • Rats
  • Tumor Cells, Cultured

Substances

  • Cysteine Proteinase Inhibitors
  • Ionophores
  • Oligopeptides
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • acetyl-aspartyl-glutamyl-valyl-aspartal
  • Calcimycin
  • CASP3 protein, human
  • Casp3 protein, rat
  • Caspase 3
  • Caspases
  • Cysteine Endopeptidases
  • Caspase 1