Activation of caspase-2 in apoptosis

J Biol Chem. 1997 Aug 22;272(34):21010-7. doi: 10.1074/jbc.272.34.21010.

Abstract

Members of the CED-3/interleukin-1beta-converting enzyme (ICE) protease (caspase) family are synthesized as proforms, which are proteolytically cleaved and activated during apoptosis. We report here that caspase-2 (ICH-1/NEDD-2), a member of the ICE family, is activated during apoptosis by another ICE member, a caspase-3 (CPP32)-like protease(s). When cells are induced to undergo apoptosis, endogenous caspase-2 is first cleaved into three fragments of 32-33 kDa and 14 kDa, which are then further processed into 18- and 12-kDa active subunits. Up to 50 microM N-acetyl-Asp-Glu-Val-Asp-aldehyde (DEVD-CHO), a caspase-3-preferred peptide inhibitor, inhibits caspase-2 activation and DNA fragmentation in vivo, but does not prevent loss of mitochondrial function, while higher concentrations of DEVD-CHO (>50 microM) inhibit both. In comparison, although the activity of caspase-3 is very sensitive to the inhibition of DEVD-CHO (<50 nM), inhibition of caspase-3 activation as marked by processing of the proform requires more than 100 microM DEVD-CHO. Our results suggest that the first cleavage of caspase-2 is accomplished by a caspase-3-like activity, and other ICE-like proteases less sensitive to DEVD-CHO may be responsible for activation of caspase-3 and loss of mitochondrial function.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Apoptosis*
  • Caspase 2
  • Caspase 3
  • Caspases*
  • Cell-Free System
  • Cysteine Endopeptidases / metabolism*
  • Cysteine Proteinase Inhibitors / pharmacology
  • DNA Fragmentation
  • Enzyme Activation
  • Enzyme Precursors / metabolism
  • Humans
  • Mitochondria
  • Oligopeptides / pharmacology
  • Proteins / metabolism*
  • Substrate Specificity
  • T-Lymphocytes
  • T-Lymphocytes, Cytotoxic / enzymology
  • Time Factors
  • Tumor Cells, Cultured

Substances

  • Cysteine Proteinase Inhibitors
  • Enzyme Precursors
  • Oligopeptides
  • Proteins
  • acetyl-aspartyl-glutamyl-valyl-aspartal
  • CASP2 protein, human
  • CASP3 protein, human
  • Caspase 2
  • Caspase 3
  • Caspases
  • Cysteine Endopeptidases