GIDE is a mitochondrial E3 ubiquitin ligase that induces apoptosis and slows growth

Cell Res. 2008 Sep;18(9):900-10. doi: 10.1038/cr.2008.75.

Abstract

Here, we report the identification of GIDE, a mitochondrially located E3 ubiquitin ligase. GIDE contains a C-terminal RING finger domain, which is mostly conserved with those of the IAP family members and is required for GIDE's E3 ligase activity. Overexpression of GIDE induces apoptosis via a pathway involving activation of caspases, since caspase inhibitors, XIAP and an inactive mutant of caspase-9 block GIDE-induced apoptosis. GIDE also activates JNK, and blockage of JNK activation inhibits GIDE-induced release of cytochrome c and Smac as well as apoptosis, suggesting that JNK activation precedes release of cytochrome c and Smac and is required for GIDE-induced apoptosis. These pro-apoptotic properties of GIDE require its E3 ligase activity. When somewhat over- or underexpressed, GIDE slows or accelerates cell growth, respectively. These pro-apoptotic or growth inhibition effects of GIDE may account for its absence in tumor cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Apoptosis* / drug effects
  • Caspase Inhibitors
  • Cell Line
  • Cell Proliferation / drug effects
  • Enzyme Activation / drug effects
  • Gene Expression Profiling
  • Humans
  • Inhibitor of Apoptosis Proteins / metabolism
  • JNK Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinases / metabolism
  • Mice
  • Mitochondria / drug effects
  • Mitochondria / enzymology*
  • Molecular Sequence Data
  • NIH 3T3 Cells
  • Protease Inhibitors / pharmacology
  • Protein Transport / drug effects
  • Transcription Factors / chemistry
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transfection
  • Ubiquitin-Protein Ligases / chemistry
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination / drug effects

Substances

  • Caspase Inhibitors
  • Inhibitor of Apoptosis Proteins
  • Protease Inhibitors
  • Transcription Factors
  • MUL1 protein, human
  • Ubiquitin-Protein Ligases
  • JNK Mitogen-Activated Protein Kinases
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7