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Nuclear factor-kappa B-inducible death effector domain-containing protein suppresses tumor necrosis factor-mediated

Z You1, H Ouyang, D Lopatin

  • 1Laboratory of Molecular Signaling and Apoptosis, the Department of Biologic and Materials Sciences, University of Michigan, Ann Arbor, Michigan 48109, USA.

The Journal of Biological Chemistry
|May 11, 2001
PubMed

Insights

Nuclear factor-kappa B (NF-kappa B) activation induces a protein called NDED, which inhibits tumor necrosis factor (TNF)-mediated apoptosis by blocking caspase-8 activity. This discovery reveals a new NF-kappa B antiapoptotic mechanism.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Immunology

Background:

  • Nuclear factor-kappa B (NF-kappa B) activation is crucial for inhibiting tumor necrosis factor (TNF)-mediated apoptosis.
  • NF-kappa B regulates antiapoptotic molecules like Bcl-2 family proteins.
  • The role of NF-kappa B in apoptosis regulation requires further elucidation.

Purpose of the Study:

  • To investigate the role of a novel NF-kappa B-inducible protein, NDED, in TNF-mediated apoptosis.
  • To determine the mechanism by which NDED suppresses apoptosis.
  • To elucidate the relationship between NF-kappa B, NDED, and caspase-8 activity.

Main Methods:

  • NF-kappa B activation and inhibition studies using I kappa B alpha.
  • Quantitative analysis of NDED mRNA expression.
  • Apoptosis assays in NF-kappa B null cells with NDED restoration.
  • Caspase-8 activity and processing assays.
  • Etoposide-induced apoptosis assays.

Main Results:

  • NDED expression is dependent on NF-kappa B activation.
  • Inhibition of NF-kappa B suppressed TNF-induced NDED mRNA expression.
  • Restoration of NDED inhibited TNF-induced apoptosis in NF-kappa B null cells.
  • NDED suppressed TNF-mediated apoptosis by inhibiting caspase-8 enzymatic activity, not processing.
  • NDED did not inhibit etoposide-induced apoptosis, which is caspase-8 independent.

Conclusions:

  • NF-kappa B transcriptionally induces the DED-containing protein NDED.
  • NDED suppresses TNF-mediated apoptosis by inhibiting caspase-8 activity.
  • This study provides new insights into the antiapoptotic mechanisms regulated by NF-kappa B.

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