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Human Daxx regulates Fas-induced apoptosis from nuclear PML oncogenic domains (PODs)

S Torii1, D A Egan, R A Evans

  • 1The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.

The EMBO Journal
|November 2, 1999
PubMed

Insights

Human Daxx (hDaxx) enhances sensitivity to Fas-induced apoptosis by affecting caspase activation. This nuclear protein localizes to PML oncogenic domains (PODs) and represses transcription, influencing cell death pathways.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Immunology

Background:

  • Daxx protein initially identified for binding Fas receptor and linking to Jun N-terminal kinase (JNK) mediated apoptosis.
  • Fas receptor is a key mediator of programmed cell death.

Purpose of the Study:

  • To investigate the role of human Daxx (hDaxx) in Fas-mediated apoptosis.
  • To elucidate the mechanism by which hDaxx influences cellular sensitivity to apoptosis.

Main Methods:

  • Overexpression of hDaxx in cells.
  • Assays for apoptosis induction by various stimuli.
  • Analysis of caspase activation and JNK induction.
  • Subcellular localization studies of hDaxx.
  • Transcriptional repression assays.
  • Mutagenesis studies.
  • Synergistic treatment with arsenic trioxide (As(2)O(3)).

Main Results:

  • Overexpression of hDaxx specifically enhanced sensitivity to Fas-induced apoptosis, but not other death stimuli.
  • hDaxx overexpression accelerated caspase activation without affecting JNK induction.
  • hDaxx localizes to the nucleus within PML oncogenic domains (PODs) and exhibits transcriptional repression activity.
  • Localization to PODs correlated with enhanced Fas-induced cell death.
  • Arsenic trioxide synergized with hDaxx to further increase sensitivity to Fas-induced apoptosis.

Conclusions:

  • hDaxx enhances Fas-induced apoptosis through a nuclear mechanism, independent of direct Fas binding.
  • hDaxx's ability to repress transcription and localize to PODs is crucial for its role in sensitizing cells to Fas-mediated death.
  • These findings suggest hDaxx modulates the transcription of genes involved in Fas-induced caspase activation and apoptosis.

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