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Mutant p53 disrupts the stress MAPK activation circuit induced by ASK1-dependent stabilization of Daxx

Tetsuya Kitamura1, Yayoi Fukuyo, Masahiro Inoue

  • 1Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri, USA.

Cancer Research
|October 1, 2009
PubMed

Insights

Tumor necrosis factor-alpha (TNFalpha) triggers Daxx protein accumulation via apoptosis signal-regulating kinase 1 (ASK1) activation, enhancing cell death. Mutant p53 disrupts this Daxx-ASK1 feedback loop, promoting stress tolerance in cancer cells.

Area of Science:

  • Cellular stress response
  • Protein regulation
  • Signal transduction pathways

Background:

  • Daxx protein regulates apoptosis signal-regulating kinase 1 (ASK1).
  • ASK1 activation leads to c-Jun NH2-terminal kinase (JNK) and p38 pathway activation.
  • Stressors like tumor necrosis factor-alpha (TNFalpha) activate these pathways.

Purpose of the Study:

  • To investigate the role of Daxx in TNFalpha-induced ASK1 activation.
  • To elucidate the mechanism of Daxx protein accumulation upon TNFalpha treatment.
  • To determine the impact of mutant p53 on the Daxx-ASK1 signaling pathway.

Main Methods:

  • Western blotting to detect protein levels and phosphorylation.
  • Depletion of mutant p53 using RNA interference.
  • Cell viability assays to assess TNFalpha-induced cell death.

Main Results:

  • TNFalpha treatment leads to Daxx protein accumulation by inhibiting its proteasomal degradation, mediated by ASK1.
  • ASK1 directly phosphorylates Daxx at Ser(176) and Ser(184), which is crucial for sustained JNK activation.
  • Tumorigenic mutant p53 binds to Daxx, inhibiting ASK1 activation, Daxx phosphorylation, and stabilization, thereby conferring stress tolerance.

Conclusions:

  • Daxx acts as both an activator and a downstream target of ASK1, forming a positive feedback loop that amplifies JNK/p38 signaling.
  • This Daxx-ASK1 feedback loop is critical for stress-induced cell death.
  • Mutant p53 disrupts this circuit, promoting cancer cell survival under stress conditions.

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