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

Tetsuya Kitamura, Yayoi Fukuyo, Masahiro Inoue, Nobuko T. Horikoshi, Masanobu Shindoh, Buck E. Rogers, Anny Usheva, Nobuo Horikoshi*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


Daxx is a regulatory protein for apoptosis signal-regulating kinase 1 (ASK1) which activates c-Jun NH2-terminal kinase (JNK) and p38 pathways in response to stressors such as tumor necrosis factor-α (TNFα). Here, we show that TNFα treatment induces the accumulation of Daxx protein through ASK1 activation by preventing its proteasome-dependent degradation. ASK1 directly phosphorylates Daxx at Ser176 and Ser 184 and Daxx is required for the sustained activation of JNK. Tumorigenic mutant p53, which binds to Daxx and inhibits Daxx-dependent activation of ASK1, prevents Daxx phosphorylation and stabilization. When mutant p53 was depleted in cancer cells, Daxx was accumulated and the cell-killing effect of TNFα was restored. Our results indicate that Daxx not only activates ASK1 but also is a downstream target of ASK1 and that accumulated Daxx further activates ASK1. Thus, the Daxx-ASK1 positive feedback loop amplifying JNK/p38 signaling plays an important role in the cell-killing effects of stressors, such as TNFα. Tumorigenic mutant p53 disrupts this circuit and makes cells more tolerable to stresses, as its gain-of-function mechanism.

Original languageEnglish (US)
Pages (from-to)7681-7688
Number of pages8
JournalCancer Research
Issue number19
StatePublished - Oct 1 2009

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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