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Mutant p53 Disrupts the Stress MAPK Activation Circuit Induced by ASK1-Dependent Stabilization of Daxx

¹ Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri; ² Department of Oral Pathology and Biology, Hokkaido University Graduate School of Dental Medicine, Sapporo, Japan; ³ Department of Parasitology, Kurume University Medical School, Kurume, Japan; and ⁴ Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston Massachusetts

Requests for reprints: Nobuo Horikoshi, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 3 Blackfan Circle, CLS-728, Boston, MA 02215. Phone: 617-735-3308; Fax: 617-735-3327; E-mail: nhorikos{at}bidmc.harvard.edu.

Key Words: mutant p53 • Daxx • ASK1 • phosphorylation • protein stabilization

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- (TNF). Here, we show that TNF treatment induces the accumulation of Daxx protein through ASK1 activation by preventing its proteasome-dependent degradation. ASK1 directly phosphorylates Daxx at Ser¹⁷⁶ and Ser¹⁸⁴ 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 TNF 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 TNF. Tumorigenic mutant p53 disrupts this circuit and makes cells more tolerable to stresses, as its gain-of-function mechanism. [Cancer Res 2009;69(19):7681–8]

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