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

<div>Abstract<p>Daxx is a regulatory protein for apoptosis signal–regulating kinase 1 (ASK1) which activates c-<i>Jun</i> 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 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 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. [Cancer Res 2009;69(19):7681–8]</p></div>