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

作者：Kitamura Tetsuya; Fukuyo Yayoi; Inoue Masahiro; Horikoshi Nobuko T; Shindoh Masanobu; Rogers Buck E; Usheva Anny; Horikoshi Nobuo

来源：Cancer Research, 2009, 69(19): 7681-7688.

DOI：10.1158/0008-5472.CAN-09-2133

Daxx is a regulatory protein for apoptosis signal-regulating kinase 1 (ASK1) witich activates c-fun NH(2)-terminal kinase (JNK) and p38 pathways in response to stressors such as tumor necrosis factor-alpha (TNF alpha). Here, we show that TNF alpha treatment induces the accumulation of Daxx protein through ASK1 activation by preventing its proteasome-dependent degradation. ASK1 directly phosphorylates Daxx at Ser(176) and Ser(184) and Daxx is required for the sustained activation of JNK Tumorigertic 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 alpha 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 alpha. 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]

• 出版日期2009-10-1