TRAF2 regulates JNK and IKK activation in response to TNF-α stimulation. This study found that TNF-α and oxidative stress induce TRAF2 phosphorylation and that this phosphorylation inhibits apoptosis by promoting the prolonged phase of IKK activation while inhibiting the prolonged phase of JNK activation.

The tumor microenvironment is characterized by hypoxia, low glucose and oxidative stress. Cancer-cell adaptation to such chronic stress has profound consequences for malignant progression and the response to therapy. Numerous studies have demonstrated that the NF-κB signaling pathway promotes tumor progression and metastasis, whereas its inhibition sensitizes cancer cells to stress-induced apoptosis. TNF receptor associated factor 2 (TRAF2) is an adaptor protein that regulates the activation of the JNK and NF-κB signaling cascades in response to TNFα stimulation. We mapped two phosphorylation sites (Ser-11 and Ser-55) on the N-terminal RING domain of TRAF2, and reported that phosphorylation at these sites increases basal and TNFα-induced NF-κB activation. Recently we found that oxidative stress induces TRAF2 phosphorylation at both Ser-11 and Ser-55, and that this phosphorylation plays a critical role in cell survival in the context of chronic oxidative stress: cells that expressed a TRAF2 mutant in which both Ser-11 and Ser-55 are replaced by Ala (TRAF2-S11/55A) underwent apoptosis even when the cells were subjected to sublethal oxidative stress. Analysis of both JNK and IKK pathways revealed that oxidative stress induces strong and prolonged JNK, but not IKK, activation in cells expressing TRAF2-S11/55A, suggesting that TRAF2 phosphorylation promotes cell survival by inhibiting the prolonged phase of JNK activation. Importantly, TRAF2 was found to be constitutively phosphorylated in some malignant cancer cell lines, as well as in some human tumor tissues. In addition, basal TRAF2 phosphorylation is elevated in H-Ras-V12-transformed cells, and its inhibition significantly sensitized the cells to oxidative stress-induced apoptosis. These results unveil a new layer of mechanism for cancer cell adaptation to oxidative stress modulated by TRAF2 phosphorylation, and suggest that inhibiting TRAF2 phosphorylation could be a new target for anti-cancer drug development. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1692.