Association of TRAF2 with the short form of cellular FLICE-like inhibitory protein prevents TNFR1-mediated apoptosis

Dong-Joon Kim,Young-Youl Kim,Chan Park,Bermseok Oh

doi:10.1186/1750-2187-3-2

Dong-Joon Kim, Young-Youl Kim + Show 2 more

Open Access

https://doi.org/10.1186/1750-2187-3-2

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Abstract

BackgroundWe have previously shown that c-FLIPL is a more potent inhibitor than c-FLIPS of Fas ligand-induced apoptosis and that c-FLIPL physically binds to Daxx, an alternative Fas-signaling adaptor. Here we examined whether c-FLIPS effectively inhibits TNFR1-mediated apoptosis and triggers JNK activation through its interaction with TRAF2.ResultsSome cancer cell lines, such as DU145, AGS, and PC3, have higher levels of c-FLIPS than other cell lines, such as SNU-719 and T24. The expression of c-FLIPS correlated with the susceptibility to TNFR1-mediated apoptosis. In contrast to DU145 and PC3, which are resistant to TNFR1-mediated apoptosis, T24 and SNU719 were sensitive to TNF-α treatment. To address the role of c-FLIPS in TNFR1-mediated apoptosis, we examined the molecular interaction between c-FLIPS and TRAF2. As expected, western blot analysis revealed that TRAF2 antibody immunoprecipitated a greater amount of c-FLIPS than c-FLIPL. Also, we measured the involvement of c-FLIPS in TNF-α-induced JNK activation and apoptosis by comparing these in TNF-α-resistant and TNF-α-sensitive cell lines. Treatment with TNF-α increased the phosphorylated JNK level in SNU719 and T24 cells, whereas DU145 and AGS cells were resistant to TNF-α-mediated apoptosis.ConclusionWe now report that the short form of c-FLIPS is a more efficient inhibitor of TNF-receptor 1-mediated apoptosis signaling than the long form of the protein.

Highlights

We have previously shown that c-FLIPL is a more potent inhibitor than c-FLIPS of Fas ligand-induced apoptosis and that c-FLIPL physically binds to Daxx, an alternative Fas-signaling adaptor
Inhibition of Tumor necrosis factor receptor 1 (TNFR1)-mediated apoptosis is dependent on the expression levels of c-FLIPS To examine the relationship between the expression level of c-FLIPS and the apoptotic response, we used real-time PCR to examine the expression of c-FLIP in human cancer cell lines
We have shown previously that c-FLIPL is a more potent inhibitor than c-FLIPS of Fas ligand-induced apoptosis and that c-FLIPL physically binds to Daxx through an interaction between its C-terminal domain and the Fasbinding domain of Daxx, an alternative Fas-signaling adaptor [26]

Summary

Introduction

We have previously shown that c-FLIPL is a more potent inhibitor than c-FLIPS of Fas ligand-induced apoptosis and that c-FLIPL physically binds to Daxx, an alternative Fas-signaling adaptor. It is currently believed that the engagement of TNFR1 triggers the recruitment of the DD-containing adaptor molecule, TRADD, followed by the DDcontaining Ser/Thr kinase RIP1 [6]. This signaling complex is required for TRAF2/5 and c-IAP1 binding, which leads to triggering of the NF-κB and JNK signaling pathways [7]. TNFR1 binding by its ligand triggers these pathways, and can induce apoptosis by alternately binding the DD-containing adaptor FADD (through TRADD), which facilitates caspase 8 recruitment and activation [8]

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