Association of TRAF2 with the short form of cellular FLICE-like inhibitory protein prevents TNFR1-mediated apoptosis
نویسندگان
چکیده
BACKGROUND 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. Here we examined whether c-FLIPS effectively inhibits TNFR1-mediated apoptosis and triggers JNK activation through its interaction with TRAF2. RESULTS Some 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-alpha 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-alpha-induced JNK activation and apoptosis by comparing these in TNF-alpha-resistant and TNF-alpha-sensitive cell lines. Treatment with TNF-alpha increased the phosphorylated JNK level in SNU719 and T24 cells, whereas DU145 and AGS cells were resistant to TNF-alpha-mediated apoptosis. CONCLUSION We 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.
منابع مشابه
Distinct signaling pathways in TRAIL- versus tumor necrosis factor-induced apoptosis.
Trimeric tumor necrosis factor (TNF) binding leads to recruitment of TRADD to TNFR1. In current models, TRADD recruits RIP, TRAF2, and FADD to activate NF-kappaB, Jun N-terminal protein kinase (JNK), and apoptosis. Using stable short-hairpin RNA (shRNA) knockdown (KD) cells targeting these adaptors, TNF death-inducing signaling complex immunoprecipitation demonstrates competitive binding of TRA...
متن کاملStat1 as a component of tumor necrosis factor alpha receptor 1-TRADD signaling complex to inhibit NF-kappaB activation.
Activated tumor necrosis factor alpha (TNF-alpha) receptor 1 (TNFR1) recruits TNFR1-associated death domain protein (TRADD), which in turn triggers two opposite signaling pathways leading to caspase activation for apoptosis induction and NF-kappaB activation for antiapoptosis gene upregulation. Here we show that Stat1 is involved in the TNFR1-TRADD signaling complex, as determined by employing ...
متن کاملDissection of TNF Receptor 1 Effector Functions: JNK Activation Is Not Linked to Apoptosis While NF-κB Activation Prevents Cell Death
Through its type 1 receptor (TNFR1), the cytokine TNF elicits an unusually wide range of biological responses, including inflammation, tumor necrosis, cell proliferation, differentiation, and apoptosis. We investigated how TNFR1 activates different effector functions; the protein kinase JNK, transcription factor NF-kappaB, and apoptosis. We found that the three responses are mediated through se...
متن کاملLMP1 signal transduction differs substantially from TNF receptor 1 signaling in the molecular functions of TRADD and TRAF2.
The Epstein-Barr virus latent membrane protein 1 (LMP1) binds tumor necrosis factor receptor (TNFR)-associated factors (TRAFs) and the TNFR-associated death domain protein (TRADD). Moreover, it induces NF-kappaB and the c-Jun N-terminal kinase 1 (JNK1) pathway. Thus, LMP1 appears to mimick the molecular functions of TNFR1. However, TNFR1 elicits a wide range of cellular responses including apop...
متن کاملTWEAK inhibits TRAF2-mediated CD40 signaling by destabilization of CD40 signaling complexes.
We found recently that TNF-like weak inducer of apoptosis (TWEAK) and fibroblast growth factor-inducible-14 (Fn14) by virtue of their strong capability to reduce the freely available cytoplasmic pool of TNFR-associated factor (TRAF)2 and cellular inhibitors of apoptosis (cIAPs) antagonize the functions of these molecules in TNFR1 signaling, resulting in sensitization for apoptosis and inhibitio...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید
ثبت ناماگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید
ورودعنوان ژورنال:
- Journal of Molecular Signaling
دوره 3 شماره
صفحات -
تاریخ انتشار 2008