
<ArticleTitle>Involvement of <prot>FAN</prot> in TNF-induced apoptosis.</ArticleTitle>
<AbstractText><prot>TNF-alpha</prot> is a pleiotropic cytokine activating several signaling pathways initiated at distinct intracellular domains of the TNF receptors. Although the C-terminal region is believed to be responsible for apoptosis induction, the functions of more membrane-proximal domains, including the domain that couples to neutral sphingomyelinase activation, are not yet fully elucidated. The roles of this region and of the associated adapter protein <prot>FAN</prot> (<prot>factor associated with neutral SMase activation</prot>) in the cytotoxic response to TNF have been investigated. We have now shown that stable expression in human fibroblasts of a dominant negative form of <prot>FAN</prot> abrogates TNF-induced ceramide generation from sphingomyelin hydrolysis and reduces caspase processing, thus markedly inhibiting TNF-triggered apoptosis. However, the cytotoxic responses to daunorubicin and exogenous ceramide remain unaltered, as do the TNF-induced <prot>p42</prot>/<prot>p44</prot> <prot>MAPK</prot> activation and <prot>CD54</prot> expression. Fibroblasts from <prot>FAN</prot>-knockout mice also proved to be resistant to TNF toxicity. These findings highlight the previously unrecognized role of the adapter protein <prot>FAN</prot> in signaling cell death induction by TNF.</AbstractText>
