Fas and tumor necrosis factor receptor-mediated cell death: similarities and distinctions.

Abstract

SummaryFas antigen and two tumor necrosis factor receptors (TNFR), p55 and p75, are implicated in the triggering of cell death upon stimulation by natural ligands and specific monoclonal antibodies. However, the relative efficiency of each receptor, the mechanisms that regulate their function and the signaling pathways they employ, remain to be elucidated. In this study, fusion proteins, composed of the extracellular domain of CD40 and the intracellular and transmembrane domains of Fas, TNFRp55 and TNFRp75, were stably expressed in a human melanoma cell line that is deficient in Fas and TNFR expression. Transfectants were stimulated by a soluble recombinant form of the CD40 ligand gp39, and the effect on cell viability determined. Engagement of all three fusion proteins by the gp39 ligand induced lethal signals, but the rate at which cell death occurred was distinct. Fas-derived signals were observed to have the most rapid effect, killing most cells within hours of stimulation, whereas TNFILp55-and TNFILp75-associated signals resulted in cell death within 2-3 d after engagement by ligand. It is interesting to note that optimal cell killing by all three fusion proteins was dependent on a critical, low to intermediate, cell surface expression level. High levels of fusion protein expression, on the other hand, were associated with inhibition of cell death. Our results provide a model to study Fas and TNFRmediated cell death and suggest a novel mechanism for the regulation of death signals triggered by members of the TNFR family.

Tumor necrosis factor receptor-associated factors (TRAFs)—a family of adapter proteins that regulates life and death

“…Receptors that contain a so-called death domain in their cytoplasmic tail, for example, TNFRI, CD95, DR3, and TRAMP, in some instances can initiate complex cascades of proteases and kinases that lead to apoptosis (Itoh et al 1991;Tartaglia et al 1993;Clement and Stamenkovic 1994;Cleveland and Ihle 1995;Stanger et al 1995;Chinnaiyan et al 1996;Muzio et al 1996;Ting et al 1996;Huang et al 1997;Saitoh et al 1998). However, signal transduction through these receptors in other instances can also lead to activation of JNK and NF-B, which has been shown to be crucial for lymphocyte activation and the induction of lymphocyte effector functions (Su et al 1994;Chinnaiyan et al 1996;Bodmer et al 1997).…”

Fas- and Tumor Necrosis Factor-mediated Apoptosis Uses the Same Binding Surface of FADD to Trigger Signal Transduction

“…However, clear differences in these two cell death pathways have been observed (12,13). Fas-mediated cell death occurs much more rapidly than that triggered by TNF (14). A dominant-negative version of FADD blocks TNF-and Fas-induced apoptosis, indicating that FADD functions as the common signaling conduit for cytokine-mediated cell death (15,16).…”

CD4+/FOXP3+ Regulatory T Cells in End-Stage Kidney Disease: Molecular Pathways Trough Cell-Cycle Arrest and Apoptosis

“…Activation of the Fas pathway results in oligomerization of Fas and recruitment of Fas-associated death domain (FADD) and FADD homologous, IL-1 beta-converting enzyme (ICE)-like protease (FLICE), which then activate caspases. The observation that the FLICE inhibitory protein is down-regulated by oxLDL further supports the involvement of the Fas pathway in oxLDL-induced apoptosis [52][53][54]. Finally, mildly oxidized LDL causes an overexpression of Fas at the Tregs surface.…”