G. Natoli et al., APOPTOTIC, NON-APOPTOTIC, AND ANTI-APOPTOTIC PATHWAYS OF TUMOR-NECROSIS-FACTOR SIGNALING, Biochemical pharmacology, 56(8), 1998, pp. 915-920
Early events in the signalling of tumor necrosis factor-receptor 1 (TN
F-R1), which is the main TNF receptor on most cell types, have been cl
arified recently. A multimolecular signal transducing complex from whi
ch several pathways originate rapidly forms upon TNF-induced aggregati
on of the receptor. Although fully capable of transducing apoptotic si
gnals, which depend on the adapter Fas-associated death domain protein
(FADD) and on the subsequent recruitment/activation of the apoptotic
proteases, TNF-R1 usually does not kill cells; this is due to the indu
ction of a complex cytoprotective response that requires TNF-receptor
associated factor 2 (TRAF2), a signal transducer that couples TNF-R1 t
o both nuclear factor kappa B (NF kappa B)-dependent and NF kappa B-in
dependent transcriptional events implicated in induction of genes prot
ecting from TNF cytotoxicity. Although absolutely required for cytopro
tection, TNF-receptor associated factor 2 is not sufficient to protect
cells from TNF, thus suggesting that it may act in concert with addit
ional TNF-R1 complex components. In this commentary, we will discuss s
ome critical aspects of TNF-R1 signal transduction that are not fully
understood: Why do cells not die before the protective protein synthes
is has occurred! What are the mechanisms implicated in the termination
of each TNF-R1-elicited response! Are there regulatory mechanisms cap
able of influencing the composition of the TNF-R1 complex and, consequ
ently, the propagation of specific signals! (C) 1998 Elsevier Science
Inc.