Apoptotic, non-apoptotic, and anti-apoptotic pathways of tumor necrosis factor signalling.
Early events in the signalling of tumor necrosis factor-receptor 1 (TNF-R1), which is the main TNF receptor on most cell types, have been clarified recently. A multimolecular signal transducing complex from which several pathways originate rapidly forms upon TNF-induced aggregation of the receptor. Although fully capable of transducing apoptotic signals, 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 induction of a complex cytoprotective response that requires TNF-receptor associated factor 2 (TRAF2), a signal transducer that couples TNF-R1 to both nuclear factor kappaB (NFkappaB)-dependent and NFkappaB-independent transcriptional events implicated in induction of genes protecting from TNF cytotoxicity. Although absolutely required for cytoprotection, TNF-receptor associated factor 2 is not sufficient to protect cells from TNF, thus suggesting that it may act in concert with additional TNF-R1 complex components. In this commentary, we will discuss some critical aspects of TNF-R1 signal transduction that are not fully understood: Why do cells not die before the protective protein synthesis has occurred? What are the mechanisms implicated in the termination of each TNF-R1-elicited response? Are there regulatory mechanisms capable of influencing the composition of the TNF-R1 complex and, consequently, the propagation of specific signals?
Fondazione Andrea Cesalpino and Istituto I Clinica Medica, Universita degli Studi di Roma La Sapienza, Rome, Italy. levmax@mix.it
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D000818:Animals; D015703:Antigens, CD / Q000502:physiology*; D017209:Apoptosis / Q000502:physiology*; D029681:Arabidopsis Proteins; D016923:Cell Death / Q000502:physiology; D019610:Cytoprotection; D044943:Fatty Acid Desaturases / Q000502:physiology; D006801:Humans; D010940:Plant Proteins / Q000502:physiology; D011506:Proteins / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D047888:Receptors, Tumor Necrosis Factor, Type I; D015398:Signal Transduction / Q000502:physiology*; D047992:TNF Receptor-Associated Factor 2; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D015703:Antigens, CD; D029681:Arabidopsis Proteins; D010940:Plant Proteins; D011506:Proteins; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047992:TNF Receptor-Associated Factor 2; D014409:Tumor Necrosis Factor-alpha; D044943:Fatty Acid Desaturases; C084083:Fad7 protein, Arabidopsis