Signaling to gene activation and cell death by tumor necrosis factor receptors and Fas.

Tumor necrosis factor (TNF) receptors and Fas elicit a wide range of biological responses, including cell death, cell proliferation, inflammation, and differentiation. The pleiotropic character of these receptors is reflected at the level of signal transduction. The cytotoxic effects of TNF and Fas result from the activation of an apoptotic/necrotic program. On the other hand, TNF receptors, and under certain conditions also Fas, exert a proinflammatory function that results from the induction of several genes. In this context, the transcription factor nuclear factor-kappa B (NF-kappaB) plays an important role. NF-kappaB is also important for the induction of several antiapoptotic genes, which explains at least partially why several cell types can only be killed by TNF in the presence of transcription or translation inhibitors. It is the balance between proapoptotic and antiapoptotic pathways that determines whether a cell will finally die or proliferate. A third signal transduction pathway that is activated in response to TNF is the mitogen-activated protein kinase cascade, which plays an important role in the modulation of transcriptional gene activation.