TNF Signaling Pathway

1. TNF Signaling Pathway SIGMA-ALDRICH

2. TNF Signaling Pathway When bound to tumor necrosis factor (TNF), the TNF receptor (TNFR) (55 kDa) transduces growth regulatory signals into the cell. TNF is mitogenic in normal cells; however, TNF initiates programmed cell death (PCD) or apoptosis in transformed cells causing DNA fragmentation and cytolysis. Functional studies have identified a conserved region within the receptor, termed the death domain (DD), a protein-protein interaction motif that is necessary to transmit the apoptotic signal. The TNF-induced survival pathway is mediated by the transcription factor NF-B. Activation of NF- B occurs via phosphorylation of I B at Ser32 and Ser36, resulting in the dissociation and subsequent nuclear localization of active NF- B. Recent studies have demonstrated that cells in which the NF- B signaling pathway is blocked are more likely to undergo apoptosis in response to TNF. Therefore, the availability of NF- B may play a critical role in the ability of TNF to act as an apoptosis-inducer and anti-tumor agent. References Plumpe, J., et al., NF- B determines between apoptosis and proliferation in hepatocytes during liver regeneration. Am. J. Physiol. Gastrointest. Liver Physiol., 278, G173-G183 (2000). Pimentel-Muinos, F.X., and Seed, B., Regulated commitment of TNF receptor signaling: a molecular switch for death or activation. Immunity, 11, 783-793 (1999). Schwandner, R., et al., TNF receptor death domain-associated proteins TRADD and FADD signal activation of acid sphingomyelinase. J. Biol. Chem., 273, 5916-5922 (1998).