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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--kB. Activation of NF-kB occurs via phosphorylation of I-kB at Ser32 and Ser36, resulting in the dissociation and subsequent nuclear localization of active NF--kB. Recent studies have demonstrated that cells in which the NF--kB signaling pathway is blocked are more likely to undergo apoptosis in response to TNF. Therefore, the availability of NF--kB may play a critical role in the ability of TNF to act as an apoptosis-inducer and anti-tumor agent.
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References:
Plumpe, J., et al., NF-kB 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).
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