Apoptosis and survival Anti-apoptotic TNFs/NF-kB/IAP pathway
Anti-apoptotic TNFs/NF-kB/IAP pathway Members of the tumour necrosis factor ligand family (TNFs) may induce both apoptoticand anti-apoptotic pathways. TNFs transduces cellular responses through activation ofdifferent TNF-receptors (TNFRs). One important mechanism of cell survival is activation of transcription of differentanti-apoptotic proteins by TNFs via nuclear factors of the kappa light polypeptide inB-cells ( NF-kB ) signaling cascade . Some TNFs/TNFRs activateexpression of anti-apoptotic members of the inhibitor of apoptosis protein (IAP) family.For example, expression of baculoviral IAP repeat-containing 2 ( c-IAP1 ),baculoviral IAP repeat-containing 3 ( c-IAP2 ), baculoviral IAP repeat-containing4 ( XIAP1 ) and/or baculoviral IAP repeat-containing 5 ( Survivin ) may bestimulated by: . tumor necrosis factor, member 2 ( TNF-alpha )/ tumor necrosisfactor receptor superfamily, member 1A ( TNF-R1 ) and TNF-alpha/ tumornecrosis factor receptor superfamily, member 1B ( TNF-R2 ) ,; . tumor necrosis factor (ligand) superfamily, member 15 ( TL1A )/tumor necrosis factor receptor superfamily, member 25 ( DR3 ) ; . tumor necrosis factor (ligand) superfamily, member 8 ( CD30L )/tumor necrosis factor receptor superfamily, member 8 ( CD30 ) ,; . tumor necrosis factor (ligand) superfamily, member 13 ( APRIL )/tumor necrosis factor receptor superfamily, member 13B ( TACI ) and/orAPRIL/ tumor necrosis factor receptor superfamily, member 17 ( BCMA ). TNFRs transduce cellular responses through activation of different TNFR -associatedfactors (TRAFs). These are TRAF2 and TRAF5. TRAF3 serves as anegative regulator of the NF-kappaB pathway for many receptors TNFRs . Further, the activation and nuclear translocation of NF-kB proteins can occurafter the ligation of selected cell-surface TNFRs. TRAF2 activates the inhibitor of kappa light polypeptide gene enhancer inB-cells, kinases alpha and beta ( IKK ), directly or via NIK kinase . IKK subsequently phosphorylates NF-kB inhibitor ( I-kB ).Phosphorylation of I-kB leads to its ubiquitination and degradation within the 26Sproteasome. Degradation of I-kB liberates different NF-kB transcriptionfactors, enablng its rapid translocation from the cytoplasm into the nucleus where ittriggers transcription of the target genes . The signal from TNF-R1 may be mediated by TNFR1-associated death domainprotein ( TRADD )/ receptor TNFR-interacting serine-threonine kinase 1 (RIPK1 ) pathway . In addition, TNF-R1/ TNF-R2 signal may be mediated by NIK/IKK/ v-rel reticuloendotheliosis viral oncogene homolog A ( RelA ) . Then, different NF-kB transfactors (including RelA ) activatetranscription of anti-apoptotic members of the IAP family ( c-IAP1, c-IAP2, XIAP and Survivin ), which inhibit various pro-apoptotic proteins .