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Apoptosis and survival Anti-apoptotic TNFs/NF-kB/Bcl-2 pathway


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Apoptosis and survival Anti-apoptotic TNFs/NF-kB/Bcl-2 pathway

Anti-apoptotic TNFs/NF-kB/Bcl-2 pathway

The members of the tumour necrosis factor ligand family (TNFs) may induce bothapoptotic and anti-apoptotic pathways. TNFs transduces cellular responses throughactivation of different TNF-receptors (TNFRs).

One important mechanism of cell survival is the activation of transcription ofdifferent anti-apoptotic proteins by TNFs via the nuclear factors of kappa lightpolypeptide in B-cells ( NF-kB ) signaling cascade [1].

Some TNFs/TNFRs may activate expressions of anti-apoptotic members of the Bcl-2family. For example, expression of B-cell CLL/lymphoma 2 ( Bcl-2 ), BCL2-like 1 (Bcl-XL ) and/or BCL2-related protein A1 ( BFL1 ) may be stimulated 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 ) [2],[3];

. tumor necrosis factor (ligand) superfamily, 4 member ( OX40L )/tumor necrosis factor receptor superfamily, member 4 ( OX40 ) [4];

. tumor necrosis factor (ligand) superfamily, member 5 ( CD40L )/tumor necrosis factor receptor superfamily, member 4 ( CD40 ) [5];

. tumor necrosis factor (ligand) superfamily, member 11 ( RANK L )/tumor necrosis factor receptor superfamily, member 11A ( RANK ) [6],[7];

. tumor necrosis factor (ligand) superfamily, member 12 ( TWEAK )/tumor necrosis factor receptor superfamily, member 12A ( FN14 ) [8];

. tumor necrosis factor (ligand) superfamily, member 13b ( BAFF )/tumor necrosis factor receptor superfamily, member 13B ( TACI ), tumor necrosisfactor (ligand) superfamily, member 13 ( APRIL )/ TACI, BAFF/tumor necrosis factor receptor superfamily, member 17 ( BCMA ) and APRIL/BCMA [9];

. nerve growth factor, beta polypeptide ( NGF )/ tumor necrosisfactor receptor superfamily, member 16 ( NGFR ) [10].

TNFRs transduces cellular responses via activation of different TNFR -associatedfactors (TRAFs). These are TRAF2, TRAF5 and TRAF6, mainly.TRAF3 serves as a negative regulator of the NF-kappaB pathway for many TNFRs[11], [12], [7].

Further, activation and nuclear translocation of NF-kB proteins can occurafter the ligation of the cell-surface TNFRs by one of two pathways (canonical andnon-canonical).

In a canonical pathways, TRAF2 activates the inhibitor of kappa lightpolypeptide gene enhancer in B-cells, kinase gamma ( IKK gamma )/ inhibitor ofkappa light polypeptide gene enhancer in B-cells, kinase alpha (IKK alpha )/inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta ( IKKbeta ) complex, which subsequently phosphorylates NF-kB inhibitor (I-kB ). Phosphorylation of I-kB leads to it ubiquitination and degradationwithin the 26S proteasome. Degradation of I-kB liberates different NF-kBtransfactors, allowing its rapid translocation from the cytoplasm into the nucleus whereit triggers the transcription of target genes [1].

In addition, the signal from TNF-R1 may be mediated via TNFR1-associated deathdomain protein ( TRADD )/ receptor TNFR-interacting serine-threonine kinase 1 (RIPK1 ) pathway [13]. The signal from NGFR may be mediated viathe interleukin-1 receptor-associated kinase 1 and 2 ( IRAK1/2 )/ TRAF6/sequestosome 1 ( p62 )/ protein kinase C, zeta ( PKC-zeta ) pathway [14].

In the non-canonical pathway, TRAFs stimulate NIK kinase, which subsequentlyactivates IKK alpha by phosphorylation. IKK alpha promotes the processingof NF-kB2 from p100 to p52 form. Further processed NF-kB2 is bound to v-relreticuloendotheliosis viral oncogene homolog B ( RelB ). NF-kB p52/RelBdimer is translocated into the nucleus to affect gene transcription. The non-canonicalpathway is independent of IKK beta and IKK gamma [1].

In addition, the TNF-R1/ TNF-R2 signal may be mediated via NIK/IKK/ v-rel reticuloendotheliosis viral oncogene homolog A ( RelA ) [3].

Then different NF-kB transfactors activate transcription of anti-apoptoticmembers of the Bcl-2 family ( Bcl-2, Bcl-XL and BFL1 ), whichinhibit various pro-apoptotic proteins [15], [16].