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 both apoptotic and anti-apoptotic pathways. TNFs transduces cellular responses through activation of different TNF-receptors (TNFRs).

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

Some TNFs/TNFRs may activate expressions of anti-apoptotic members of the Bcl-2 family. 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 necrosis factor receptor superfamily, member 1A (TNF-R1) and TNF-alpha / tumor necrosis 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 necrosis factor (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 necrosis factor receptor superfamily, member 16 (NGFR) [10].

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

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

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

In addition, the signal from TNF-R1 may be mediated via TNFR1-associated death domain protein (TRADD)/ receptor TNFR-interacting serine-threonine kinase 1 (RIPK1) pathway [13]. The signal from NGFR may be mediated via the 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 subsequently activates IKK alpha by phosphorylation. IKK alpha promotes the processing of NF-kB2 from p100 to p52 form. Further processed NF-kB2 is bound to v-rel reticuloendotheliosis viral oncogene homolog B (RelB). NF-kB p52/RelB dimer is translocated into the nucleus to affect gene transcription. The non-canonical pathway 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-apoptotic members of the Bcl-2 family (Bcl-2, Bcl-XL and BFL1), which inhibit various pro-apoptotic proteins [15], [16].

References:

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