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 activation of transcription of different anti-apoptotic proteins by TNFs via nuclear factors of the kappa light polypeptide in B-cells (NF-kB) signaling cascade [1]. Some TNFs/TNFRs activate expression 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-containing 4 (XIAP1) and/or baculoviral IAP repeat-containing 5 (Survivin) 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, member 15 (TL1A)/ tumor necrosis factor receptor superfamily, member 25 (DR3) [4];

. tumor necrosis factor (ligand) superfamily, member 8 (CD30L)/ tumor necrosis factor receptor superfamily, member 8 (CD30) [5], [6];

. tumor necrosis factor (ligand) superfamily, member 13 (APRIL)/ tumor necrosis factor receptor superfamily, member 13B (TACI) and/or APRIL/ tumor necrosis factor receptor superfamily, member 17 (BCMA) [7].

TNFRs transduce cellular responses through activation of different TNFR-associated factors (TRAFs). These are TRAF2 and TRAF5. TRAF3 serves as a negative regulator of the NF-kappaB pathway for many receptors TNFRs [8].

Further, the activation and nuclear translocation of NF-kB proteins can occur after the ligation of selected cell-surface TNFRs.

TRAF2 activates the inhibitor of kappa light polypeptide gene enhancer in B-cells, kinases alpha and beta (IKK), directly or via NIK kinase [2]. IKK subsequently phosphorylates NF-kB inhibitor (I-kB). Phosphorylation of I-kB leads to its ubiquitination and degradation within the 26S proteasome. Degradation of I-kB liberates different NF-kB transcription factors, enablng its rapid translocation from the cytoplasm into the nucleus where it triggers transcription of the target genes [1].

The signal from TNF-R1 may be mediated by TNFR1-associated death domain protein (TRADD)/ receptor TNFR-interacting serine-threonine kinase 1 (RIPK1) pathway [9].

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

Then, different NF-kB transfactors (including RelA) activate transcription of anti-apoptotic members of the IAP family (c-IAP1, c-IAP2, XIAP and Survivin), which inhibit various pro-apoptotic proteins [10].

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