Anti-apoptotic TNFs/NF-kB/IAP pathway
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 .
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) ,
- 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/or APRIL/ tumor necrosis factor receptor superfamily, member
17 (BCMA) .
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 .
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 . 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 .
The signal from TNF-R1 may be mediated by TNFR1-associated death
domain protein (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)
activate transcription of anti-apoptotic members of the IAP family (c-IAP1,
c-IAP2, XIAP and Survivin), which inhibit various
pro-apoptotic proteins .