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
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
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 .
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