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 [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].
References:
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Human disease resulting from gene mutations that interfere with appropriate nuclear factor-kappaB activation.
Immunological reviews 2005 Feb;203:21-37
- Shishodia S, Aggarwal BB
Guggulsterone inhibits NF-kappaB and IkappaBalpha kinase activation, suppresses expression of anti-apoptotic gene products, and enhances apoptosis.
The Journal of biological chemistry 2004 Nov 5;279(45):47148-58
- Aggarwal S, Ichikawa H, Takada Y, Sandur SK, Shishodia S, Aggarwal BB
Curcumin (diferuloylmethane) down-regulates expression of cell proliferation and antiapoptotic and metastatic gene products through suppression of IkappaBalpha kinase and Akt activation.
Molecular pharmacology 2006 Jan;69(1):195-206
- Wen L, Zhuang L, Luo X, Wei P
TL1A-induced NF-kappaB activation and c-IAP2 production prevent DR3-mediated apoptosis in TF-1 cells.
The Journal of biological chemistry 2003 Oct 3;278(40):39251-8
- Hubinger G, Schneider C, Stohr D, Ruff H, Kirchner D, Schwanen C, Schmid M, Bergmann L, Muller E
CD30-induced up-regulation of the inhibitor of apoptosis genes cIAP1 and cIAP2 in anaplastic large cell lymphoma cells.
Experimental hematology 2004 Apr;32(4):382-9
- Durkop H, Hirsch B, Hahn C, Stein H
cIAP2 is highly expressed in Hodgkin-Reed-Sternberg cells and inhibits apoptosis by interfering with constitutively active caspase-3.
Journal of molecular medicine (Berlin, Germany) 2006 Feb;84(2):132-41
- Roth W, Wagenknecht B, Klumpp A, Naumann U, Hahne M, Tschopp J, Weller M
APRIL, a new member of the tumor necrosis factor family, modulates death ligand-induced apoptosis.
Cell death and differentiation 2001 Apr;8(4):403-10
- Hauer J, Puschner S, Ramakrishnan P, Simon U, Bongers M, Federle C, Engelmann H
TNF receptor (TNFR)-associated factor (TRAF) 3 serves as an inhibitor of TRAF2/5-mediated activation of the noncanonical NF-kappaB pathway by TRAF-binding TNFRs.
Proceedings of the National Academy of Sciences of the United States of America 2005 Feb 22;102(8):2874-9
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Signal transduction by tumor necrosis factor and its relatives.
Trends in cell biology 2001 Sep;11(9):372-7
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IAP proteins: blocking the road to death's door.
Nature reviews. Molecular cell biology 2002 Jun;3(6):401-10