Pathway Map Details

Apoptosis and survival_Anti-apoptotic TNFs/NF-kB/IAP pathway

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APRIL(TNFSF13), IKK-alpha, TNF-R1, TNF-R2, NF-kB, c-IAP2, XIAP, Survivin, CD30(TNFRSF8), IKK-beta, TRAF5, NIK(MAP3K14), TNF-alpha, BCMA(TNFRSF17), IKK-gamma, RelA (p65 NF-kB subunit), IKK (cat), RIPK1, TL1A(TNFSF15), TRAF3, TRAF2, c-IAP1, TACI(TNFRSF13B), DR3(TNFRSF12), TRADD, I-kB, CD30L (TNFSF8)


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].


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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
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    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
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    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
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