Pathway Map Details

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



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Object list (links open in MetaCore):

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)

Description:

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:

  1. Orange JS, Levy O, Geha RS
    Human disease resulting from gene mutations that interfere with appropriate nuclear factor-kappaB activation. Immunological reviews 2005 Feb;203:21-37
  2. 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
  3. 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
  4. 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
  5. 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
  6. 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
  7. 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
  8. 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
  9. Baud V, Karin M
    Signal transduction by tumor necrosis factor and its relatives. Trends in cell biology 2001 Sep;11(9):372-7
  10. Salvesen GS, Duckett CS
    IAP proteins: blocking the road to death's door. Nature reviews. Molecular cell biology. 2002 Jun;3(6):401-10