Apoptosis and survival - Anti-apoptotic TNFs/NF-kB/IAP pathway

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