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Apoptosis and survival Apoptotic TNF-family pathways


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Apoptosis and survival Apoptotic TNF-family pathways

Apoptotic TNF-family pathways

Members of the tumour necrosis factor ligand family (TNFs) induce both apoptotic andanti-apoptotic pathways. TNFs transduce cellular responses through activation ofdifferent TNF-receptors (TNFRs) [1], [2], [3].

Different TNF/TNFRs may activate some pro-apoptotic proteins (e.g. members of thecysteine-aspartic acid protease (caspase) family) or inhibit some anti-apoptotic proteins(e.g. members of the Bcl-2 family). Thus, TNF/TNFRs exert influence on apoptosis viacaspase cascade and via mitochondrial proteins [3].

Apoptotic signals from TNFR superfamily, member 1A ( TNF-R1 ) [4],TNFR superfamily, member 12 ( DR3 ) [5], TNFR superfamily, member 10a( DR4 ) [6], TNFR superfamily, member 10b ( DR5 ) [7] and, possibly, TNFR superfamily, member 21 ( DR6 ) [7] aremediated by TNFRSF1A-associated via death domain ( TRADD ) and/or Fas(TNFRSF6)-associated via death domain ( FADD ). Receptor TNFR-interactingserine-threonine kinase 1 ( RIPK1 ) may participate in this signal transduction aswell [8].

TNF-alpha/ TNFR superfamily, member 1B ( TNF-R2 ) signal transductionis mediated by a complex of intracellular signaling molecules including TNFreceptor-associated factor 2 ( TRAF2 ) and RIPK1 [9], [10].

Adaptor proteins, such as FADD, TRADD and RIPK1 domaincontaining adaptor with death domain ( RAIDD ) transmit an activation signal toeffectors caspases Caspase-2, -8, and -10 [11].

In other pathways, TNF/TNFRs' signal transduction is influenced via inhibition ofanti-apoptotic protein members of the Bcl-2 and IAP families; e.g. B-cell CLL/lymphoma 2( Bcl-2 ) and BCL2-like 1 ( Bcl-XL ) baculoviral IAP repeat-containing 2 (c-IAP1 ), baculoviral IAP repeat-containing 4 ( XIAP ).

For example, TNF superfamily, member 6 ( LIGHT )/ TNFR superfamily, member 3 (LTBR ) signal transduction are mediated by a complex of intracellular signalingmolecules including TRAF2, TNF receptor-associated factor 2 ( TRAF3 ),c-IAP1 and diablo homolog ( Smac/Diablo ) [12].Smac/Diablo inhibits activity of anti-apoptotic proteins c-IAP1 andXIAP [13].

Nerve growth factor, beta polypeptide ( NGF )/ TNFR superfamily, member 16 (NGFR ) apoptotic signal may be mediated via different mechanisms. One suchmechanism is an activation of nerve growth factor receptor associated protein 1 (NADE ) [14].

TNF superfamily, member 7 ( CD70 )/ TNFR superfamily, member 7 ( CD27 )and TNF superfamily, member 18 ( TNFSF18 )/ TNFR superfamily, member 18 (GITR ) signal transductions are mediated by a CD27-binding (Siva) protein (CD27BP ) [15], [16]. CD27BP induces apoptosis viainhibition of anti-apoptotic proteins Bcl-2 and Bcl-XL [17],[18].