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Apoptosis and survival TNFR1 signaling pathway


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Apoptosis and survival TNFR1 signaling pathway

Role TNF-alpha in apoptosis

The tumor necrosis factor ( TNF-alpha ) is a potent cytokine produced by manycell types, including macrophages, monocytes, lymphocytes, keratinocytes and fibroblasts,in response to inflammation, infection, injury and other environmental challenges.TNF-alpha elicits a particularly broad spectrum of organismal and cellularresponses of cell proliferation, differentiation and apoptosis [1].

TNF-alpha exerts its effects through two distinct receptors, TNFR1and TNFR2 . Binding of the inherently trimeric TNF-alpha to TNFR1induces receptor trimerization and recruitment of TNFR1-associated death domain protein (TRADD), which serves as a platform to recruit at least three additional mediators:receptor-interacting protein 1 ( RIP1 ), Fas-associated death domain protein (FADD ), TNF-receptor-associated factor 2 ( TRAF2 ). The a daptor proteintransmits an activating signal from the activated receptor TNFR1 to some signalingcascades - caspase cascade with subsequent apoptosis, NF-kB activating cascade and JNKcascade [1].

Recruiting of FADD and RIPK by TRADD results in activation of thecaspase cascade followed by apoptosis. Adaptor proteins FADD and RAIDDparticipate in activation of initiator caspases caspase-2, -8, and-10 by the activated receptor TNFR1. Initiator caspases cleave andactivate effector caspases caspases-3, -6 and -7. Effector caspasesare responsible for the proteolytic cleavage of a broad spectrum of cellular targets,which ultimately leads to cell death [1], [2].

Recruiting of TRAF2 and RIPK by TRADD lead to an activation ofsurvival transcription factor NF-kB. RIPK  and TRAF2 recruitIKK-gamma and IKK alpha/beta subunits of IKK (inhibitor of nuclearfactor kappa B kinase ) complex respectively [3], [4]. It wasshown that RIPK1 and TRAF2 both are necessary for IKK activation[5].

The NF-kB pathway might intersect with the apoptotic pathway via induction ofantiapoptotic protein BCL-2 and cellular inhibitors of apoptosis ( c-IAP1,c-IAP1, XIAP ), which function as specific caspase inhibitors [6], [7]. Moreover, c-IAP1 and TRAF2 form a complexwhich direct inhibites of caspase-8 cleavage and activation underTNF-alpha signaling [8].

TNF-alpha also activates the JNK signaling cascade and results in an activationof the transcription factor AP-1 and subsequent increase proliferation.TRAF2 interact with and activate MEKK1 activating JNK cascade [9].

Involvement of the JNK cascade in TNF-alpha -mediated apoptosis iscontroversial.

It was shown that TNF-alpha -induced activation of JNK results in thecleavage of apoptotic protein Bid at the 25 position amino acid. A specific Bidcleavage product ( jBid ) approximately 21 kDa in size subsequently translocatesin the mitochondria and is capable to release Smac/DIABLO (mitochondrial Smacprotein) from mitochondria without affecting the cytochrome c localisation [10]. In the cytoplasm, Smac/DIABLO binds XIAP, c-IAP1,c-IAP2, and abolishes the inhibitory action on caspases [6].Additionally, Smac/DIABLO acts on and disrupts the TRAF2 - c-IAP1complex and abolish its inhibition on caspase-8 [10].

Some regulators of TNF-alpha -signaling were detected. Silencer of death domain( SODD ) binds TNFR1 and prevents self-aggregation and spontaneous downstreamsignaling at ligand absent.

SODD dissociates from TNFR1 upon receptor ligation [11].

BRE (brain and reproductive organ-expressed protein) inhibits bothTNF-alpha- induced activation of NF-kB and apoptotic pathways [12].

ARTS-1 (aminopeptidase regulator of TNFR1 shedding) increases TNFR1shedding and decreases membrane-associated TNFR1, thereby decreases the TNF-alphasignal [13].