Role TNF-alpha in apoptosis
The tumor necrosis factor (TNF-alpha) is a potent
cytokine produced by many cell 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 cellular responses of cell proliferation,
differentiation and apoptosis .
TNF-alpha exerts its effects through two distinct
receptors, TNFR1 and TNFR2.
Binding of the inherently trimeric TNF-alpha
to TNFR1 induces 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 adaptor protein transmits
an activating signal from the activated
receptor TNFR1 to some signaling cascades - caspase cascade
with subsequent apoptosis, NF-kB activating cascade and JNK cascade .
Recruiting of FADD and RIPK
by TRADD results in activation of the caspase cascade
followed by apoptosis. Adaptor proteins FADD and
RAIDD participate in activation of initiator
caspases caspase-2, -8, and
-10 by the activated receptor
TNFR1. Initiator caspases cleave and activate effector
caspases caspases-3, -6 and
-7. Effector caspases are responsible for the proteolytic
cleavage of a broad spectrum of cellular targets, which ultimately leads to cell death
Recruiting of TRAF2 and RIPK
by TRADD lead to an activation of survival transcription
factor NF-kB. RIPK and TRAF2
recruit IKK-gamma and IKK
alpha/beta subunits of IKK (inhibitor of nuclear factor
kappa B kinase ) complex respectively , . It was shown
that RIPK1 and TRAF2 both are
necessary for IKK activation .
The NF-kB pathway might intersect with the apoptotic
pathway via induction of antiapoptotic protein BCL-2 and
cellular inhibitors of apoptosis (c-IAP1,
c-IAP1, XIAP), which function
as specific caspase inhibitors , . Moreover,
c-IAP1 and TRAF2 form a complex
which direct inhibites of caspase-8 cleavage and activation
under TNF-alpha signaling .
TNF-alpha also activates the JNK signaling cascade and
results in an activation of the transcription factor AP-1
and subsequent increase proliferation. TRAF2
interact with and activate MEKK1 activating JNK cascade
Involvement of the JNK cascade in
TNF-alpha-mediated apoptosis is controversial.
It was shown that TNF-alpha -induced activation
of JNK results in the cleavage of apoptotic protein
Bid at the 25 position amino acid. A specific Bid cleavage
product (jBid) approximately 21 kDa in size subsequently
translocates in the mitochondria and is capable to release Smac/DIABLO
(mitochondrial Smac protein) from mitochondria without affecting the
cytochrome c localisation . In the
cytoplasm, Smac/DIABLO binds
c-IAP2, and abolishes the inhibitory action on caspases
. Additionally, Smac/DIABLO acts on and
disrupts the TRAF2- c-IAP1
complex and abolish its inhibition on caspase-8 .
Some regulators of TNF-alpha-signaling were detected.
Silencer of death domain (SODD) binds TNFR1 and prevents
self-aggregation and spontaneous downstream signaling at ligand absent.
SODD dissociates from
TNFR1upon receptor ligation .
BRE (brain and reproductive organ-expressed protein)
inhibits both TNF-alpha- induced activation of
NF-kB and apoptotic pathways .
ARTS-1 (aminopeptidase regulator of TNFR1 shedding)
increases TNFR1 shedding and decreases membrane-associated
TNFR1, thereby decreases the TNF-alpha signal .
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