an obligatory role in death receptor-induced apoptosis of cell types that do not express
caspase-10, such as many cancer cells (Kischkel et al., 2001).
Role of apoptosis signal regulating kinase (ASK1) and c-Jun amino
terminal kinase (JNK)While there is overwhelming evidence that confirms the requirement of FADD/
caspase-8-mediated signaling pathways in death receptor-induced apoptosis, other
putative death receptor signaling pathways have also been described. Apoptosis signal
regulating kinase (ASK) 1 is a mammalian MAPKKK that activates SEK1 (or MKK4),
which, in turn, activates stress-activated protein kinase (SAPK, also known as JNK:
c-Jun N-terminal kinase). Overexpression of ASK1 induces apoptotic cell death, and
ASK1 is activated in cells treated with TNF-α; TNF-α-induced apoptosis is inhibited
by a catalytically inactive form of ASK1 (Ichijo et al., 1997). These observations
suggest that ASK1 may be a key element in the mechanism of stress—and cytokine-
induced apoptosis. ASK1 leads to activation of c-Jun N-terminal protein kinase
(JNK). However, the role of JNK activation in TNF-α-induced apoptosis is less clear.
Experiments using JNK activators or dominant negative forms of the JNK substrate
c-Jun suggest a proapoptotic role of JNK in TNF-α-induced death (Verheij et al.,
1996). However, JNK-deficient mouse fibroblasts remain sensitive to TNF-α—or
CD95L-induced apoptosis (Tournier et al., 2000). Therefore JNK activation may
potentiate death receptor-induced apoptosis, but is not obligatory for this process.
4.
Regulation of death receptor-induced apoptosisDeath receptors play an instrumental role in the physiologic induction of apoptosis
during development and tissue turnover in adult animals. However, the unscheduled
activation of death receptor-induced signals could lead to inadvertent caspase
activation with devastating consequences for the organism. In order to direct the
‘instructive’ apoptosis of cells without sustaining uncontrolled cell death, death
receptor-induced signaling is tightly regulated at multiple levels (Figure 2). These
regulatory mechanisms are described below.
4.1
Expression of death and decoy receptorsAt the most apical level, death receptor-ligand interactions may be regulated by the
tissue-specific or inducible expression of death receptors or their respective ligands.
TNFR1 is expressed ubiquitously, while its ligand (TNF) is expressed mainly by
activated T cells and macrophages (Smith et al., 1994). Likewise, CD95/Fas is widely
expressed and its cell-surface expression is elevated by immune activation of
lymphocytes or in response to cytokines such as interferon-γ, TNF, and CD40 ligand
(CD40L) (Leithauser et al., 1993; Krammer, 2000). Expression of CD95 ligand
DEATH RECEPTORS IN APOPTOSIS 9