receptor-signaling pathway. By inducing the concurrent expression of multiple
antiapoptotic proteins, NF-κB exerts a multipronged inhibition of death-receptor
signals (Figure 2).
c-FLIP, is an NF-κB-inducible protein (encoded by Cflar) that prevents death
receptor-induced activation of the initiator procaspase-8 (Irmler et al., 1997; Yeh et
al., 2000). NF-κB activation is required for TNF-α-induced expression of c-FLIP
(Kreuz et al., 2001). Although TNF-α-induced induction of c-FLIP is repressed by
a degradation-resistant mutant of IκBα, c-FLIP can still be induced by TNF-α in
RelA-/- cells (Yeh et al., 2000). Therefore, the identity of the NF-κB dimer
responsible for promoting c-FLIP expression remains unknown.
The promoter of the clap2 gene contains two functional κB sites (Hong et al.,
2000). Induction of c-Iap2 by TNF-α is blocked by introduction of a
phosphorylation mutant form of iκBα that resists IKK-induced degradation (Wang,
C.Y. et al., 1998). Akin to C-IAP2, c-IAP1 and XIAP are also NF-κB-induced
proteins which block the activation of caspases (-3, -7, and -9) by death receptors
(Liston et al., 1996).
c-IAPs cannot directly interact with procaspase-8, and expression of either protein
alone is not sufficient to protect cells from TNF-α-induced death (Wang, C.Y. et al.,
1998). Therefore, the recruitment of c-IAPs to the TNFR1 signaling complex via
interactions with TRAF2 may be required for inhibition of caspase-8 and proximal
blockade of the death signal (Shu et al., 1996; Wang, C.Y. et al., 1998). TRAF1 and
TRAF2 are also NF-κB-inducible genes that, along with c-IAP1 and C-IAP2,
suppress TNF-α-induced activation of caspase-8. Since TRAF2 also serves as an
adapter that augments TNF-α-induced activation of NF-κB, TRAF2 and NF-κB
may participate in a positive feedback loop to prevent TNF-α-induced apoptosis.
Consistent with this notion, cells from TRAF2-/- mice are partially defective in TNF-
α-induced NF-κB activation and exhibit exaggerated sensitivity to TNF-α-induced
apoptosis (Lee et al., 1997; Yeh et al., 1997).
The prototypic antiapoptotic member of the Bcl-2 family, Bcl-xL, contains a κB
DNA site (TTTACTGCCC; 298/+22) in its promoter (Chen, C. et al., 2000). The
Rel-dependent induction of Bcl-xL in response to TNF-α is sufficient to protect cells
carrying a degradation-resistant form of IκB from TNF-α-induced death (Chen, C.
et al., 2000). Likewise, NF-κB-dependent expression of Bcl-xL in response to co-
stimulatory signals (CD40-CD40L or CD28-B7 interactions) serves to protects B or
T cells from CD95/Fas- or Apo2L/TRAIL-induced apoptosis (Chen, C. et al., 2000;
Ravi et al., 2001).
Bfl-1/ A1 is a hematopoietic-specific Bcl-2 homolog which contains a functional
κB site in its promoter and is induced in an NF-κB-dependent fashion in response
to TNF-α (Zong et al., 1999). Overexpression of A1 partially protects Reldeficient
cells from TNF-α-induced apoptosis (Zong et al., 1999). Since A1-/- mice exhibit
only increased neutrophil apoptosis, it is likely that A1 is dispensable for the
antiapoptotic function of NF-κB in all other tissue types (Hamasaki et al., 1998).
NF-κB may also protect cells from death receptor-induced apoptosis by
attenuating expression of the proapoptotic protein, BAX (Bentires-Alj et al., 2001).
DEATH RECEPTORS IN APOPTOSIS 17