Genetics of Apoptosis

responsible for the antiapoptotic effects of IAPs, cIAP-1 and C-IAP2 also interact
with the TNFR1-associated proteins, TRAF-1 and TRAF-2, via their BIR domains
(Rothe et al., 1995). Therefore, although c-IAPs do not directly interact with
caspase-8, it is possible their recruitment to the TNFR1 signaling complex via an
interaction with TRAF-2 may regulate caspase-8 activation and/or TRAF-dependent
signaling. Consistent with this scenario, expression of c-IAP1 or cIAP-2 alone was
not sufficient to reduce cellular sensitivity to TNF-α-induced death; however, the
expression of both c-IAP1 and C-IAP2, coupled with TRAF1 and TRAF2, suppressed
TNF-α-induced apoptosis (Wang, C.Y. et al., 1998).
The basal expression of mammalian IAPs varies in different cell types in response
to cytokines, such as TNFα. As shall be discussed below, TNF-α-induced expression
of c-IAP1, cIAP-2, and XIAP is dependent upon the NF-κB transcription factor (Chu
et al., 1997; Wang, C.Y. et al., 1998). In these physiologic situations, IAPs may serve
to keep caspases in check until they are themselves sequestered and antagonized by
the mitochondrial efflux of Smac/DIABLO in response to death signals. However,
the constitutively high expression of IAPs, such as survivin, in many different types
of tumor cells may render such cells abnormally resistant to death receptor-induced
apoptosis (Ambrosini et al., 1997).

4.6

NF-κB—a master regulator of death receptor-induced apoptosis

While each of the regulatory mechanism(s) described above serves to interrupt specific
steps along the death receptor-induced signaling pathway, the master regulator
responsible for orchestrating the coordinated control of death receptor-induced
apoptosis is NF-κB, a family of heterodimeric transcription factors (Rel proteins) that
plays an important role in determining lymphocyte survival during immune,
inflammatory, and stress responses (Sha et al., 1995; Beg and Baltimore, 1996; Liu,
Z.G. et al., 1996; Van Antwerp et al., 1996; Wang, C.Y. et al., 1996; Attar et al.,
1997; Franzoso et al., 1998; Alcamo et al., 2001; Senftleben et al., 2001b; Karin and
Lin, 2002). Mammals express five Rel proteins that belong to two classes (Grimm
and Baeuerle, 1993; Karin and Ben Neriah, 2000). Members of one group (RelA, c-
Rel, and RelB) are synthesized as mature proteins, while the other (encoded by NFkb1
and NFkb2) includes precursor proteins (p105 and p100, respectively) that undergo
proteolysis to yield their mature products (p50 and p52 NF-κB proteins).
NF-κB dimers containing RelA or c-Rel are held in an inactive cytoplasmic
complex with inhibitory proteins, the iκBs. Phosphorylation of iκBs at two critical
serine residues (Ser^32 and Ser^36 in IκBα, Ser^19 and Ser^23 in IκBβ) in their N-terminal
regulatory domain by the IκB kinase (IKK) complex targets them for rapid ubiquitin-
mediated proteasomal degradation (Karin and Ben Neriah, 2000). IKK is a
multisubunit protein kinase consisting of two catalytic subunits, IKKα and IKKβ,
which phosphorylate IκB, and a regulatory subunit, IKKγ (also called NEMO, NF-
κB essential modifier/modulator or IKKAP1), which is required for activation of
IKKα/IKKβ heterodimers in response to proinflammatory cytokines, such as TNF-

14 GENETICS OF APOPTOSIS