To Be, or Not To Be: NF-JB Is The Answer - Role of Rel/NF-jB in The Regulation of Apoptosis

Oncogene (2003) 22, 89618982
& 2003 Nature Publishing Group All rights reserved 0950-9232/03 $25.00
www.nature.com/onc
To be, or not to be: NF-jB is the answer role of Rel/NF-jB in the

regulation of apoptosis
Jerome Kucharczak1,4, Matthew J Simmons1,2,4, Yongjun Fan1,4 and Celine Gelinas*,1,3
1
Center for Advanced Biotechnology and Medicine, 679 Hoes Lane, Piscataway, NJ, USA; 2Graduate Program in Biochemistry and
Molecular Biology, Piscataway, NJ, USA; 3Department of Biochemistry and Cancer Institute of New Jersey, Robert Wood Johnson
Medical School, University of Medicine and Dentistry of New Jersey, Piscataway, NJ, USA
During their lifetime, cells encounter many life or death

situations that challenge their very own existence. Their
survival depends on the interplay within a complex yet
precisely orchestrated network of proteins. The Rel/NFjB signaling pathway and the transcription factors that it
activates have emerged as critical regulators of the
apoptotic response. These proteins are best known for
the key roles that they play in normal immune and
inammatory responses, but they are also implicated in
the control of cell proliferation, differentiation, apoptosis
and oncogenesis. In recent years, there has been remarkable progress in understanding the pathways that activate
the Rel/NF-jB factors and their role in the cells decision
to either ght or surrender to apoptotic challenge.
Whereas NF-jB is most commonly involved in suppressing apoptosis by transactivating the expression of
antiapoptotic genes, it can promote programmed cell
death in response to certain death-inducing signals and in
certain cell types. This review surveys our current
understanding of the role of NF-jB in the apoptotic
response and focuses on many developments since this
topic was last reviewed in Oncogene 4 years ago. These
recent ndings shed new light on the activity of NF-jB as
a critical regulator of apoptosis in the immune, hepatic,
epidermal and nervous systems, on the mechanisms
through which it operates and on its role in tissue
development, homoeostasis and cancer.
Oncogene (2003) 22, 89618982. doi:10.1038/sj.onc.1207230
Keywords: Rel; NF-kB; apoptosis; transcription factor;
tumor necrosis factor; lymphocyte; neurodegenerative
disease; hepatocyte; cancer therapy
Introduction
The signaling pathways that control the life and death of
a cell are of prime interest in modern biology. Mutations
affecting components of these pathways are often
*Correspondence: C Gelinas, Center for Advanced Biotechnology and
Medicine, 679 Hoes Lane, Piscataway, NJ, USA;
E-mail: gelinas@cabm.rutgers.edu
4
These authors contributed equally
implicated in diseases arising from too much or too

little apoptosis, such as neurodegeneration and cancer.
The vertebrate Rel/NF-kB transcription factors are
critical players in the control of the apoptotic response
to a variety of stimuli. They are best known for their
pivotal roles in immune, inammatory and acute phase
responses, but they also play important roles in cell
growth, apoptosis and oncogenesis (reviewed in Silverman and Maniatis, 2001; Karin and Lin, 2002; Li and
Verma, 2002).
The Rel/NF-kB family is comprised of the vertebrate
c-Rel, RelA, RelB, p105/NF-kB1 and p100/NF-kB2
proteins, the viral oncoprotein v-Rel, Xenopus X-Rel1,
and the Drosophila Dorsal, Dif and Relish factors.
These structurally related proteins share extensive
sequence similarity in their N-terminal Rel homology
domain (RHD) that enables them to translocate to the
nucleus, form dimers with one another and bind to kB
DNA sites (GGGRNNYYCC). The distinct C-terminal
ends of vertebrate Rel/NF-kB factors participate in
transcriptional activation (v-Rel, c-Rel, RelA, RelB) or
in the control of Rel protein activity (p105/NF-kB1,
p100/NF-kB2). The latter group shares homology with
the IkB family of Rel protein regulators that control
their subcellular localization and inhibit their DNAbinding activity (IkBa, IkBb, IkBe, Bcl-3, p105/NF-kB1,
p105/NF-kB2).
Studies in recent years have provided important
insights into the pathways that lead to NF-kB activation
(reviewed in Karin and Ben-Neriah, 2000). In most
cells, Rel/NF-kB subunits are sequestered in the
cytoplasm as inactive homo- or heterodimers, bound
to one of several IkB factors. The rapid and transient
activation of NF-kB complexes in response to a wide
variety of stimuli generally involves phosphorylation
of IkB by the IkB kinase complex (IKK), which
contains the catalytic subunits IKKa and IKKb and
the regulatory IKKg/NEMO protein. Phosphorylation
targets IkB for degradation via the ubiquitin
proteasome pathway and culminates in the nuclear
translocation of active Rel/NF-kB dimers, their binding
to DNA and the transcriptional activation of cellular
genes involved in immune responses, inammation,
viral infection, cell proliferation and survival. In turn,
nuclear NF-kB factors trigger the resynthesis of IkBa,
giving rise to an autoregulatory loop that terminates the
Rel/NF-jB and apoptosis

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activation process. Phosphorylate IkBa to promote its

degradation (Schwarz et al., 1996; Miyamoto et al.,
1998; Romieu-Mourez et al., 2001; Shen et al., 2001;
Kato et al., 2003). In addition to the classical NF-kB
signaling pathway, a noncanonical NF-kB cascade has
been identied to involve signaling via the NF-kBinducing kinase (NIK) and IKKa, and results in the
processing of p100/NF-kB2 to mature p52/NF-kB2
(Senftleben et al., 2001; Xiao et al., 2001). Hundreds
of NF-kB-regulated genes have been identied (reviewed
in Pahl, 1999). While it is clear that the particular
combination of NF-kB subunits within distinct NF-kB
homo- or heterodimers is in a large part responsible for
determining the subsets of genes that they activate, a
recent study has added a new dimension to this concept.
Experiments with cell lines decient for single or
multiple NF-kB subunits revealed that the in vivo
specicity of cellular gene activation does not only lie
within the sequence of the kB DNA site, but is also
likely to be greatly inuenced by combinatorial protein
protein interactions with other promoter-bound factors
(Hoffmann et al., 2003). This additional level of
regulation is likely to help determine the specicity of
gene activation to ensure a differential response to
different stimuli.
The last few years have seen a virtual explosion in the
number of studies investigating the role of NF-kB in
apoptosis in different systems, and important progress
was made in understanding the mechanisms involved.
Here, we review the pro- and antiapoptotic effects of
NF-kB, its important involvement in different physiological contexts, the mechanisms by which it operates
and those that regulate its activity.
Lessons in survival: studies of NF-kBs pro- and
antiapoptotic functions in knockout mice and model cell
systems
All ve members of the mammalian Rel/NF-kB family
and several components of the NF-kB signaling pathway have been targeted by homozygous inactivation in
mice to characterize their function. The phenotypes of
these animals have been reviewed in detail (reviewed in
Li and Verma, 2002). These studies revealed distinct
roles for individual NF-kB subunits in innate and
adaptive immune responses, and also unveiled a pivotal
role for NF-kB in regulating apoptosis in the immune
and nervous systems, in the liver, and in hair follicles
and epidermal appendages. This section focuses on
those that revealed a link to apoptosis, on studies in in
vitro cell systems that support these ndings and
emphasizes recent discoveries that shed further light
on the subject.
NF-kB: life and death decisions in the immune system
A protective role for NF-kB in B cells The survival of
peripheral B cells in response to antigen depends on Bcell receptor (BCR)-mediated activation of NF-kB and
the induction of antiapoptotic target genes. Early
studies in B-lymphocyte cell lines demonstrated a vital
Oncogene
role for NF-kB in this process, as suppression of

endogenous NF-kB activity invariably led to apoptosis
in cells treated with anti-IgM antibodies, whereas
ectopic expression of c-rel restored viability (Wu et al.,
1996a, b). Consistent with these ndings, primary B cells
from c-rel-decient mice undergo apoptosis upon
mitogenic stimulation, and this phenotype is rescued
by transgenes encoding c-Rel itself, or its antiapoptotic
targets Bcl-2, Bcl-xL or B-1/A1 (Kontgen et al., 1995;
Grumont et al., 1998, 1999; Tumang et al., 1998;
Owyang et al., 2001). Whereas p50/NF-kB1 is important
for the survival of quiescent B cells, combined inactivation of p50 and c-rel in double knockout mice
established a critical role for these factors in mitogenactivated B cells (Grumont et al., 1998). The pathway
leading to NF-kB activation in response to BCR
engagement has been elucidated (Figure 1A). As
anticipated, inactivation of individual components of
this cascade, including B-lineage-specic depletion of
IKKb or IKKg/NEMO, results in dramatic inhibition of
NF-kB stimulation following BCR engagement and
increased apoptosis (Petro et al., 2000; Leitges et al.,
2001; Petro and Khan, 2001; Tan et al., 2001; Martin
et al., 2002; Pasparakis et al., 2002b; Li et al., 2003). In
some of these studies, this was correlated with a failure
to induce expression of antiapoptotic proteins Bcl-xL
and Bcl-2.
Contrary to the single knockouts of c-rel or relA, B
cells from compound c-rel/relA double knockout
embryos fail to mature to the IgM(lo)IgD(hi) stage
due to premature death by apoptosis, coincident with
impaired expression of Bcl-2 and B-1/A1 (Grossmann
et al., 2000). A bcl-2 transgene could rescue this
phenotype. In contrast, expression of a bcl-xl transgene
into bone marrow cells transduced with a transdominant
form of IkBa could not surmount the impairment for
maturation to follicular B cells in recipient mice,
although it restored viability to pre-B/immature B-cell
subsets (HC Liou, personal communication). Together,
these results emphasize an important role for individual
NF-kB subunits in B-cell survival, maturation and
function.
NF-kB has also been implicated in attenuating
apoptosis in response to the cytokine BAFF
(also known as BlyS), which is necessary for peripheral
B-cell development, as illustrated by the phenotype
of mice expressing nonfunctional BAFF receptor
(BAFF-R) or lacking BAFF (Schiemann et al., 2001).
Recent studies showed that in quiescent B cells,
BAFF activates NF-kB through both the classical and
the noncanonical NF-kB pathways, with predominance
for the latter (Figure 1A; Kayagaki et al., 2002;
Hatada et al., 2003). Whereas binding of BAFF to
BAFF receptor 3 (BR3) leads to processing of p100/NFkB2 to p52, one study revealed a requirement for the
NF-kB subunit of p50 for the survival function of
BAFF (Hatada et al., 2003). As a consequence
of BAFF-mediated NF-kB activation, antiapoptotic
genes encoding Bcl-2, Bcl-xL and B-1/A1 are activated,
but only in mature B cells (Do et al., 2000; Hsu et al.,
2002).

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Figure 1 NF-kB activation in adaptative and innate immune responses (A) B-cell activation triggers the NF-kB signaling pathway in
the adaptive immune response. (a) BCR activation by antigen leads to the recruitment of a functional complex containing Syk, Btk,
BLNK and PLC-g2. Activation of PLC-g2 provokes the release of calcium and diacylglycerol to activate PKC-b and induce both the
classical and noncanonical NF-kB pathways via phosphorylation of IKKa and IKKb. Both pathways lead to the activation of NF-kBresponsive genes. Contrary to PKC-b, PKC-z does not activate NF-kB via IKK, but rather directly phosphorylates RelA to enhance its
transcriptional activity. (b) BAFF signaling in B cells induces the noncanonical NF-kB pathway. BAFF-R engagement leads to the
activation of NIK that phosphorylates and activates IKKa. In turn, IKKa phosphorylates p100/NF-kB2 in an IKKg/NEMOindependent manner. This initiates ubiquitin-mediated proteolytic processing of p100 to p52. Formation of p52 heterodimers with
RelB results in NF-kB-dependent gene activation. (B) Engagement of cell surface TLRs and cytosolic NOD receptors activates NF-kB
signaling in the innate immune response. (a) The binding of bacterial LPS to TLR4 triggers recruitment of MyD88 and the serine/
threonine kinase IRAK, leading to its association with adaptor protein TRAF6 and MAP3K. This intracellular signaling cascade
converges on activation of the IKK kinase complex and NF-kB to induce gene expression. (b) Ligands such as MDP, released
following phagocytosis of bacteria, are recognized by cytosolic NOD receptors. Activation of some NODs can induce two different
signaling pathways. One pathway activates the classical NF-kB signaling cascade in a RICK- and RIP-dependent manner, resulting in
NF-kB-dependent expression of proinammatory cytokines, and in the case of NOD2 of prosurvival factor B-1/A1. The other
pathway leads to caspase activation and cell death
Anti- and proapoptotic roles for NF-kB in T cells The

full activation of na ve T cells requires engagement of
the T-cell receptor (TCR) and costimulatory signaling
by CD28. This leads to NF-kB activation and consequent cell survival via induction of antiapoptotic
genes, and to proliferation via synthesis of IL-2 and
GM-CSF. Studies with wild-type and p50/c-Rel/
CD4 T cells demonstrated that activation of NF-kB
following TCR engagement in conjunction with CD28
costimulation is critically required to induce expression
of antiapoptotic genes bcl-xl and bcl-2 and promote Tcell viability (Zheng et al., 2003). Similar results were
observed in CD4 T cells expressing a super-repressor
form of IkBa (Khoshnan et al., 2000). Whereas
cessation of TCR stimulation in wild-type T cells caused
a rapid drop in endogenous NF-kB levels along with
apoptosis, enforced expression of IKKb enabled cells to
survive in the absence of sustained TCR stimulation
(Zheng et al., 2003). A recent analysis of activated
CD4 or CD8 T cells indicated that while induction of
the NF-kB targets Bcl-xL and its homologue B-1/A1 is
transient, that of Bcl-2 is delayed and IL-2 dependent
(Verschelde et al., 2003).
In the absence of CD28-derived costimulatory signals,

apoptosis of antigenically stimulated na ve T cells can be
inhibited in vivo by adjuvant-induced inammation.
Microarray analyses revealed that sustained T cell
response in a model of adjuvant-induced survival was
correlated with increased expression of the IkB-related
Bcl-3 protein (Mitchell et al., 2002a). Retroviralmediated transfer of Bcl-3 itself or a subdomain
containing its rst and second ankyrin repeats could
confer survival to activated T cells in vitro and in vivo
(Mitchell et al., 2001, 2002b). Unlike other IkB
molecules, Bcl-3 is generally found in the nucleus where
it modulates transcription via interaction with homodimers of p50/NF-kB1 or p52/NF-kB2. It was thus
postulated that Bcl-3 might enhance cell viability in this
context by inducing the expression of NF-kB-regulated
genes. These results reveal a mechanism underlying the
protective effects of inammation and innate immunity
toward T-cell apoptosis in the adaptive immune
response (reviewed in Gerondakis and Strasser, 2001).
A recently published report has unveiled a new way
for NF-kB to antagonize cell death in antigenically
stimulated na ve T cells in the absence of costimulatory
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J Kucharczak et al
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Table 1 Products of NF-kB-regulated target genes with anti- or proapoptotic activities
Antiapoptotic proteins
Function in apoptosis
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procaspase-9
procaspase-9
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Inhibits TNF-induced JNK activation
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(1998)
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Bcl-2
Antagonizes proapoptotic Bcl-2 family members
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B-1/A1

NR13
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and Johnson (2001)
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Zong et al. (1999), Grumont et al. (1999), Wang et al.
(1999), Lee et al. (1999a)
Lee et al. (1999b)
Adaptor molecules
TRAF-1
TRAF-2
Adaptor molecule, augments NF-kB activation

Adaptor molecule, augments NF-kB activation
Wang et al. (1998), Schwenzer et al. (1999)

Wang et al. (1998)
Others
A20
MnSOD
Blocks the TNFa death pathway

Clears reactive oxygen species
IAPs
c-IAP1
c-IAP2
XIAP
c-FLIP
Interferes with activation of procaspase-8 and -10
Krikos et al. (1992), Malewicz et al. (2003)

Bernard et al. (2002, 2001a), Delhalle et al. (2002),
Tanaka et al. (2002)
Kreuz et al. (2001), Micheau et al. (2001)
DcR1 (decoy receptor 1)

GADD45b
Decoy Trail DR
Inhibits TNFa-induced JNK activation
Prevents Fas-induced apoptosis in B cells
Bernard et al. (2001)

De Smaele et al. (2001), Jin et al. (2002)
Zazzeroni et al. (2003)
Ligands
FasL (CD95L)
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Fas (CD95)
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Bcl-2 family
Bcl-xS
Antagonizes prosurvival Bcl-2 family members
Chen et al. (2003)
Proapoptotic proteins
signal, that is, by suppressing expression of the p53related p73 protein (Wan and DeGregori, 2003). In this
study, inhibition of NF-kB in T cells by a superrepressor form of IkBa triggered E2F- and p73dependent apoptosis upon cell activation. In contrast,
cells lacking p73 survived despite inhibition of NF-kB.
The mechanism by which NF-kB downregulates p73
remains to be claried, but the presence of putative NFkB binding sites in the vicinity of p73s rst exon gave
rise to speculation that NF-kB might interfere with E2Fmediated transactivation of p73. This study is consistent
with prior work implicating E2F1 and p73 in inducing
apoptosis in activated mature T cells (reviewed in Green,
2003). This newly uncovered interplay between NF-kB
Oncogene
and the Cdk-Rb-E2F pathway to control the outcome

of T cells following receptor engagement suggests that in
the absence of costimulatory signal to activate NF-kB,
E2F-mediated induction of p73 could perhaps serve to
eliminate autoreactive T cells from the peripheral
repertoire (reviewed in Green, 2003). These results
provide new insights into the role of NF-kB in the
survival of antigen-stimulated na ve T cells.
In contrast to the antiapoptotic activity of NF-kB
described above, others showed that NF-kB contributes
to apoptosis during activation-induced cell death
(AICD) in mature T cells. In this context, NF-kB
triggered the Fas-death cascade by directly activating
the expression of Fas ligand (FasL) (Table 1; Kasibhatla

J Kucharczak et al
8965
et al., 1999; Lin et al., 1999; Zheng et al., 2001). The

expression of a dominant IkB molecule (IkBaM)
inhibited both FasL expression and apoptosis. However,
it remains to be determined how this pathway of AICD
relates to that involving Cdk-Rb-E2F and p73 described
above.
The protective role of NF-kB during T-cell development is also a subject of debate. Studies indicate that
NF-kB is required for the survival of developing
thymocytes, as pre-T cells in which NF-kB expression
was abolished undergo spontaneous apoptosis, whereas
a constitutively active form of IKK allowed cells to
differentiate to the CD4 CD8 double-positive stage
(Voll et al., 2000). This agrees with the impaired
thymocyte development observed in transgenic mice
expressing IkB in the T-cell lineage (Boothby et al.,
1997; Esslinger et al., 1997). In contrast, others reported
a proapoptotic role for NF-kB in double-positive
CD4 CD8 thymocytes (Hettmann et al., 1999; Kim
et al., 2002a). T-cell-specic expression of a CD2-IkBaM
transgene conferred resistance to anti-CD3-mediated
apoptosis (Hettmann et al., 1999). Further studies will
help to determine how NF-kB elicits different apoptotic
responses in different contexts.
A possible role for NF-kB in suppressing apoptosis in the
innate immune response A link between NF-kB and
apoptosis has also surfaced in the innate immune
response, which plays a fundamental role in the
detection and elimination of pathogens. The nucleotidebinding oligomerization domain (NOD) proteins act as
cytosolic regulators of inammation and apoptosis
(Figure 1B; reviewed in Inohara and Nunez, 2003).
NOD1 and NOD2 activate the canonical NF-kB pathway in a RICK-dependent manner (Bertin et al., 1999;
Geddes et al., 2001; Ogura et al., 2001; Kobayashi et al.,
2002). NOD1 and IPAF activate caspase-1 to form an
inammasome required for cleavage of IL-1b during
the innate immune response (Poyet et al., 2001; Grenier
et al., 2002; Martinon et al., 2002; Wang et al., 2002a;
Yoo et al., 2002). In addition to promoting expression of
proinammatory cytokines, NOD-mediated activation
of NF-kB was shown in one instance to also promote
transcription of antiapoptotic genes, as demonstrated by
activation of the prosurvival Bcl-2 family member B-1/
A1 following activation of NOD2 by bacterial muramyl
dipeptide (MDP) (Inohara et al., 2003). Interestingly
NOD1, NOD2, IPAF and DEFCAP can also induce cell
death in overexpression studies. In light of the dual
capacity of some NOD proteins to both promote
apoptosis and activate NF-kB, it is speculated that in
a physiological context NF-kB-dependent activation of
antiapoptotic genes by NOD2 might serve to modulate
its proapoptotic effect (Inohara and Nunez, 2003).
Further experimentation will test this hypothesis.
Toll-like receptors (TLRs) recognize extracellular
microbial components in myelomonocytic cells and
activate the NF-kB signaling pathway via IL-1-receptor-associated kinase (IRAK) and tumor necrosis factor
(TNF) receptor-associated factor TRAF6 to induce
production of proinammatory cytokines and costimulatory molecules and trigger a defensive reaction
(Figure 1B; reviewed in Takeda and Akira, 2001).
TLR activation has also been reported to trigger
apoptosis in some cases e.g. (Aliprantis et al., 2000). A
recent example comes from the 19-kDa Mycobacterium
tuberculosis protein (p19) that increased the rate of
apoptosis of infected macrophages in a caspase-8dependent manner (Lopez et al., 2003). However, it is
unclear whether NF-kB induces expression of antiapoptotic genes in this context. A recent report indicated
that TLR4 activation increases neutrophil survival in an
NF-kB- and mitogen-activated protein kinase (MAPK)dependent manner via production of survival cytokines
(Sabroe et al., 2003). Thus it appears that similar to the
NOD pathway, a picture is emerging in which both NFkB and apoptosis can be triggered upon TLR activation
in some instances. Prolonged cell survival in these cases
depends on the proper balance between proapoptotic
and prosurvival signals induced in NF-kB-dependent or
-independent manners.
A critical role for NF-kB in suppressing hepatocyte
apoptosis
NF-kB was ascribed both benecial and damaging
effects in the liver, owing to its role in liver development,
regeneration and carcinogenesis (reviewed in Taub,
1998). Several years ago, the dramatic phenotype of
RelA-decient mice provided compelling evidence to
support a protective role for NF-kB in suppressing liver
apoptosis. RelA animals succumb by days 15.516.5 of
embryogenesis due to massive apoptosis of hepatocytes
(Beg and Baltimore, 1996; reviewed in Li and Verma,
2002). Mouse embryos lacking both RelA and NF-kB1
(i.e. the classical p50/p65 NF-kB dimer) died earlier, at
about E13 of gestation (Horwitz et al., 1997). The
combined inactivation of RelA and c-Rel in compound
knockouts also led to advanced death compared to
RelA embryos, suggesting that the lack of RelA can be
alleviated to some extent by c-Rel (Grossmann et al.,
1999; Grossmann et al., 2000). Not surprisingly, the
recent analysis of animals decient for upstream
components of the NF-kB signaling cascade revealed a
similar phenotype. Mice lacking IKKb, IKKg/NEMO
or both IKKa/IKKb showed embryonic lethality
between E12.5E14.5 (Li et al., 1999a, c, 2000; Tanaka
et al., 1999; Rudolph et al., 2000). Homozygous deletion
of the IKK kinase homologue T2K (TBK1, NAK),
which associates with TRAF2 but is not a component of
the IKK complex, also led to severe liver degeneration
(Bonnard et al., 2000). The massive hepatocyte apoptosis in RelA and IKKb knockout animals was attributed
to increased sensitivity to circulating TNFa, as embryonic liver apoptosis was not observed in compound
knockouts for RelA and TNFa, or IKKb and TNF-R1
(Doi et al., 1999; Alcamo et al., 2001). This agrees with
the increased sensitivity of mouse embryonic broblasts
(MEFs) and macrophages from relA mice to TNFainduced apoptosis (Beg and Baltimore, 1996). It is
interesting however that MEFs from T2K/ mice are
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J Kucharczak et al
8966
not sensitized to TNFa nor is NF-kB DNA-binding

activity affected, although NF-kBs transcriptional
activity is impaired in these cells (Bonnard et al.,
2000). These recent ndings suggest a role for T2K in
suppressing embryonic liver apoptosis that apparently
does not depend on degradation of IkB or NF-kB DNA
binding.
Studies in hepatocytes treated with transforming
growth factor-b (TGF-b) further support a protective
role for NF-kB. Prior studies indicated that TGF-b
induces apoptosis by stabilizing IkBa and inactivating
NF-kB (Arsura et al., 1997). Recent work has shed
further light on the subject by showing that TGF-b1
inhibits the ability of CK2 to stabilize IkBa in
immortalized hepatocytes (Cavin et al., 2003). Transient
activation of NF-kB via a TAK1/IKK pathway was also
described to play a role in increasing IkBa synthesis to
repress NF-kB in liver epithelial cells, allowing TGF-b1induced cell death to proceed through AP-1/SMAD
(Arsura et al., 2003).
An essential role for NF-kB in the development and
survival of hair follicles and epidermal appendages
An important role for NF-kB in epidermal homeostasis
and the development of skin appendages has only
recently come to light. Five independent lines of
investigation support this conclusion: (1) Mice that
ubiquitously express a super-repressor of NF-kB
(IkBDN) display impaired development of hair follicles
and exocrine glands due to increased apoptosis
(Schmidt-Ullrich et al., 2001). This phenotype is
reminiscent of the human epidermal disorder hypohidrotic (anhydrotic) ectodermal dysplasia (HED), and is
indistinguishable from that of mice with mutations in
the genes encoding the TNF-related ligand ectodermal
dysplasia (EDA) (tabby), its TNFR-related receptor
ectodysplasin receptor (EDAR) (Downless) and
crinkled (Cr or Edaradd for EDAR-associated death
domain (DD)), a novel DD-containing adaptor that
binds EDAR and mediates engagement of the NF-kB
pathway (Headon et al., 2001; Yan et al., 2002). (2)
Heterozygous IKKg/NEMO females survive to birth
but show traits reminiscent of those associated with
human incontinentia pigmenti (IP), the rst genetic
disorder attributed to NF-kB dysfunction (SchmidtSupprian et al., 2000; reviewed in Smahi et al., 2002).
Mice heterozygous for IKKg have skin lesions with
granulocyte inltration, keratinocyte apoptosis and
abnormal development of teeth, eyes and hair. TNFa
plays an essential role in the development of IP lesions
as human IP cells are highly sensitive to TNF-induced
apoptosis and fail to elicit an NF-kB response. Patients
with EDA also show abnormal development of ectoderm-derived structures (teeth, hair, nails, sweat glands)
and display hypomorphic NEMO mutations (reviewed
in Smahi et al., 2002). (3) Conditional deletion of IKKb
in the epidermis and hair follicles recapitulates many of
the traits seen in IKKg/NEMO / embryos, with the
notable exception that the extensive keratinocyte apoptosis seen in NEMO knockouts was not observed in the
Oncogene
skin of IKKb-decient embryos (Pasparakis et al.,

2002a). The mutant phenotype caused by conditional
inactivation of IKKb in the epidermis was suppressed in
a TNFR-decient background. (4) TRAF6-decient
mice suffer from HED due to impaired development
of epidermal appendages (Naito et al., 2002). Although
TRAF6 does not associate with EDAR, it associates
with X-linked ectodysplasin-A2 receptor (XEDAR)
expressed in epidermal appendages and is essential for
XEDAR-mediated NF-kB activation. (5) Loss of
tumor suppressor CYLD causes the autosomal dominant syndrome cylindromatosis (turban tumor syndrome), that predisposes patients to benign tumors of
hair follicles and cells of the sweat and scent glands
(reviewed in Wilkinson, 2003). Interestingly, CYLD was
recently shown to interact directly with TRAF2
and IKKg/NEMO and to function as a TRAF2
deubiquitinating enzyme to negatively regulate IKKmediated activation of NF-kB downstream of CD40,
XEDAR and EDAR (Brummelkamp et al., 2003;
Kovalenko et al., 2003; Trompouki et al., 2003). Loss
of CYLD activates TNFa signaling through NF-kB and
decreases apoptosis, whereas agents that antagonize
NF-kB signaling interfere with cell death inhibition
caused by loss of CYLD (Brummelkamp et al., 2003).
Altogether, the studies in this section highlight a critical
role for NF-kB in suppressing apoptosis to allow
differentiation and survival of hair follicles and epidermal appendages.
A double-edged sword: anti- and proapoptotic effects of
NF-kB in the nervous system
Functional NF-kB complexes (mostly p50 and p65) are
present in essentially all cell types of the nervous system,
including neurons, astrocytes, microglia and oligodendrocytes. Among the many stimuli that can activate NFkB in this system are membrane depolarization, nerve
growth factor (NGF), opioids, the secreted form of bamyloid protein, TNF and glutamate (reviewed in
Mattson and Camandola, 2001). However, the role of
NF-kB within the developing and mature central
nervous system has been controversial. While some
studies report a proapoptotic role, most indicate a
cytoprotective effect.
Accumulating evidence points to NF-kB as a survival
determinant for neurons. Consistent with its expression
pattern during development of the nervous system, NFkB was implicated in NGF-mediated protection of
developing sensory neurons to cytokines (Hamanoue
et al., 1999; Middleton et al., 2000). Moreover,
inhibition of NF-kB in primary rat cortical neurons
with a super-repressor form of IkBa, a dominantnegative form of NIK, or NF-kB inhibitors parthenolide, SN50 or BAY 11-7082 triggers rapid activation of
an intrinsic apoptotic program and is accompanied by
reduced levels of NF-kB-regulated transcripts for
antiapoptotic genes Bcl-2, Bcl-xL and B-1/A1, in
particular (Bhakar et al., 2002; Chiarugi, 2002).
Similarly, cultured relA/ neurons show reduced
survival compared to wild type (Hamanoue et al.,

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1999). Incidentally, despite the fact that homozygous

inactivation of bcl-2 or bcl-x is embryonic lethal,
embryos show severe loss of neurons in the central
and peripheral nervous systems, suggesting a protective
role for these NF-kB targets in developing neurons
(Motoyama et al., 1995; Michaelidis et al., 1996). In the
PC12 model cell system, NGF stimulation was shown to
activate NF-kB via the p75(NTR) and TrkA receptors
and to result in different physiological effects (Foehr
et al., 2000b). Whereas NF-kB activation via the
p75(NTR) receptor signicantly blocked apoptosis, its
activation via TrkA induced neurite process formation.
Similarly, overexpression of NIK induced PC12 cell
differentiation and antagonized cell death via the IKK
and MAPK signaling cascades (Foehr et al., 2000a).
Consistent with these ndings in cultured cells, embryos
from IKKa/IKKb double knockout mice show defects
in neurulation due to increased apoptosis. These were
not apparent in the single knockouts, and it should be
noted that embryos from IKKg/NEMO/ mice lack
neuronal defects (Li et al., 2000). It was proposed that
IKKa and IKKb have redundant effects during
neuronal development and that NF-kB-independent
mechanisms might be involved in the neuronal phenotype of the IKKa/IKKb double knockout, akin to the
NF-kB-independent effects observed on the skin phenotype of IKKa/ mice (Hu et al., 1999; Li et al., 1999b;
Takeda et al., 1999).
Several experiments indicate that NF-kB is also
neuroprotective in response to injury and that NF-kB
decoys abolish protection (reviewed in Mattson and
Camandola, 2001). NF-kB was shown to antagonize
neurodegeneration in this context by triggering expression of various antiapoptotic genes including inhibitor
of apoptosis proteins (IAPs) that protect neurons in
experimental models of stroke or seizure, manganese
superoxide dismutase (MnSOD) a mitochondrial antioxidant enzyme that is neuroprotective, and cell death
inhibitors Bcl-2 and Bcl-xL (Mattson and Camandola,
2001). NF-kB was also ascribed a cytoprotective effect
when induced by amyloid deposits in vivo and in cell
culture studies of neurons (reviewed in Mattson and
Camandola, 2001). Indeed, exposure of cortical neurons
to the amyloid beta-peptide associated with Alzheimers
disease leads to neurodegeneration and is accompanied
by increased levels of IkBa and decreased NF-kB
activity (Bales et al., 1998). In contrast, the neuroprotective alpha-secretase-derived form of the beta-amyloid
precursor protein activates NF-kB and protects against
apoptosis induced by the neurotoxic amyloid betapeptide (Guo et al., 1998). Increased NF-kB activity was
also observed in other neurodegenerative disorders, such
as Parkinsons disease and amyotrophic lateral sclerosis,
whereby it may correspond to an early defense mechanism against oxidative stress and mitochondrial dysfunction (reviewed in Mattson and Camandola, 2001).
Consistent with this notion, p50-decient animals
treated with a mitochondrial toxin in an experimental
model of Huntingtons disease showed increased striatal
neuronal damage and failure to upregulate MnSOD, in
contrast to wild-type mice (Yu et al., 2000).
Contrary to the work described above, other reports

described a proapoptotic effect for NF-kB in in vitro and
in vivo models of neuronal cell injury (reviewed in
Barkett and Gilmore, 1999; Denk et al., 2000). Many of
them converge on tumor suppressor p53, which was
implicated as a detrimental factor for neuronal viability
in response to ischemia/reperfusion and excitotoxic
insult (Crumrine et al., 1994; Morrison et al., 1996;
Xiang et al., 1996). For instance, activation of the
NMDA receptor by the excitotoxin quinolic acid
triggers NF-kB activation and a concomitant increase
of p53 and c-Myc expression in rat striatum, whereas its
suppression prevented cell death (Qin et al., 1999). A
more recent study involving stimulation of rat striatal
neurons with the glutamate receptor agonist kainic acid
produced similar results (Nakai et al., 2000). Since NFkB was described as a positive regulator of both p53 and
c-Myc expression (Duyao et al., 1990; La Rosa et al.,
1994; Wu and Lozano, 1994), activation of NF-kB in
these excitotoxic models of Huntingtons disease was
proposed to induce expression of c-Myc and p53 to
trigger cell death.
Recently, individual NF-kB subunits were suggested
to have opposing roles in modulating neuronal survival
following exposure to the neurotoxin glutamate.
Whereas glutamate activated p50/NF-kB1 and p65/
RelA in cultured rat cerebellar granule cells and mouse
hippocampal slices, treatment with IL-1b that promotes
neuron survival activated expression of c-Rel along with
p50/NF-kB1 and p65/RelA (Pizzi et al., 2002). NF-kB
inhibition with antisense oligonucleotides implicated
RelA in glutamate-mediated cell death, while c-Rel
was essential for IL-1b-mediated survival in cerebellar
granule cells. These results imply that the particular
composition of NF-kB complexes may be a key factor in
establishing neuronal cell survival or cell death. In this
regard, a neuron-specic factor distinct from NF-kB
was previously described to bind to kB DNA sites
(neuronal kB binding factor, NkBF) (Moerman et al.,
1999). A recent follow-up on this work showed that
NkBF consists of Sp1-related proteins and that its
binding to kB DNA motifs can be competed by
oligonucleotides containing an Sp1-binding motif
(Mao et al., 2002). Activation of ionotropic glutamate
receptors reduced the activity of NkBF, consistent with
the proteolytic degradation of Sp1-related factors in this
context. It therefore appears that non-NF-kB-related
factors may also play a role in determining neuronal cell
fate. Future work will undoubtedly help to establish the
contribution of this factor relative to that of bona de
NF-kB in the response of neurons to apoptotic signals.
Another important factor in the balance between the
pro- and antiapoptotic effects of NF-kB in the nervous
system appears to be the cell type. While many studies
have proposed that NF-kB guards neurons from
degeneration, its activation in microglia appears to
foster neuronal cell death (reviewed in Mattson and
Camandola, 2001). Indeed, whereas homozygous inactivation of p50/NF-kB1 in mice signicantly reduced
ischemic neuronal death (Schneider et al., 1999), NF-kB
activation in microglia promoted ischemic neuronal
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degeneration most likely due to production of neurotoxic reactive oxygen species (ROS) and excitotoxins by
activated microglia. Thus, while NF-kB may suppress
the death of cells in which it is activated, its ability to
induce expression of cytotoxic agents such as nitric
oxide may promote the demise of other cells (reviewed in
Mattson and Camandola, 2001). Although the consequences of NF-kB activation in the nervous system
remain somewhat controversial, it seems that some of
the discrepancies might derive from the analysis of
different cell types, experimental conditions, inducing
signals and the particular NF-kB subunits involved
(reviewed in Denk et al., 2000). These issues deserve
further investigation.
Implication of NF-kB in the cell response to viral infection
For many viruses, activation of NF-kB has been linked
to their transforming activity. The rst identied
member of the Rel/NF-kB family, v-Rel, is in fact a
viral protein derived from the cellular gene c-Rel. As the
oncogene of the avian Rev-T retrovirus that causes fatal
lymphoma in infected young birds, v-Rel suppresses
apoptosis from a variety of death signals, and this
appears to be important for its oncogenic effect
(reviewed in Gilmore, 1999). Indeed, cells that conditionally express v-Rel readily undergo apoptosis upon
inactivation of the protein (White et al., 1995; Zong
et al., 1997). This is consistent with the resilience of
tumor-derived cells transformed by v-Rel to proapoptotic stimuli (Neiman et al., 1991). Recent work suggests
that the oncogenic potential of Rel proteins arises at
least in part from their ability to upregulate antiapoptotic proteins. Both v-Rel mutants with impaired
transforming activity due to transactivation domain
mutations or weakly transforming Rel proteins could be
rescued by coexpression of death suppressors Bcl-xL or
Bcl-2 (White and Gilmore, 1996; Gilmore et al., 2001;
Rayet et al., 2003). In support of this idea, v-Rel
upregulates expression of c-IAP1 in transformed cells
and does so at higher levels than its cellular homologue
c-Rel (Kralova et al., 2002).
The Tax oncoprotein of human T-cell leukemia virus
type-1 (HTLV-1) immortalizes T cells in an NF-kBdependent manner and is implicated in adult T-cell
leukemia (ATL). Suppression of NF-kB in Tax-induced
mouse tumor cells sensitizes them to proapoptotic
stimuli (Portis et al., 2001). As seen in HTLV-1immortalized T cells and those of ATL patients, Taxmediated activation of NF-kB induces death-suppressive genes, such as Bcl-xL, Bcl-2 and B-1/A1 (Harhaj
et al., 1999; Tsukahara et al., 1999; Nicot et al., 2000).
NF-kB is also linked to transformation by the oncogenic
human herpesvirus EpsteinBarr Virus (EBV) that is
implicated in Burkitts lymphoma. Its latent membrane
protein 1 (LMP1) suppresses apoptosis and is required
for human B-cell transformation by EBV (CahirMcFarland et al., 2000; Feuillard et al., 2000; He et al.,
2000; reviewed in Hiscott et al., 2001). LMP1 was
recently shown to upregulate expression of B-1/A1 via
a novel NF-kB-like binding site and this increase
Oncogene
conferred protection against apoptosis induced by

growth factor deprivation in an EBV-positive cell line
exhibiting a latency type I infection (DSouza et al.,
2000, 2003). Contrary to these ndings and others,
LMP1 was recently reported to induce cell death via
NF-kB-dependent activation of caspase-3 (Nitta et al.,
2003). In this study, LMP1 failed to induce death in
absence of RelA or upon inhibition of NF-kB. Although
the reason for this discrepancy remains to be determined, the use of different cell types should be noted.
The human herpesvirus 8 is linked to Kaposis sarcoma
and primary effusion lymphoma. Its v-FLIP protein
suppresses apoptosis triggered by growth factor deprivation by persistently activating the IKK kinase
complex thereby inducing expression of Bcl-xL (Liu
et al., 2002; Sun et al., 2003). Lastly, gammaherpesviruses establish latent infections in lymphocytes and are
implicated in nasopharyngeal carcinoma, Kaposis
sarcoma and B-cell lymphomas. NF-kB was recently
implicated in promoting latency in gammaherpesvirusinfected cells, as its overexpression in epithelial and
broblast cells suppressed replication of murine herpesvirus 68 (MHV68) and blocked activation of lytic
promoters from MHV68 and Kaposis sarcoma-associated herpesvirus (KSHV) (Brown et al., 2003). In
contrast, NF-kB inhibition in KSHV-infected cells led
to lytic protein synthesis and virus reactivation.
There are a number of other examples in which
viruses utilize NF-kB to block apoptosis as a means to
enhance their replication or their pathogenicity (reviewed in Hiscott et al., 2001; Santoro et al., 2003). The
effects of HIV-encoded proteins Tat, Vpr, Nef and
envelope glycoprotein gp120 on the NF-kB pathway,
and in turn those that NF-kB exerts on HIV replication
and apoptosis are well documented and were reviewed
extensively (reviewed in Barkett and Gilmore, 1999;
Hiscott et al., 2001; Santoro et al., 2003). The herpes
simplex virus 1 envelope glycoprotein D and hepatitis C
virus core protein induce NF-kB and confer resistance
to apoptotic stimuli-like TNFa (Tai et al., 2000;
Goodkin et al., 2003; Medici et al., 2003). Encephalomyocarditis virus (EMCV) also abrogates apoptosis via
NF-kB as a means to enhance its pathogenic effects. In
fact, p50/ mice survive EMCV infections that would
otherwise kill wild-type animals (Schwarz et al., 1998).
Interestingly, African swine fever virus (ASFV) encodes
two proteins that have opposite effects on NF-kB
activation (reviewed in Gilmore et al., 2003). The
early viral protein A238L acts like a degradationresistant mutant of IkB to blunt the initial burst of
NF-kB activity that follows infection and suppress host
immune and inammatory responses. On the other
hand, the IAP-like ASFV protein A224L is expressed
later during the course of infection and activates
NF-kB via the IKK kinase complex to seemingly
suppress apoptotic caspases and lengthen the infection
(Rodriguez et al., 2002).
On the ip side, certain viruses exploit the NF-kB
cascade to induce cell death. Precedents include Dengue,
Sindbis and Reovirus that promote apoptosis in infected
cells, whereas death was inhibited by NF-kB decoys or

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in cells lacking p50 or p65 (Lin et al., 1995; Marianneau

et al., 1997; Connolly et al., 2000; Jan et al., 2000).
However, the generality of NF-kBs proapoptotic effects
in the pathogenicity of aviviruses was recently brought
into question, as contrary to Dengue, Taiwanese
Japanese Encephalitis virus could replicate and trigger
apoptosis in cells in which NF-kB activity was stably
suppressed (Liao et al., 2001).
Lastly, other viral proteins such as human adenovirus
E1A suppress NF-kB to sensitize cells to proapoptotic
stimuli (Shao et al., 1997, 1999). E1A blocks the activity
of the IKK complex, and was recently shown to
antagonize expression of the NF-kB-regulated antiapoptotic protein c-FLIP(s) that inhibits caspase-8
activation during TNFa signaling (Shao et al., 1999;
Perez and White, 2003). Overall, although distinct
viruses interface differently with the NF-kB signaling
cascade, it is clear that many of them have evolved
means to inuence this important pathway to advantage
the host or the virus during infection.
NF-kB weighs in the balance to regulate life and death
decisions in death receptor (DR) pathways: new insights
TNFa is a key cytokine that regulates immune
responses, cell differentiation and apoptosis. Activation
of TNF receptors TNFR1 or TNFR2 by TNFa
represents the quintessential pathway balancing the
induction of cell death with its inhibition through
activation of NF-kB. Although many players involved
in the TNFR signaling cascade have been identied, the

mechanism(s) that determine whether the death or
survival branch of the pathway will prevail has not
been entirely claried. A recent study by Micheau and
Tschopp (2003) sheds new light on the issue. Their study
demonstrates that two separate complexes can form
following trimerization of TNFR1 in response to TNFa
and recruitment of TRADD and RIP1 (Figure 2).
Complex I binds TRAF2, leading to NF-kB activation
and consequent transcriptional activation of caspase-8
inhibitor FLIP (CASPER). Complex II arises when
TNFR1, TRADD and RIP1 are modied, possibly via
mono- and/or diubiquitination, and contrary to expectation, the complex dissociates from TNFR1. When
released freely into the cytoplasm, complex II recruits
FADD, likely through an interaction between the
TRADD and FADD DDs. Caspase-8 and either the
proapoptotic caspase-10 (for death) or the caspase
regulator c-FLIP(L) (for survival) are then recruited in
a mutually exclusive interaction. The onset of apoptosis
depends upon how effectively complex I induces cFLIP(L) synthesis to suppress death signaling by
complex II. These new ndings imply that the deathregulating complex forms in the cytosol, consistent with
prior work that failed to demonstrate a direct physical
association of FADD and caspase-8 with TNFR1
(Harper et al., 2003). The results also agree with earlier
studies with c-FLIP (CASPER) knockout mice, whereby
elimination of FLIP highly sensitized cells to TNFa- and
FasL-induced apoptosis (Yeh et al., 2000).
Figure 2 TNF-R1 activation upon binding of cytokine TNFa leads to the formation of two sequential complexes. Complex I is
comprised of TRADD, RIP1 and TRAF2, and is responsible for activating NF-kB signaling, which upregulates antiapoptotic genes.
Following modication (possibly mono- or diubiquitination) and endocytosis, the protein complex recruits FADD, procaspase-8 and 10, producing complex II, which initiates an apoptotic signal pathway. The fate of the cell is determined by the balance between NFkB-dependent antiapoptotic genes and proapoptotic factors that act in the death cascade, through interactions that can occur at
different steps along the death pathway. Binding of FLIP competes with procaspase-10 in complex II, while the antiapoptotic Bcl-2
family members B-1/A1, Bcl-xL, NR13 and Bcl-2 block the release of cytochrome c from mitochondria. IAPs, including XIAP, cIAP1 and c-IAP2, can bind and silence effector caspases. A complete list of antiapoptotic NF-kB target genes is found in Table 1
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Other factors were found to also weigh in the balance

to favor the life- or death-promoting branches of this
pathway. These include caspase-3-mediated proteolysis
of IKKb to suppress NF-kB activation during TNFainduced apoptosis (Tang et al., 2001b). Another
mechanism by which NF-kB can protect cells against
TNFa-induced demise involves inhibition of lysosomemediated apoptosis (Liu et al., 2003). Cell treatment
with TNFa triggers the lysosomal release of cathepsin B,
shown in recent years to play an important role in
mitochondria-independent cell death via caspase-dependent and -independent pathways. The inhibitory effect
of NF-kB in this context is mediated by upregulation of
the serine protease inhibitor Spi2A, a potent inhibitor of
cathepsin B (Liu et al., 2003). NF-kB has also been
found to help scavenge oxygen radicals induced by TNFa
by upregulating new enzymes involved in ROS metabolism (G Franzoso, personal communication).
Distinct effects for distinct subunits Parenthetically, it
seems that not all NF-kB subunits have the same
capacity to suppress apoptosis induced by DRs.
Whereas RelA is required to protect cells from TNFa,
some groups reported that c-Rel is dispensable for
viability in response to TNFR- and Fas-mediated
apoptosis. Indeed, c-Rel/ broblasts are refractory to
TNF-mediated cell death, as are c-Rel/ B cells from
Fas-mediated apoptosis (Owyang et al., 2001; Chen
et al., 2003). In contrast, c-Rel is well recognized to be
necessary for protecting B cells from antigen receptormediated cell death (Wu et al., 1996b; Grumont et al.,
1998; Owyang et al., 2001). Subunit-specic regulation
was also suggested in the Apo2L/TRAIL signaling
pathway, although the protective activity of NF-kB in
this context has been the subject of controversy. One
report showed that T-cell death induced by HTLV-1
Tax is dependent on NF-kB signaling and involves
activated expression of DR ligand TRAIL (RiveraWalsh et al., 2001). In contrast, inhibition of NF-kB in
breast cancer cells induced expression of DR5 (TRAILR2) and adaptor protein TRADD, sensitizing cells to
TRAIL-induced apoptosis (Chen et al., 2003). Overexpression of RelA could protect MEFs from TRAILinduced apoptosis by inhibiting expression of caspase-8,
DR4 (TRAIL-R1) and DR5 (TRAIL-R2), and enhancing expression of inhibitors of apoptosis c-IAP1 and cIAP2 to decrease simultaneously formation of DR
complexes and inhibit active pathways. Conversely
when c-Rel was expressed under the same conditions,
DR4, DR5 and the proapoptotic Bcl-xS protein were
upregulated, concomitant with inhibition of c-IAP1, cIAP2 and survivin. However, these effects may be cell
specic as c-Rel expression in HeLa cells increased
resistance to TRAIL by upregulating the decoy receptor
protein DcR1 (Bernard et al., 2001b). In another study,
RelA-mediated induction of Bcl-xL was implicated in
suppressing TRAIL-mediated apoptosis (Ravi et al.,
2001), although others do not support an important role
for Bcl-xL in this pathway (Walczak et al., 2000). Since
many of these studies evaluated the effects of NF-kB
subunits using protein overexpression and in different
Oncogene
cell systems, future analyses looking at their activity

under more physiological conditions will certainly help
to clarify their effects.
Crosstalk between NF-kB and JNK: something to live for
In addition to turning on NF-kB signaling, TNF
induces the stress-activated Jun kinase (JNK), a member
of the MAPK family. Although JNK can cause cell
death by activating the mitochondrial apoptotic pathway, it can also promote cell survival depending on the
cell context. The existence of negative crosstalk between
the NF-kB and JNK pathways has recently come to
light and was implicated to be responsible for the
transient activation of JNK in response to TNFa (De
Smaele et al., 2001; Javelaud and Besancon, 2001; Tang
et al., 2001a; Reuther-Madrid et al., 2002; Papa et al.,
2003; reviewed in Franzoso et al., 2003). While some
reports indicate that this negative interplay is specic to
TNFa signaling and does not affect JNK activation by
IL-1 or UV rays (Tang et al., 2001a; Lin, 2003; A Lin,
personal communication), others also observed NF-kBmediated suppression of JNK activation in cells
stimulated with IL-1b (Reuther-Madrid et al., 2002).
Different NF-kB-regulated genes were proposed to be
responsible for inhibition of the JNK signaling cascade.
Tang et al. (2001a) studies with IKKb/ and RelA/
MEFs showed that NF-kB suppresses JNK activity by
upregulating expression of the caspase inhibitor Xchromosome-linked inhibitor of apoptosis (XIAP),
although others noted that the protective activity of
XIAP depends upon JNK1 activation (Sanna et al.,
2002). Other studies found that GADD45b/MyD118, an
NF-kB target gene that belongs to the GADD45 family
of factors involved in cell cycle control and DNA repair,
is involved in suppressing JNK signaling at the level of
JNKK2/MKK7 (De Smaele et al., 2001; Papa et al.,
2003). The NF-kB-regulated zinc-nger protein A20,
which antagonizes TNF induction of JNK, is another
possible contender (Lademann et al., 2001). Nevertheless, elimination of XIAP in MEFs was not sufcient
to abolish inactivation of JNK by NF-kB (A Lin,
personal communication). Similarly, Amanullah et al.
(2003) commented that mice decient for gadd45b
apparently show no defect in TNFa signaling or cell
survival. Some differences in experimental conditions
have been noted between this study and that of
De Smaele et al., but it remains to be determined
whether these might explain these discrepancies (Zazzeroni et al., 2003b). Recent work by Sakon et al. (2003)
proposed that NF-kB prevents sustained JNK activity
in TNF-treated cells by inhibiting accumulation of
reactive oxygen species. Based on these analyses, it
appears that a combination of these or other NF-kBregulated genes might be necessary to suppress JNK
activity in response to TNF. There is a consensus that
further analyses will be needed to clarify the contribution of these and other NF-kB-regulated factors to the
control of JNK signaling.
It is undisputed that suppression of NF-kB activity
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of this activation on the fate of the cell remains

somewhat controversial. Several analyses found that in
the absence of NF-kB, persistent JNK activity is
proapoptotic (De Smaele et al., 2001; Javelaud and
Besancon, 2001; Tang et al., 2001a; Lamb et al., 2003).
In contrast Reuther-Madrid et al. (2002) showed that
persistent activation of JNK is antiapoptotic in TNFatreated NF-kB-null cells, and that inhibitors of JNK
enhanced TNF-induced killing in this context. Thus,
opposite results were obtained in studies that both used
the same RelA/ MEFs activated by TNF and treated
with JNK inhibitor SP600125, although there were some
differences in the dose and duration of the TNFa
treatment (Tang et al., 2001a; Reuther-Madrid et al.,
2002). It should perhaps be noted that not 100% of the
cells died upon suppression of persistently activated
JNK in TNF-treated RelA/ MEFs in the former study,
and that cell death protection was not 100% effective
following JNK inhibition in the latter.
Recent work in JNK/ broblasts indicates that JNK
induces expression of transcription factor JunD and that
NF-kB collaborates with this JNK/JunD pathway in
wild-type cells to enhance expression of c-IAP2, a
caspase inhibitor that also interacts with TRAF2 and
inhibits TNF-induced apoptosis (Lamb et al., 2003).
These ndings imply that NF-kB-mediated cell survival
in cells treated with TNF requires the transient
activation of JNK, and that when NF-kB is absent
JNK activation is persistent and apoptosis ensues
(Lamb et al., 2003). Clearly, the interplay between the
JNK and NF-kB signaling pathways is important but
nonetheless complex. It is a topic of intense investigation
that will undoubtedly continue to shed new light on the
regulation of cell fate.
Answering the suicide hotline: how NF-kB regulates
programmed cell death
As illustrated above, the relationship between NF-kB
and apoptosis is intricate. To complicate things further,
while NF-kB generally exploits its transcriptional
activity to regulate the expression of genes that function
in death signaling, there are an increasing number of
reports that indicate other modes of action. This section
reviews recent developments in this arena.
Mechanisms for NF-kB-mediated protection from
apoptosis
Transcriptional activation of antiapoptotic genes As
summarized in Table 1, NF-kB activates the transcription of many genes capable of suppressing cell death
(reviewed in Barkett and Gilmore, 1999; Karin and Lin,
2002; Burstein and Duckett, 2003). By and large, this is
the most common way for NF-kB to antagonize
apoptosis. Genes in this category contain functional
NF-kB-binding sites in their regulatory region, undergo
NF-kB-mediated activation in response to death-inducing stimuli, and can suppress apoptosis under conditions where NF-kB is inactivated, although several show
partial activity in this context. This most likely reects
the need for cooperative action to antagonize different

apoptotic challenges in different cells efciently. Among
them are prosurvival members of the mammalian Bcl-2
gene family Bcl-xL, NR13 and B-1/A1 (Grumont et al.,
1999; Lee et al., 1999a, b; Wang et al., 1999b; Zong et al.,
1999; Chen et al., 2000). Bcl-2 itself recently joined this
group, owing to its NF-kB-dependent induction that
conferred protection against hypoxia- and nitric oxideinduced injury in primary hippocampal neurons and its
ability to promote the survival of peripheral B cells in
response to c-Rel and RelA (Tamatani et al., 1999;
Grossmann et al., 2000). Factors in this group suppress
the release of proapoptotic cytochrome c and Smac/
Diablo from mitochondria and can block programmed
cell death in response to varied stimuli including TNFa,
antigen receptor ligation and chemotherapeutic agents
like etoposide (Grumont et al., 1999; Lee et al., 1999a;
Wang et al., 1999b; Zong et al., 1999; Reed and Green,
2002; Sun et al., 2002).
Other antiapoptotic NF-kB target genes include
XIAP that inhibits the processing of procaspase-9 and
the activities of caspase-7 and -3, and was implicated in
NF-kB-mediated suppression of JNK signaling (Stehlik
et al., 1998; Tang et al., 2001a). The cellular inhibitors of
apoptosis c-IAP1, c-IAP2 and the TNF receptorassociated factors TRAF1 and TRAF2, are also
activated in response to NF-kB and were implicated to
act jointly with one another to suppress TNF-induced
cell demise in RelA/ MEFs, although coexpression of
c-IAP1 and c-IAP2 alone was adequate to confer
resistance to etoposide-induced death (Chu et al.,
1997; You et al., 1997; Deveraux et al., 1998; Stehlik
et al., 1998; Wang et al., 1998; Schwenzer et al., 1999;
Chen et al., 2003). The zinc-nger protein A20 was
described several years ago as a dual inhibitor of NF-kB
activation and TNF-provoked death (reviewed in
Beyaert et al., 2000). Recent work uncovered a role for
A20 in controlling the balance between the Fas and
TNF death pathways during AICD in T cells (Malewicz
et al., 2003). c-FLIP is a potent negative regulator of
DR-induced apoptosis (Kreuz et al., 2001; Micheau
et al., 2001). Gadd45b is a new recruit to the
antiapoptotic NF-kB-regulated targets. It was implicated in NF-kB-mediated suppression of JNK in
response to TNF, and in mediating the cytoprotective
activity of CD40 against Fas-induced death in B cells
(De Smaele et al., 2001; Zazzeroni et al., 2003a).
MnSOD also belongs to this category, as an NF-kBinduced enzyme that scavenges cytotoxic ROS generated
by various apoptotic pathways (Bernard et al., 2001a,
2002; Delhalle et al., 2002; Tanaka et al., 2002). Lastly,
there have been new developments regarding the
controversial role of the immediate-early response gene
iex-1 in NF-kB-mediated survival. A variant of IEX-1
(IEX-1L) was previously reported to mediate cytoprotection by NF-kB (Wu et al., 1998), but its role in
suppressing apoptosis has been the subject of controversy (Schafer et al., 1999; Arlt et al., 2001; Schilling
et al., 2001; B Rayet and C Gelinas, unpublished data).
Of late, Wu (2003) published that whereas IEX-1
sensitizes some cells to apoptosis when overexpressed
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J Kucharczak et al
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in vitro, its constitutive expression in the lymphocytes of

IEX-1 transgenic mice prevents activated T cells from
undergoing stimuli-induced apoptosis. In this in vivo
context, IEX-1 gave rise to a lupus-like condition and
the mice developed T-cell lymphomas. These provocative new ndings deserve further investigation.
Alternative means to enhance cell survival A few reports
have suggested alternative means for NF-kB to enhance
cell viability. Three recent examples come to mind. The
rst comes from studies of p53-mediated cell death in
IKKa/IKKb/ double knockout MEFs, in which
IKKb-mediated activation of NF-kB led to increased
levels of Mdm2, destabilization of p53 and resistance to
doxorubicin-induced apoptosis (Tergaonkar et al.,
2002). The second is the suppression of caspase-8,
DR4 (TRAIL-R1) and DR5 (TRAIL-R2) gene expression by RelA in cells stimulated with the death-inducing
ligand TRAIL (Chen et al., 2003). This came along with
enhanced expression of c-IAP1 and c-IAP2. The third
example is one in which expression of the proapoptotic
Bcl-2 family member Bax was increased following
expression of a dominant inhibitor of NF-kB in cancer
cell lines (Bentires-Alj et al., 2001). Although a
functional NF-kB-binding site was identied in the
Bax promoter region, this site was dispensable for NFkB-mediated suppression of Bax promoter activation by
p53. Nevertheless, it is conceivable that suppression of
Bax activation by NF-kB might contribute to the
survival of some tumor cells, although the mechanism
for this repression needs to be claried. Finally, NF-kB
and IkB subunits have been observed to localize to
mitochondria, and to suppress mitochondrial gene
expression (Bottero et al., 2001; Cogswell et al., 2003).
Bottero et al. (2001) showed an interaction between
mitochondrial IkB and the ANT adenine nucleotide
transporter, which regulates the mitochondrial permeability transition. In light of the critical role of this
organelle in the execution and amplication of many
apoptotic programs, these intriguing new ndings give
rise to speculation that NF-kB-dependent mechanisms
operating at the level of mitochondria may perhaps
contribute to its protective activity. However, further
investigation is needed to ascertain this.
Mechanisms through which NF-kB promotes cell death
Despite a large body of evidence supporting the
antiapoptotic role of NF-kB, there are a growing
number of scenarios in which NF-kB behaved in a
proapoptotic fashion. One such study published a few
years ago concluded that tumor suppressor p53 activates
NF-kB via MEK1 and pp90rsk, and that NF-kB plays a
vital role in p53-mediated apoptosis (Ryan et al., 2000).
Inhibition of MEK1 or absence of RelA abrogated p53induced cell death. However, overexpression of RelA in
a p53-decient background failed to induce apoptosis,
suggesting that RelA might be necessary but not
sufcient for the proapoptotic phenotype of p53.
A recently published pair of papers from the group of
N Perkins offers an interesting counterpoint to this
Oncogene
theory. In the rst, Rocha et al. (2003a) demonstrate

that the tumor suppressor ARF, which normally
activates p53 by inhibiting Mdm2, can also inhibit the
transcriptional activity of NF-kB in cells stimulated with
TNFa or the chemotherapeutic agent etoposide (N
Perkins, personal communication). This inhibitory effect
is independent of p53 and Mdm2, and serves to
downregulate expression of antiapoptotic proteins controlled by NF-kB, such as Bcl-xL. The study shows that
ARF induces association of the RelA transactivation
domain with histone deacetylase 1 (HDAC1) to repress
NF-kBs transcriptional activity in a promoter-specic
manner. The second paper addresses the effect of p53 on
NF-kB-mediated transcription and cell cycle regulation
(Rocha et al., 2003b). Cyclin D1, involved in the G1
S phase transition, is transcriptionally regulated by NFkB primarily through a Bcl-3/p52 complex (Westerheide
et al., 2001). Rocha et al. (2003b) show that p53
suppresses expression of Bcl-3, an IkB-related protein
that acts as a transcriptional coactivator with p52. At
the same time, p53 promotes association of p52 with
HDAC1 to repress cyclin D1 transcription. Since ARF
is able to regulate p53, these ndings create a scenario in
which ARF negatively regulates the antiapoptotic and
proproliferative activities of NF-kB, thereby creating a
situation where NF-kB is no longer able to inhibit cell
death without necessarily promoting it either. When
extrapolated to the ndings of Ryan et al., these exciting
new results lead one to speculate that perhaps p53 does
not activate a proapoptotic activity of NF-kB, but
rather neutralizes its capacity to stimulate expression of
antiapoptotic genes that would otherwise counteract
p53-dependent apoptosis. In this scenario, ARF and p53
might be thought of as guardians of the antiapoptotic
and proproliferative activities of NF-kB. It will be
intriguing to see if future experiments conrm these
predictions.
There exist several other studies in which NF-kB
sensitized cells to death-inducing signals (for example,
Jung et al., 1995; Grimm et al., 1996; Lin et al., 1998;
Hettmann et al., 1999). In some of these cases, NF-kB
induced expression of death-promoting genes (Table 1).
These include tumor suppressor p53, the DR Fas and its
ligand FasL and TNFa (Collart et al., 1990; Shakhov
et al., 1990; Wu and Lozano, 1994; Kasibhatla et al.,
1998, 1999; Matsui et al., 1998; Chan et al., 1999; Zheng
et al., 2001). For instance, NF-kB induces FasL
expression in T cells in response to AICD (Kasibhatla
et al., 1999). Recently, nitric oxide-induced activation of
p38 was implicated in triggering NF-kB-mediated
expression of p53, leading to upregulation of the
proapoptotic Bcl-2 family member Bax, just as cyanide-induced activation of NF-kB resulted in activation
of the proapoptotic Bcl-xS and Bax proteins (Kim et al.,
2002b; Shou et al., 2002). Other examples include NFkB-dependent activation of DR ligand TRAIL and
TNF receptor family member DR6 (Baetu et al., 2001;
Kasof et al., 2001; Rivera-Walsh et al., 2001; Siegmund
et al., 2001). In one study, c-Rel induced expression of
TRAIL receptors DR4 (TRAIL-R1), DR5 (TRAIL-R2)
and the proapoptotic Bcl-2 family member Bcl-xS to

J Kucharczak et al
8973
sensitize cells to TRAIL-induced apoptosis (Chen et al.,

2003). Although the antiapoptotic bcl-xl transcript was
previously shown to be transcriptionally regulated by
NF-kB, this the rst report of the proapoptotic product
Bcl-xS being induced by NF-kB. Since Bcl-xL and BclxS are derived by alternative splicing, this raises the
possibility that in some instances c-Rel is perhaps
capable of inuencing the splicing reaction to benet
production of one form over the other.
Activation of death-causing genes is not the only way
in which NF-kB is involved in promoting apoptosis.
While c-Rel upregulates expression of MnSOD to
suppress cell death by converting toxic O
2 to H2O2,
over time the buildup of hydrogen peroxide itself
triggers apoptosis (Bernard et al., 2002). This underscores the idea that timing and environment can convert
an antiapoptotic signal into a death signal. NF-kB can
also work indirectly to upregulate the expression of
other transcription factors that in turn activate genes
that regulate cell death and/or proliferation. Examples
include p53, IRF-1 that works along with NF-kB to
stimulate production of the death-promoting inducible
nitric oxide synthase after ischemic injury, and E2F3a
that induces expression of cyclin E to promote cell cycle
progression (Wu and Lozano, 1994; Cheng et al., 2003;
reviewed in Denk et al., 2000). Finally, one study last
year claimed that the presence of a DD in p100/NF-kB2
allows it to promote apoptosis via recruitment to DRs
and activation of apical caspase-8 (Wang et al., 2002b).
It was suggested that the loss of this proapoptotic effect
might be necessary for the oncogenic activity of
rearranged nf-kB2 genes observed in human lymphomas. However, others have expressed concerns regarding the physiological relevance of these ndings in light
of experimental conditions and of the phenotype of mice
in which expression p100/NF-kB2 was inactivated
(Hacker and Karin, 2002). The involvement of p100/
NF-kB2 as an activator of cell death therefore remains
contentious.
Factors that influence NF-kBs decision between life and
death
There are several factors that inuence the transcriptional activity and biological function of NF-kB and this
in turn might affect its capacity to weigh in the balance
between life and death. This section highlights those that
were recently implicated in modulating its transcriptional activity, its relationship with factors that regulate
death signaling, and its effect on cell cycle control.
Modulation of NF-kBs transcriptional activity
Post-translational modication has surfaced as an
important means to modulate NF-kBs transcriptional
activity. The IKK complex, casein kinase II and AKT
are among the kinases that can phosphorylate the
transactivation domains of RelA or c-Rel in response to
NF-kB-inducing stimuli (Wang and Baldwin, 1998;
Sakurai et al., 1999; Martin and Fresno, 2000; Wang
et al., 2000; Mayo et al., 2002; Sizemore et al., 2002;
Yang et al., 2003). On the other hand, the catalytic

subunit of protein kinase A (PKAc), MSK1 and PKCz
phosphorylate the RHD of RelA (Zhong et al., 1997;
Duran et al., 2003; Vermeulen et al., 2003). In the case of
PKAc, this modication is necessary for RelA interaction with transcriptional coactivator p300 (Zhong et al.,
1998, 2002). Another RelA-interacting factor, protein
phosphatase 2A, was implicated in its dephosphorylation (Yang et al., 2001). Acetylation of NF-kB subunits
adds another level of regulation, as acetylation of RelA
prevented its association with newly synthesized IkBa
and interaction with corepressor HDACs (Ashburner
et al., 2001; Chen et al., 2001). The effects of these
different modications on the pro- and antiapoptotic
activities of NF-kB remain to be explored. However, a
RelA mutant that could no longer be phosphorylated by
PKAc (S276A) failed to rescue TNF-induced apoptosis
of RelA/ MEFs, and a knockin of this mutation is
lethal in mice (Okazaki et al., 2003; S Ghosh, personal
communication). Moreover, Akt was shown to suppress
cell death by stimulating the transactivation potential of
RelA (Madrid et al., 2000).
c-Rel and RelA functionally interact with diverse
transcriptional coactivators. The TAFII105 component
of TFIID was shown to mediate NF-kB-dependent
transactivation of antiapoptotic genes like A20, whereas
a dominant-negative TAFII105 mutant sensitized cells
to TNF-induced killing (Yamit-Hezi and Dikstein, 1998;
Yamit-Hezi et al., 2000). Novel interactions between
NF-kB and tumor suppressors ARF and BRCA1 have
recently surfaced. ARF inhibited NF-kB-mediated
transcription in a promoter-specic manner and downregulated expression of the antiapoptotic Bcl-xL protein
(Rocha et al., 2003a). Conversely, interaction of the
RHD of RelA with BRCA1 enhanced NF-kB-mediated
transcription of the proapoptotic gene Fas (Benezra
et al., 2003). Lastly, c-Rel was recently shown to act in
concert with AP-1 and C/EBPb to recruit coactivators
TAFII250 and p300 and upregulate B-1 gene expression in activated T cells via an enhanceosome-like
complex (Edelstein et al., 2003). In studies with null
broblasts, c-Myc was revealed to sensitize cells to
TNF-induced death by inhibiting p65-mediated transactivation of B-1/A1 (You et al., 2002).
Interplay between NF-kB and factors that regulate death
signaling
NF-kB participates in a number of other interactions
with proteins involved in the apoptotic cascade, which
affect its protective activity to either break or amplify
the survival response.
Caspase-mediated cleavage of NF-kB and IkB: alternative means to promote cell death Cysteine proteases
known as caspases are major effectors of apoptosis that
are activated upstream or downstream of mitochondria
and cleave substrates in a sequence-specic manner.
Among their targets are structural proteins, nuclear
lamins and a number of apoptosis regulators, such as
Bcl-2 (Johnson and Boise, 1999). It is perhaps not
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J Kucharczak et al
8974
surprising that in order to blunt the cells survival

response, NF-kB is a substrate for caspase cleavage.
Caspase-3-mediated cleavage of RelA, p50 and c-Rel
upon treatment with death-inducing ligands FasL or
TNFa has come to light (Ravi et al., 1998; Barkett et al.,
2001). Caspase-mediated processing of IkB was portrayed as another means to suppress the protective
activity of NF-kB and promote an apoptotic response.
Independent studies showed that the N-terminus of IkBa
undergoes caspase-3-mediated cleavage, coincident with
apoptosis (White et al., 1995; White and Gilmore, 1996;
Barkett et al., 1997; Jung et al., 1998; Reuther and
Baldwin, 1999). The product of this cleavage is an IkBa
molecule that is resistant to signal-induced degradation
by the proteasome, and that acts as a constitutive
inhibitor of NF-kB to promote cell death (Reuther and
Baldwin, 1999). Lastly, the Drosophila caspase homologue Dredd interacts with the Drosophila NF-kB factor
Relish to promote its endoproteolytic cleavage (Stoven
et al., 2003). This processing of Relish generates a RHD
fragment capable of DNA binding and a stable
fragment resembling IkB. In this particular case, this
caspase action contributes a gain-of-function toward
Relish and is independent of apoptosis.
A new role for FADD as a regulator of NF-kB
signaling FADD is best known for its role as an
adaptor that recruits caspase-8 to activated Fas receptors to signal downstream activation of cell death.
However, there have been reports of late implicating
FADD in the regulation of NF-kB signaling, although
the outcome of this regulation is contentious. Initial
reports showed that FADD and caspase-8 activate NFkB via IKK, independent of the proteolytic activity of
caspase-8 but dependent on its death effector domaincontaining prodomain (Chaudhary et al., 2000; Hu et al.,
2000; Schaub et al., 2000). Contrary to this claim, recent
work showed that FADD activates caspase-8 in
response to TNF or TLR-4 signaling, but that it
simultaneously suppresses NF-kB activation from
TLR-4 possibly via interaction with adaptor protein
MyD88 (Bannerman et al., 2002). Consistent with this
model, FADD/ MEFs showed enhanced activation of
NF-kB upon lipopolysaccharide (LPS) treatment. The
discrepancies between these studies might be explained
by differences in experimental conditions (transient vs
stable expression), in cell type and/or stimulation
(reviewed in Duckett, 2002). Undoubtedly, further
studies into this novel function of FADD will help to
understand its effects on NF-kB and its implication in
the control of the cell death response.
Bcl-2 feedsback to downregulate NF-kB activity Whereas NF-kB transactivates prosurvival members of the
Bcl-2 family (Table 1), there have been some reports in
which Bcl-2 suppressed NF-kB activity by stabilizing
IkBa, by blunting the transactivation potential of RelA
or by inuencing the nuclear accumulation of NF-kB
subunits (Ivanov et al., 1995; Lin et al., 1995; Grimm
et al., 1996; de Moissac et al., 1998; Badrichani et al.,
1999).
Oncogene
Positive feedback of IAPs to amplify NF-kBs protective

activity IAPs were reported to increase NF-kB activity, and by the same token, enhance its antiapoptotic
function. H-IAP1, a member of the IAP family, could
promote IkBa degradation, thereby potentiating the
ability of NF-kB to suppress TNFa-induced apoptosis
(Chu et al., 1997). These results imply that the IAPs,
which are transcriptionally activated by NF-kB, may
provide positive feedback to amplify its cytoprotective
activity.
Effects of NF-kB on cell cycle control
Since aberrant proliferation signals are often conducive
to cell suicide, it is relevant to review recent ndings that
pertain to the effects that NF-kB exerts on cell cycle
control. Consistent with the implication of NF-kB in
promoting cell proliferation, NF-kB was shown to
regulate the expression of cyclins D1, D2, D3 and more
recently cyclin E (Guttridge et al., 1999; Hinz et al.,
1999, 2001; Hsia et al., 2002). For example, B cells from
c-rel/ or NF-kB1/c-rel/ double-knockout mice
show defective proliferative response to mitogenic
stimulation that results in G1 phase arrest (Kontgen
et al., 1995; Hsia et al., 2002; Pohl et al., 2002). Hsia et al.
(2002) linked the proliferative defect of c-rel/ B cells to
a failure to express cyclins D3 and E. Recently, the same
group reported that c-Rel activates expression of
transcription factor E2F3a that, in turn, is likely to
transactivate cyclin E (Cheng et al., 2003). Others
showed that NF-kB-mediated transactivation of cyclin
D1 is essential for the transforming activity of the
oncoprotein v-Abl, and is increased in mammary
carcinomas arising in MMTV-c-Rel transgenic mice
(Nakamura et al., 2002; Romieu-Mourez et al., 2003). In
agreement with these ndings tumor suppressor p53,
which plays a central role in cell cycle control, was
revealed to inhibit cyclin D1 expression by favoring
formation of nonfunctional p52/HDAC1 complexes
over transcriptionally active p52/Bcl-3 complexes (Rocha et al., 2003b). Furthermore, RelA participates in
proteinprotein interactions with the cell cycle regulatory complex cyclin E-Cdk2 via its association with
CBP/p300, and with the p16Ink4 cyclin-dependent
kinase inhibitor (Perkins et al., 1997; Wolff and
Naumann, 1999). An additional interplay between NFkB and the Cdk/E2F pathway is highlighted by the
direct interaction of E2F1 with RelA that antagonized
the antiapoptotic activity of NF-kB, by preventing
activation of MnSOD (Tanaka et al., 2002).
While NF-kB is often associated with increased cell
proliferation, it can suppress cell proliferation in certain
cell types (Abbadie et al., 1993; Seitz et al., 1998; Sheehy
and Schlissel, 1999; van Hogerlinden et al., 1999;
Bernard et al., 2001c). For example, the epidermis of
mice expressing p50/p65 is hypoplastic, contrary to that
of mice expressing a super-repressor IkB in the skin that
is hyperplastic (Seitz et al., 1998). NF-kB appears to
inhibit the proliferation of keratinocytes by inducing the
cyclin-dependent kinase inhibitor p21/Waf1 (van Hogerlinden et al., 1999; Seitz et al., 2000; Hinata et al.,

J Kucharczak et al
8975
2003). This agrees with earlier studies showing that

overexpression of c-Rel in the human epithelial cell line
HeLa arrested proliferation, coincident with stabilization of p53 and induction of p21/WAF1 (Bash et al.,
1997). In light of these ndings, it will be interesting to
unravel the molecular mechanisms that govern the proand antiproliferative actions of NF-kB in different cell
types.
Antiapoptotic activity of NF-kB: its implication in cancer
and therapy
A link between aberrant NF-kB activity and cancer was
initially suggested by the acute oncogenicity of its viral
oncoprotein v-Rel that causes aggressive lymphomas in
animal models (reviewed in Gilmore, 1999). Since then,
constitutive nuclear NF-kB activity has emerged as a
hallmark for many human leukemias, lymphomas and
solid tumors, most commonly due to persistent activation of the IKK complex (reviewed in Rayet and
Gelinas, 1999; Karin et al., 2002). These include
Hodgkins lymphoma, diffuse large B-cell lymphoma
(DLBCL), acute lymphoblastic leukemia, chronic myelogenous leukemia, ATL and breast cancer among many
others (Bargou et al., 1997; Nakshatri et al., 1997; Sovak
et al., 1997; Cogswell et al., 2000; Kordes et al., 2000;
Davis et al., 2001; Hinz et al., 2001; Kalaitzidis et al.,
2002). Amplication and overexpression of rel/nf-kB
genes is another means by which NF-kB is deregulated
in cancer (reviewed in Rayet and Gelinas, 1999).
Moreover, several oncoproteins including Ha-Ras and
Bcr-Abl rely on NF-kB to mediate their transforming
activity, although recent work showed that NF-kB
activation by Ras and Bcr-Abl does not involve IKK
(Finco et al., 1997; Mayo et al., 1997; Reuther et al.,
1998; Arsura et al., 2000; Hanson et al., 2003). Since
human tumors frequently contain mutations in ras
genes, and Bcr-Abl is involved in acute lymphoblastic
leukemia and chronic myelogenous leukemia, it is
reasonable to expect that activation of these oncogenes
in human tumors may be yet another way to activate
NF-kB in cancer constitutively.
Lately, studies in primary cell cultures and animal
models provided evidence that mammalian NF-kB
proteins can have a proactive role in carcinogenesis.
MMTV-driven expression of the mouse c-rel gene gave
rise to late-onset mammary carcinomas in transgenic
mice, whereas retroviral-mediated overexpression of the
human or mouse c-rel genes malignantly transformed
primary chicken spleen cells that could induce tumors in
vivo (Gilmore et al., 2001; Fan et al., 2003; RomieuMourez et al., 2003). Although the exact role of NF-kB
in the pathogenesis of human tumors remains to be
determined, it is clear that in many instances suppression of apoptosis is an important part of its contribution. Indeed, inhibition of NF-kB sensitizes many tumor
cells to death-inducing stimuli, including chemotherapeutic agents (reviewed in Baldwin, 2001; Lin and
Karin, 2003). For example, delivery of a recombinant
super-repressor IkB to chemoresistant tumors in mouse
xenograft models provoked tumor regression by sensi-
tizing them to chemotherapeutic treatment with the

topoisomerase I inhibitor CPT-11 (Wang et al., 1999a;
Cusack et al., 2000). Consistent with this work, NF-kB
inhibition in many human tumor-derived cell lines,
including malignant ReedSternberg (H-RS) cells of
Hodgkins disease and DLBCLs, induces spontaneous
apoptosis or/and sensitizes them to killing by TNFa or
anticancer drugs (Table 2; for example, Bargou et al.,
1997; Davis et al., 2001). These results agree with the
elevated levels of NF-kB-dependent antiapoptotic proteins observed in many human tumors, including B-1/
A1, c-IAP2, Bcl-xL and Bcl-2. These ndings suggest
that suppression of NF-kB might enhance the efcacy of
anticancer treatments. In this regard, it is tempting to
speculate that part of the therapeutic effects of anti-Her2/neu monoclonal antibodies (Herceptin) used in conjunction with chemotherapy to treat Her-2/neu-positive
breast cancers might perhaps derive from suppression of
NF-kBs anti-apoptotic effects, as decreased NF-kBbinding activity was observed following treatment of a
breast cancer cell line with anti-neu antibodies (Pianetti
et al., 2001). However, the exact role of NF-kB in BcrAbl-induced leukemias remains to be claried, since its
antiapoptotic activity is not necessary for Bcr-Ablmediated cell survival (Reuther et al., 1998).
Since many chemotherapeutic agents trigger NF-kB
activation, hence decreasing their effectiveness, many
investigators have sought to characterize the mechanisms involved and to identify compounds that could
circumvent this problem (reviewed in Baldwin, 2001;
Garg and Aggarwal, 2002). A study by Panta et al.
(2003) identied that anthracyclines induce a novel
pathway of ATM and DNA-PK signaling, which leads
to NF-kB activation and chemoresistance via a MEK/
ERK/p90rsk cascade. Recently, the same group developed a new class of cytoplasmic-targeted anthracyclines
that can provoke apoptosis with improved cytotoxicity
and are unaffected by NF-kB-induced antiapoptotic
genes (Bilyeu et al., 2003). The discovery that IKKmediated NF-kB activation decreases p53 stability
brings up another way for NF-kB to counter the
efciency of chemotherapeutic treatment with agents
like doxorubicin (Tergaonkar et al., 2002). Since IkB
undergoes ubiquitin-mediated degradation via the proteasome, proteasome inhibitors have been used as an
alternative approach to suppress NF-kB in tumor cells.
Among them, bortezomib (PS-341; Velcade) is a potent
and selective proteasome inhibitor that was shown to
sensitize tumor cells to chemotherapy and radiation in
preclinical models, for example, in human colorectal
cancer cells in a xenograft model (Cusack et al., 2001;
reviewed in Lenz, 2003). PS-341 has since been approved
for treatment of multiple myeloma and has shown
promising results in early phase clinical trials for
lymphoma, prostate cancer and lung cancer (reviewed
in Lenz, 2003; Richardson, 2003). However, since the
proteasome is involved in the degradation of many other
cellular factors, including cyclins, cyclin-dependent
kinase inhibitors p21Waf1 and p27Kip1 and tumor
suppressor p53, there is a great deal of interest in the
quest for more specic NF-kB inhibitors.
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J Kucharczak et al
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Table 2 A sample of human tumor cell lines that respond to suppression of NF-kB
Tumor cell lines
Hematopoietic tumors
EBV-transformed lymphoblastoid cells (IB4)
DLBCL (activated B-cell type)
Multiple myeloma (U266)
Hodgkins disease (H-RS cells L428)
Acute T-cell leukemia (Jurkat)
Hodgkins disease (H-RS) (L428, L540, HD-MyZ)
Solid tumors
Pancreatic ductal adenocarcinoma (MiaPaCa2, Panc1)
Fibrosarcoma (HT1080)
Colorectal cancer (LOVO, SW1463, SW837,
SW620, SW480, KM12-L4, KM12-SM, HT-29,
WiDR, CL188, CCD841, NCI H508)
Hepatocellular carcinoma
Lung adenocarcinoma (A549)
Prostate carcinoma (PC-3 and LNCaP)
Ewing sarcoma (EW7)
Pancreatic insulinoma (MIN6N8)
Epidermoid carcinoma (A431)
Response to super-repressor IkBa
References
Spontaneous apoptosis
Sensitized to TNFa-induced apoptosis
Sensitized to CD30-induced apoptosis
Sensitized to death by growth factor withdrawal
Cahir-McFarland et al. (2000)

Davis et al. (2001)
Ni et al. (2001)
Hinz et al. (2001)
Van Antwerp (1996)
Mir et al. (2000)
Bargou et al. (1997)
Sensitized to TNFa-induced apoptosis
Sensitized to CPT-11-induced apoptosis
Sensitized to CPT-11-induced apoptosis
Liptay et al. (2003),

Fujioka et al. (2003)
Wang et al. (1996)
Wang et al. (1999a)
Cusack et al. (2000)
Sensitized
Sensitized
Sensitized
Sensitized
Sensitized
Sensitized
Tietze et al. (2000)

Cheng et al. (2000)
Muenchen et al. (2000)
Javelaud et al. (2002)
Chang et al. (2003)
Anto et al. (2003)
It should be noted that while NF-kB contributes to

oncogenesis in a majority of cell types, its IkBamediated suppression in keratinocytes was recently
demonstrated to be necessary for Ras-mediated induction of invasive epidermal tumors resembling squamous
cell carcinoma (Dajee et al., 2003). Since NF-kB
mediates Ras-induced growth arrest in keratinocytes,
antagonizing NF-kB in these cells is required to
bypass this roadblock to malignant transformation. It
therefore appears that depending on the cell type, NFkB can be viewed as a positive or negative factor for
oncogenesis.
Conclusions
It is now clear that in addition to its widely recognized
role as a key regulator of immune and inammatory
responses, NF-kB has emerged as a decisive factor in the
cells response to apoptotic challenge. Indeed, over 1800
papers addressing the role of NF-kB in apoptosis were
published since the end of 1999 when this topic was last
reviewed in Oncogene. As illustrated in this review, the
effects of NF-kB on apoptosis has far-reaching consequences for normal development and/or homeostasis
in many cells and tissues, including the immune system,
hair follicles and epidermal appendages, the liver and
the nervous system. NF-kBs implication in apoptosis is
also vital to the outcome of viral infections, the onset
and progression of many cancers and their response to
radiation and chemotherapy. While NF-kB is most
commonly found to be cytoprotective, there are a
number of instances where it is proapoptotic depending
on the inducing stimulus and the cell context. A lot of
progress has been made in understanding its mode of
Oncogene
to
to
to
to
to
to
TNFa-induced apoptosis
EGF-induced apoptosis
action and its interplay with other key factors, including

JNK, Arf, p53, p73 and FADD to name a few. These
studies identied many anti- and proapoptotic NF-kBregulated genes that mediate its activity, uncovered
alternative means by which it functions and unveiled
specic protein interactions and pathways that modulate
its activity. These important new insights fuel hope that
novel approaches will be developed to control the effects
of NF-kB on apoptosis. Since deregulated NF-kB
activity is a hallmark of many different cancers, efforts
to better understand the mechanisms that drive constitutive NF-kB signaling will undoubtedly help the
development of new strategies to restrict tumor cell
growth and suppress both intrinsic and therapy-induced
chemoresistance. These might also be applicable to
other disease conditions in which NF-kB is implicated,
although serious consideration should be given to
circumstances where NF-kB is proapoptotic. The
coming years promise to bring signicant advances in
this quest. In light of its pivotal role in apoptosis, it is
clear that for many cells encountering death-inducing
stimuli, the answer to the question: To be, or not to be
truly is NF-kB.
Acknowledgements
We are very grateful to M Arsura, PG Ashton-Rickardt,
AS Baldwin Jr, D Baltimore, C Duckett, G Franzoso,
S Ghosh, T Gilmore, M Karin, A Lin, HC Liou, N Perkins,
GE Sonenshein and D Walls for communicating results
and sharing manuscripts before publication. We apologize to
many investigators whose work could not be cited due to
space limitations. We thank J Dutta, N Gupta and L
Lagos for critical comments on the review. Research
performed in this laboratory on the roles of Rel/NF-kB in
apoptosis and oncogenesis and on its antiapoptotic target
B-1/A1 is supported by grants from the National Institutes of

J Kucharczak et al
8977
Health National Cancer Institute CA54999 and CA83937 to
CG. JK is recipient of a postdoctoral fellowship from the New
Jersey Commission on Cancer Research and is partially
supported by the Foundation of the UMDNJ. MS was

partially supported by an NIH predoctoral training grant in
Biochemistry and Molecular Biology (GM08360).
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To Be, or Not To Be: NF-JB Is The Answer - Role of Rel/NF-jB in The Regulation of Apoptosis

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Oncogene (2003) 22, 89618982

To be, or not to be: NF-jB is the answer role of Rel/NF-jB in the

During their lifetime, cells encounter many life or death

implicated in diseases arising from too much or too

Rel/NF-jB and apoptosis

activation process. Phosphorylate IkBa to promote its

role for NF-kB in this process, as suppression of

Rel/NF-jB and apoptosis

Anti- and proapoptotic roles for NF-kB in T cells The

In the absence of CD28-derived costimulatory signals,

Rel/NF-jB and apoptosis

Inhibits caspase-3 and -7, prevents activation of

You et al. (1997), Deveraux et al. (1998), Wang et al.

Antagonizes proapoptotic Bcl-2 family members

Antagonizes proapoptotic Bcl-2 family members

Antagonizes proapoptotic Bcl-2 family members

Tamatani et al. (1999), Grossmann et al. (2000), Catz

Adaptor molecule, augments NF-kB activation

Wang et al. (1998), Schwenzer et al. (1999)

Blocks the TNFa death pathway

Interferes with activation of procaspase-8 and -10

Krikos et al. (1992), Malewicz et al. (2003)

DcR1 (decoy receptor 1)

Bernard et al. (2001)

Matsui et al. (1998), Kasibhatla et al. 1999

Chan et al. (1999), Kasibhatla et al. 1998

Tumor suppressor; transcription factor

Wu and Lozano (1994)

Antagonizes prosurvival Bcl-2 family members

Chen et al. (2003)

and the Cdk-Rb-E2F pathway to control the outcome

Rel/NF-jB and apoptosis

et al., 1999; Lin et al., 1999; Zheng et al., 2001). The

Rel/NF-jB and apoptosis

not sensitized to TNFa nor is NF-kB DNA-binding

skin of IKKb-decient embryos (Pasparakis et al.,

Rel/NF-jB and apoptosis

1999). Incidentally, despite the fact that homozygous

Contrary to the work described above, other reports

Rel/NF-jB and apoptosis

conferred protection against apoptosis induced by

Rel/NF-jB and apoptosis

in cells lacking p50 or p65 (Lin et al., 1995; Marianneau

in the TNFR signaling cascade have been identied, the

Rel/NF-jB and apoptosis

Other factors were found to also weigh in the balance

cell systems, future analyses looking at their activity

Rel/NF-jB and apoptosis

of this activation on the fate of the cell remains

the need for cooperative action to antagonize different

Rel/NF-jB and apoptosis

in vitro, its constitutive expression in the lymphocytes of

theory. In the rst, Rocha et al. (2003a) demonstrate

Rel/NF-jB and apoptosis

sensitize cells to TRAIL-induced apoptosis (Chen et al.,

Yang et al., 2003). On the other hand, the catalytic

Rel/NF-jB and apoptosis

surprising that in order to blunt the cells survival

Positive feedback of IAPs to amplify NF-kBs protective

Rel/NF-jB and apoptosis

2003). This agrees with earlier studies showing that

tizing them to chemotherapeutic treatment with the

Rel/NF-jB and apoptosis