In multicellular organisms, cells are constantly faced with the
choice of whether to live or die. The decision requires
integration of a complex network of intracellular and
extracellular signals, and making the right decision is essential
for survival of these organisms. Programmed cell death (PCD)
is crucial to tissue homeostasis, organ development and the
elimination of defective or ‘dangerous’ cells, such as cancerous
and virus-infected cells (Danial and Korsmeyer, 2004;
Rathmell and Thompson, 2002). Underscoring the importance
of this process, numerous diseases arise from defects in the
pathways controlling PCD. For instance, defective and
excessive cell death respectively contribute to cancer and
neurodegenerative disorders such as Alzheimer’s disease
(Danial and Korsmeyer, 2004; Rathmell and Thompson, 2002).
Ultimately, the balance between life and death might depend
on the ability of the cell to sustain activation of transcription
factors of the NF-κB family.
Among the various functions of members of the NF-κB
family, the control of PCD has arguably received the most
attention in recent years. This activity is crucial for normal
organismal physiology and is implicated in several
pathological conditions, including cancer and chronic
inflammation (Gerondakis and Strasser, 2003; Karin and Lin,
2002; Kucharczac et al., 2003; Orlowski and Baldwin, 2002).
Indeed, inhibitors of NF-κB are becoming drugs of choice in
the treatment of an increasing number of illnesses (Amit and
Ben-Neriah, 2003; Karin et al., 2004; Tak and Firestein, 2001).
However, as NF-κB has numerous functions, particularly in
immunity, there is a need for new compounds that selectively
target the pro-survival activity of NF-κB and thereby minimize
deleterious effects on the immune system. Remarkably, this
goal now appears realistic, because it is becoming increasingly
clear that – although integrated – the functions of NF-κB in
immunity and PCD are executed through distinct subsets of
The functions and regulation of NF-κB signaling have been
the subjects of excellent recent reviews (Chen and Greene,
2004; Ghosh and Karin, 2002; Karin and Ben-Neriah, 2000;
Kucharczak et al., 2003; Li and Verma, 2002; Silvermann and
Maniatis, 2001). Here, we focus instead on recent discoveries
that have revealed how NF-κB, stimulated by tumor necrosis
factor (TNF)-α, controls PCD by engaging in a crosstalk with
the JNK MAP kinase cascade – a signaling pathway that is
known to promote apoptosis. We go on to discuss the relevance
of this crosstalk to inhibition of PCD in animal physiology and
The NF-κB family
In vertebrates and invertebrates, NF-κB-family transcription
factors are master coordinators of immune and inflammatory
responses (reviewed by Chen and Greene, 2004; Karin and Ben-
Neriah, 2000; Li and Verma, 2002; Silvermann and Maniatis,
2001). They also promote cell survival. In mammals, the family
consists of Rel (c-Rel), RelA (p65), RelB, p50/p105 (NF-κB1),
and p52/p100 (NF-κB2). Each polypeptide has a Rel-homology
domain (RHD), which mediates both DNA binding and
dimerization. Usually, ubiquitous NF-κB dimers are
sequestered in the cytoplasm by inhibitory IκB proteins (IκBα,
IκBβ and IκBε) and are activated rapidly by stimuli that induce
the sequential phosphorylation and proteolysis of IκBs – a
process that depends on the IκB kinase (IKK) complex and the
ubiquitin/proteasome pathway (Fig. 1). Upon removal of the
inhibitors, NF-κB dimers enter nuclei to induce expression of
coordinate sets of target genes that regulate innate and adaptive
immunity, inflammation, cell growth and cell survival. A non-
canonical pathway for NF-κB activation, involving proteolytic
processing of p52/p100, has also been recently described
In addition to marshalling immune and inflammatory
responses, transcription factors of the NF-κB family
control cell survival. This control is crucial to a wide range
of biological processes, including B and T lymphopoiesis,
adaptive immunity, oncogenesis
chemoresistance. During an inflammatory response, NF-κB
activation antagonizes apoptosis induced by tumor necrosis
factor (TNF)-α, a protective activity that involves
suppression of the Jun N-terminal kinase (JNK) cascade.
This suppression can involve upregulation of the Gadd45-
family member Gadd45β/Myd118, which associates with
the JNK kinase MKK7/JNKK2 and blocks its catalytic
activity. Upregulation of XIAP, A20 and blockers of
reactive oxygen species (ROS) appear to be important
additional means by which NF-κB blunts JNK signaling.
These recent findings might open up entirely new avenues
for therapeutic intervention in chronic inflammatory
diseases and certain cancers; indeed, the Gadd45β-MKK7
interaction might be a key target for such intervention.
Key words: NF-κB, JNK, Gadd45β, TNF-α, Apoptosis
Linking JNK signaling to NF-κB: a key to survival
Salvatore Papa, Francesca Zazzeroni*, Can G. Pham, Concetta Bubici and Guido Franzoso‡
The Ben May Institute for Cancer Research, The University of Chicago, 924 East 57th Street, Chicago, IL 60637, USA
*Present address: Department of Experimental Medicine, The University of L’Aquila, Via Vettoio-Coppito 2, 67100 L’Aquila, Italy
‡Author for correspondence (e-mail: email@example.com)
Journal of Cell Science 117, 5197-5208 Published by The Company of Biologists 2004
(Ghosh and Karin, 2002; Senftleben et al., 2001; Xiao et al.,
Anti-apoptotic functions of NF-κB
Numerous studies have shown that NF-κB has anti-apoptotic
effects that have been implicated in a variety of biological
processes. In the B-cell lineage, this activity is required for
completion of various developmental steps, including
differentiation into mature IgMlow/IgDhighcells, as well as the
response of these cells to antigen and CD40 costimulation
(Gilmore et al., 2004; Gerondakis and Strasser, 2003).
Likewise, during an immune reaction, survival of naive T cells
depends on NF-κB activation by the T-cell receptor (TCR) and
CD28 stimulation (Green, 2003; Zheng et al., 2003; Kane et
al., 2002). NF-κB also plays an important pro-survival role
during thymocyte development (Voll et al., 2000; Boothby et
al., 1997; Esslinger et al., 1997).
The control of apoptosis by NF-κB is also crucial outside
the immune system. Deletion of RelA in mice causes
embryonic lethality at mid-gestation owing to massive liver
apoptosis (Beg et al., 1995). A hepato-protective role of NF-
κB in adults has now been confirmed by studies of animal
models of TNF receptor (TNFR)-mediated damage (Chaisson
et al., 2002; Maeda et al., 2003). Recently, the NF-κB pro-
survival activity has also been implicated in epidermal
homeostasis and hair follicle development, and accumulating
evidence indicates that it might play an important role in the
central nervous system (reviewed by Kucharczak et al., 2003;
Mattson and Camandola, 2001).
NF-κB and cancer
The association between NF-κB and cancer dates as far back
as the discovery of the molecule, when the viral oncoprotein
v-Rel was identified as the causative agent of acute avian
Journal of Cell Science 117 (22)
Complex IIComplex I
Fig. 1. TNFR1-induced pathways modulating apoptosis. Formation of complex I leads to NF-κB activation, Gadd45β induction, JNK inhibition
and cell survival. Formation of complex II leads to caspase-8/10-mediated cleavage of Bid into tBid, which then targets mitochondria to induce
cytochrome c release and, ultimately, cell death. The figure also depicts JNK activation, which results in formation of jBid; this promotes PCD
by triggering release of Smac/Diablo into the cytosol, inhibiting the TRAF2-IAP1 complex and consequently activating caspase-8. The
Gadd45β-MKK7 interaction linking the JNK and NF-κB pathways is also shown.
Control of apoptosis by NF-κB
leukemia (Gilmore, 1999). However, only recently has the
extent to which NF-κB is involved in mammalian oncogenesis
become apparent. Genes encoding NF-κB-family members
such as p52/p100, Rel, RelA and the IκB-like protein Bcl-3 are
frequently rearranged or amplified in human lymphomas
and leukemias, and inactivating mutations of IκBα occur in
Hodgkin’s lymphoma (HL) (reviewed by Kucharczak et al.,
2003; Orlowski and Baldwin, 2002; Karin et al., 2002).
Moreover, virtually all oncogene products, including the Tax
protein of human T-cell leukemia virus type 1 (HTLV-I),
EBNA2 and LMP-1 of Epstein–Barr virus (EBV), Bcr-Abl,
Her-2/Neu and oncogenic variants of Ras, can induce NF-κB
(Kucharczak et al., 2003; Orlowski and Baldwin, 2002), and
targeted overexpression of Rel in the mammary epithelium
causes tumors (Romieu-Mourez et al., 2003).
Direct evidence from both in vivo and in vitro models
indicates that control of apoptosis by NF-κB is crucial to its
promotion of oncogenesis (Karin et al., 2002; Orlowski and
Baldwin, 2002; Kucharzack et al., 2003). In the early stages of
tumorigenesis, NF-κB suppresses transformation-associated
apoptosis induced by oncoproteins such as mutated H-Ras and
Bcr-Abl (Kucharzack et al., 2003; Orlowski and Baldwin,
2002). It is also needed for survival of a growing list of late-
stage tumors, including HL, diffuse large B-cell lymphoma
(DLBCL), multiple myeloma (MM), acute lymphoblastic
leukemia (ALL), chronic myelogenous leukemia (CML) and
breast cancer (reviewed by Karin et al., 2002; Kucharzack et
al., 2003; Orlowski and Baldwin, 2002). Both primary cancer
tissues and cell culture models of these cancers exhibit
constitutively active NF-κB, and inhibition of this activity by
various means induces apoptosis.
Elevated NF-κB activity has also been associated with tumor
resistance to anticancer therapy, as well as to TNF-α-induced
apoptosis, which might help these cells evade immune
surveillance (Greten and Karin, 2004; Kucharzack et al., 2003;
Orlowski and Baldwin, 2002). Notably, NF-κB induction by
chemotherapeutic agents can blunt their efficacy even when
NF-κB is not constitutively active (Kucharzack et al., 2003;
Orlowski and Baldwin, 2002). Indeed, blockers of NF-κB
such as proteasome inhibitors (PS-341) are now being used
successfully to treat patients with MM, and early clinical trials
with these inhibitors are showing potential benefits against
lymphoma, as well as prostate and lung cancer (Lenz, 2003;
Richardson, 2003). Glucorticoids, which also block NF-κB,
are part of the therapeutic regimen for HL.
The pro-survival activity of NF-κB also plays a crucial role in
viral pathogenesis (reviewed by Kucharzack et al., 2003).
Indeed, the need for an inducible gene expression program to
maintain cell survival might have originally evolved as a
mechanism for disposing of infected cells that, because of
viral takeover, exhibit grossly defective transcription. Not
surprisingly, many viruses have adapted to this host defense
mechanism by developing their own anti-apoptotic strategies
or acquiring genes that either induce or mimic NF-κB.
Examples of such genes, many of which are implicated in viral
oncogenesis, include: v-FLIP of human herpesvirus 8 (HHV-
8), which is linked to Kaposi’s sarcoma and lymphoma; Tax of
HTLV-1, which causes adult T-cell leukemia (ATL); and of
course v-Rel, which is encoded by the avian retrovirus REV-T
(Kucharczak et al., 2003; Benedict et al., 2002).
The NF-κB-mediated control of PCD induced by
The paradigm of the anti-apoptotic activity of NF-κB is the
control of PCD induced through TNFRs is central to the anti-
apoptotic activity of NF-κB. Indeed, it was studies of the
biological responses to these receptors that originally revealed
this function (Liu et al., 1996; Van Antwerp et al., 1996; Wang
et al., 1996; Beg and Baltimore, 1996). The effects were later
found to extend to other ‘death receptors’ (DRs), including
Fas/CD95 and, probably, TRAIL-R1/DR4 and TRAIL-R2/DR5
(Kucharczak et al., 2003). TNF-α is a pleiotropic cytokine that
plays a key role in inflammation, immunity, apoptosis and
differentiation, and is arguably the most potent inducer of NF-
κB (Aggarwal, 2003; Wajant et al., 2003). Signaling through its
receptors can trigger PCD (Aggarwal, 2003; Wajant et al.,
2003). Indeed, during a physiological immune response,
TNFRs (and Fas) are crucial mediators of activation-induced
cell death (AICD) of antigen-specific T cells (Baumann et al.,
2002; Singer and Abbas, 1994; Sytwu et al., 1996; Zheng et al.,
1995). They also participate in neuronal death after ischemic
brain injury (Martin-Villalba et al., 2001) and cisplatinum-
induced nephrotoxicity in mice (Ramesh and Reeves, 2002).
Moreover, TNF-α exhibits cytotoxic activity in some tumor cell
lines in vitro (Sugarman et al., 1985).
Normally, however, stimulation with the cytokine has no
apoptotic effect unless NF-κB activation or protein synthesis
is blocked (Kucharczak et al., 2003). Interestingly, these
conditions can occur naturally. During infection with human
adenovirus, virally encoded E1A suppresses NF-κB and
sensitizes cells to TNF-α-induced death (Perez and White,
2003; Shao et al., 1997; Shao et al., 1999). Likewise, reovirus-
induced neuronal apoptosis depends on TNFRs and other DRs
(Richardson-Burns et al., 2002), and the increased sensitivity
of T cells from aged individuals to TNF-α-induced PCD has
been associated with reduced activation of NF-κB (Aggarwal
et al., 1999; Aggarwal et al., 2000; Gupta, 2002). Finally, NF-
κB activation can be severely impaired in certain genetic
diseases, such as incontinentia pigmenti – a rare disorder
caused by inactivating rearrangements of the IKKγ gene (also
known as NEMO) that sensitize cells to TNF-α-induced
apoptosis (Smahi et al., 2002).
Tchopp and colleagues recently provided important insights
into the bases for the dichotomy of TNF-α signaling (Micheau
and Tschopp, 2003) (see also Wajant et al., 2003). Upon ligand
engagement, TNFR1 recruits to its cytoplasmic tail the death
domain (DD)-containing proteins TRADD and RIP1, which
then form one of two complexes. Complex I – which also
contains TRAF2 – binds to the TNFR1 tail, inducing NF-κB
activation and, thereby, cell survival. When ubiquitylated, the
TRADD-RIP1 complex instead localizes to the cytosol, where
it associates with FADD, yielding complex II, which then
recruits and activates procaspase-8 and procaspase-10 to
induce cell death.
The suppression of TNF-α-induced apoptosis by NF-κB is
crucial for the survival of the organism and its response to
injury. In mice lacking RelA, liver apoptosis and embryonic
lethality are rescued by deletion of TNFR1 (Alcamo et al.,
2001; Doi et al., 1999). The resistance to TNF-α-induced
apoptosis that NF-κB confers on the liver has also been
observed in adults (Chaisson et al., 2002; Maeda et al., 2003).
Overactivation of NF-κB by TNF-α can be detrimental too. For
instance, when caused by loss of the de-ubiquitinase CYLD,
itinappropriately blocks apoptosis, thereby promoting
oncogenesis (Brummelkamp et al., 2003; Kovalenko et al.,
2003; Trompouki et al., 2003). NF-κB-mediated inhibition of
TNFR-induced PCD is also involved in chronic inflammatory
diseases (Liu and Pope, 2003) (see below).
The pro-survival mechanisms of NF-κB-mediated
Although other modes of action might exist (see Kurcharczak
et al., 2003), the suppression of apoptosis by NF-κB is, by and
large, a transcriptional event. NF-κB-regulated genes that are
capable of blocking PCD have been identified (reviewed by
Karin and Lin, 2002; Kurcharczak et al., 2003). Interestingly,
the NF-κB-activated pro-survival program appears to be
specifically tailored for each tissue and biological context. The
bases for this plasticity are not fully understood, but the
program seems to be dictated by the particular milieu of NF-
κB dimers and transcription factors present in each tissue, and
the specific network of interactions and modifications induced
by the apoptotic stimulus (Hoffmann et al., 2003).
In some circumstances, the genes that are most relevant to
the NF-κB anti-apoptotic activity seem to have been identified.
For instance, several studies now indicate that, in peripheral B
and T lymphocytes, NF-κB pro-survival signaling induced by
antigen receptor and CD40 or CD28 costimulation targets
members of the Bcl-2 family such as Bcl-xL, Bfl-1/A1 and Bcl-
2 itself (Grossmann et al., 2000; Grumont et al., 1999; Hsu et
al., 2002; Khoshnan et al., 2000; Lee et al., 1999; Willis et
al., 2003; Wu et al., 1996; Zong et al., 1999). However, in
many other instances, including oncogenesis and cancer
chemoresistance, the critical targets of NF-κB remain largely
The resistance to TNF-α-induced apoptosis that NF-κB
confers has been associated with: upregulation of: the Bcl-2
family members Bcl-xLand A1/Bfl-1; the catalytically inactive
relative of caspase-8, FLIPL; the combination of TRAF1/2 and
inhibitor of apoptosis protein (IAP) 1/2; and X-chromosome-
linked IAP (XIAP; also known as hILP) (reviewed by Karin and
Lin, 2002; Kurcharczak et al., 2003). NF-κB might also induce
expression of the cathepsin inhibitor, Spi2A, to blunt the
lysosomal pathway for PCD (Liu et al., 2003). Indeed, these
factors appear to be important mediators of anti-apoptotic NF-
κB signaling in certain tissues, and their effects on apoptotic
pathways have been well characterized. Nevertheless, most of
these factors are only expressed in certain cell types, and their
levels are not controlled by NF-κB or TNF-α in others.
Moreover, they can only partly inhibit PCD in NF-κB-deficient
cells. Hence, they cannot fully account for the protective effects
of NF-κB (see De Smaele et al., 2001).
Suppression of JNK signaling
Several groups have shown that there is a crosstalk between the
NF-κB and JNK pathways (De Smaele et al., 2001; Tang et al.,
2001; Javelaud and Besacon, 2001). The JNK isoforms (JNK1-
JNK3) are the downstream components in one of the major
mitogen-activated protein (MAP) kinase cascades (reviewed by
Chang and Karin, 2001; Davis, 2000). Normally, signaling
through the JNK and p38 MAP kinase cascades is associated
with induction of cell death, whereas signaling through the
ERK MAP kinase cascade promotes cell growth and survival.
The pro-apoptotic role of JNK is evident from analyses of
JNK-knockout mice. Mouse embryonic fibroblasts (MEFs)
lacking both JNK1 and JNK2 are resistant to PCD induced by
various stress stimuli, and JNK3–/–neurons have severely
impaired apoptotic responses to excitotoxins (Davis, 2000;
Tournier et al., 2000; Yang et al., 1997). Moreover, knocking
out either JNK1 or JNK2 can protect peripheral T cells against
AICD, and JNK1-deficient or JNK2-deficient thymocytes are
refractory to anti-CD3-induced death in vivo (Arbour et al.,
2002; Sabapathy et al., 1999; Sabapathy et al., 2001) (see also
Dong et al., 2002; Rincon and Pedraza-Alva, 2003). Consistent
with this pro-apoptotic role of JNK is the observation that T
cells lacking JNK1 or the JNK kinase MKK7/JNKK2 mount a
hyper-proliferative response to antigen stimulation (Dong et
al., 1998; Sasaki et al., 2001).
There is now general agreement that JNK also plays an
important role in TNFR-mediated apoptosis. Normally,
however, cells survive TNF-α treatment (see above) and, thus,
JNK inhibition has no apparent effect on cell viability – this
might explain why early studies failed to uncover a pro-
apoptotic role for JNK in TNFR signaling (Franzoso et al.,
2003). In fact, this role was revealed by analyses performed
under conditions allowing PCD – that is, inhibition of NF-κB.
Inhibition of JNK signaling by pharmacological agents or
dominant-negative kinase mutants effectively rescues NF-κB-
deficient cells from TNF-α-induced death (De Smaele et al.,
2001; Tang et al., 2001; Javelaud and Besacon, 2001).
Likewise, knocking out MKK7/JNKK2 virtually abrogates
TNF-α-induced death in RelA-null cells (Deng et al., 2003).
Expression of IκBαM – a potent blocker of NF-κB – yields
similar results in JNK1–/–and JNK2–/–MEFs (Lamb et al.,
2003) (F.Z. and G.F., unpublished observations). Furthermore,
fibroblasts lacking the TNFR-induced MAP kinase kinase
kinase (MAPKKK) apoptosis signal-regulated kinase 1
(ASK1) – an upstream activator of JNK (and p38) (Davis,
2000) – are significantly protected against the apoptotic effects
of the cytokine (Tobiume et al., 2001). Interestingly, however,
like JNK-null MEFs, these cells retain normal sensitivity to
Fas-induced killing (Tobiume et al., 2001; Tournier et al.,
2000), which suggests that JNK does not participate in this
killing. Nevertheless, this might still occur in certain tumor
lines (Zazzeroni et al., 2003a).
The relevance of the JNK cascade to apoptosis signaling is
highlighted by the finding that activation of this cascade is
controlled by NF-κB. Indeed, suppression of NF-κB by
ablation of RelA or IKKβ, or expression of IκBαM, leads to
persistent (rather then transient) JNK induction by TNF-α, and
it seems to be the persistence of this induction that ultimately
causes the cell to succumb to PCD (De Smaele et al., 2001;
Javelaud and Besancon, 2001; Tang et al., 2001) (see also
Franzoso et al., 2003). Caspases can activate various
MAPKKKs (Davis, 2000; Roulston et al., 1998), but the effects
of NF-κB on JNK signaling are not affected by protective cell
treatment with the caspase blocker z-VADfmkand so do not
Journal of Cell Science 117 (22)
Control of apoptosis by NF-κB
appear to be a secondary consequence of caspase inhibition
(Javelaud and Besancon, 2001; Franzoso et al., 2003). In short,
the containment of the JNK cascade is crucial for the control
of TNF-α-induced apoptosis, and this critically depends on
NF-κB. Curiously, although confirming the inhibitory effects
of NF-κB on JNK signaling, another study has suggested that,
in TNF-α-treated NF-κB-deficient cells, persistent JNK
activation promotes cell survival (Reuther-Madrid et al., 2002).
The bases for the discrepancy with other studies are not clear.
Clearly, there are also JNK-independent mechanisms by
which TNFRs can trigger PCD. In NF-κB-deficient cells,
protection by JNK inactivation is not complete, and JNK-null
MEFs eventually succumb to treatment with TNF-α (De
Smaele et al., 2001; Javelaud and Besancon, 2001; Tang et
al., 2001; Lamb et al., 2003). Nevertheless, there is now
compelling evidence to demonstrate an obligatory role for
JNK in efficient apoptosis in response to the cytokine.
Paradoxically, in most cells, activation of JNK by TNF-α
occurs without significant death. This is probably because –
unlike UV and other stress stimuli – TNF-α only causes
transient elevation of JNK activity, which normally is not a
signal for PCD (Davis, 2000; Franzoso et al., 2003). For pro-
apoptotic activity, JNK must signal chronically, as during
inhibition of NF-κB. Indeed, constitutive JNK activation –
through expression of MKK7-JNK fusion proteins – seems
sufficient on its own to induce cell death (Lei et al., 2002). Still,
the actual role of JNK in TNF-α-induced apoptosis signaling
might be influenced by cell-type-specific elements.
The importance of this antagonistic crosstalk between NF-
κB and JNK has recently been documented in animal models.
Karin and colleagues have shown that NF-κB activation is
required to antagonize hepato-toxicity induced by systemic
challenge with lipopolysaccharide (LPS) or concanavalin A
(ConA) – two agents that provoke liver damage through
TNFR-induced cell death (Maeda et al., 2003). This study
shows that conditional deletion of IKKβ results in markedly
increased induction of JNK by these agents and that
suppression of this induction by ablation of either JNK1 or
JNK2 blunts TNFR-mediated hepatic injury (Maeda et al.,
2003). It is plausible that the pro-survival activity of NF-κB
in the fetal liver may also involve attenuation of pro-apoptotic
An evolutionarily conserved crosstalk
Evidence for the importance of the NF-κB–JNK crosstalk also
comes from its evolutionary conservation. In Drosophila, the
duration of JNK induction in response to LPS is directly
controlled by the NF-κB protein Relish (Park et al., 2004).
Here, LPS signals through the Imd pathway, which is named
after the insect ortholog of the TNFR pathway kinase RIP and
controls immunity to Gram-negative bacteria through two main
branches: the JNK and IKK/Relish cascades (Hoffmann and
Reichhart, 2002; Silverman and Maniatis, 2001). These
branches diverge downstream of the MAPKKK TAK1 to direct
transcription of distinct subsets of genes in a temporally
coordinated manner (Boutros et al., 2002). Whereas Relish-
responsive genes exhibit sustained expression, JNK targets are
characterized by transient induction, owing to Relish-mediated
shut down of JNK signaling – a process involving proteosomal
degradation of TAK1 promoted by unidentified Relish targets
(Park et al., 2004). Notably, the Relish-mediated attenuation of
the JNK cascade might also control apoptosis. Indeed, the
Drosophila TNF-α homolog, Eiger, depends on JNK – rather
than on the caspase-8 homolog, Dredd – to induce death (Igaki
et al., 2002; Moreno et al., 2002). Thus, the role of JNK in
apoptosis signaling appears to be a remnant of a primordial
death mechanism engaged by TNF-α, which only later in
evolution began to exploit the FADD/caspase-dependent
pathway, yet maintaining its connection to NF-κB.
Mechanisms for TNFR-induced JNK pro-apoptotic
Whereas in some circumstances, JNK-induced apoptosis
involves modulation of gene expression, apoptosis induced by
stress stimuli or TNF-α appears to be mediated by factors that
are already present in the cell (Davis, 2000; Tournier et al.,
2000). A recent study has shown that JNK activation by TNF-
α causes caspase-8-independent processing of Bid, a BH3-only
member of the Bcl-2 family (Bouillet and Strasser, 2002;
Danial and Korsmeyer, 2004), into jBid, which then targets
mitochondria to trigger selective release of the apoptogenic
factor Smac/Diablo (Fig. 1) (Deng et al., 2003) (see also Chai
et al., 2000; Verhagen et al., 2000). In the cytosol, this factor
then binds to and antagonizes IAP1, thereby relieving caspase-
8 from the inhibitory effects of the TRAF2-IAP1 complex (see
also Wajant et al., 2003). In keeping with the evolutionary
conservation of the JNK apoptotic mechanism in flies, Eiger-
induced JNK activation in flies triggers death through Hid,
Reaper and Grim, the functional equivalents of mammalian
Smac/Diablo (Igaki et al., 2002; Moreno et al., 2002).
The JNK-jBid-Smac/Diablo pathway represents a newly
identified link between the intrinsic (mitochondrial) and
extrinsic (DR) pathways of apoptosis. In this link (seemingly
specific for TNFRs), mitochondria appear to lie upstream of
caspase-8 (Deng et al., 2003), which contrasts with the
‘classical’, caspase-8–tBid–cytochrome-c pathway (shared by
Fas and TRAIL-Rs), in which mitochondria are downstream of
this caspase (Fig. 1) (Barnhart et al., 2003). Interestingly, this
might explain the somewhat puzzling observation that, despite
greatly impaired JNK induction and near-normal NF-κB
activity, TRAF2-null cells exhibit hypersensitivity to TNF-α-
induced apoptosis (Yeh et al., 1997). According to this model,
loss of TRAF2 should prevent recruitment of IAP1 to the
TRADD–FADD–caspase-8 complex, thereby causing caspase-
8 activation without a need for JNK-mediated release of
Smac/Diablo (Fig. 1).
Why does only prolonged JNK induction lead to cell death?
One possibility is that the effectors of JNK pro-apoptotic
signaling become available in the cell only some time after
TNF-α stimulation. Alternatively, these effectors (for instance,
jBid or Smac/Diablo) might have to accumulate in significant
amounts before they can trigger apoptosis. It is also possible
that the JNK apoptotic activity can be counteracted, but
only temporarily, by concomitant activation of pro-survival
pathways, such as the ERK, Akt/PKB or perhaps NF-κB
pathway (Chang and Karin, 2001; Davis, 2000). Indeed,
despite the well-documented ability of JNK to trigger
apoptosis, the actual biological response to its activation also
depends (apart, of course, from its duration) upon the stimulus
and tissue (Chang and Karin, 2001; Davis, 2000).
JNK and pro-survival signaling
Curiously, in the presence of NF-κB, transient JNK activation
might actually protect cells from apoptosis following TNFR
stimulation. Recent studies of JNK1–/–and JNK2–/–fibroblasts
have shown that this is mediated by the transcription factor
JunD, which might collaborate with NF-κB to upregulate
expression of anti-apoptotic factors such as IAP2 (Lamb et al.,
2003). Thus, in TNF-α-treated cells, NF-κB-mediated survival
could require transient activation of JNK. Note, however, that
these studies used nonspecific inhibitors of protein synthesis,
such as CHX and emetine, and there is evidence that these
inhibitors can bypass the requirement for JNK in death
signaling (Deng et al., 2003).
Gadd45β and MKK7: critical targets
NF-κB controls the JNK cascade by inducing target genes.
Curiously, these targets seem to differ between insects and
mammals. Screens for cDNAs that block TNF-α-induced
apoptosis in RelA–/–fibroblasts identified Gadd45β (also
known as Myd118) – one of a family of structurally related,
acidic and predominantly nuclear proteins – as an effector of
the suppressive activity of NF-κB (De Smaele et al., 2001).
Although their exact structures and functions are not known,
Gadd45 proteins have been implicated in cell-cycle control,
DNA repair and several other processes (Carrier et al., 1999;
Nakayama et al., 1999; Vairapandi et al., 2000; Wang et al.,
1999a; Yang et al., 2000; Zhan et al., 1999; Zhang et al., 1999;
Zhao et al., 2000). Gadd45β upregulation by TNF-α requires
NF-κB, and expression of Gadd45β in NF-κB-null cells
abrogates induction of the JNK cascade by TNF-α.
Importantly, this expression also blocks the caspase-
independent phase of TNF-α-induced JNK signaling, and
Gadd45β inactivation blunts the normal downmodulation of
this signaling (De Smaele et al., 2001; Papa et al., 2004).
Hence, Gadd45β is a bona fide inhibitor of the JNK pathway.
The JNK kinase MKK7/JNKK2 is a target of Gadd45β and,
indirectly, of NF-κB (Papa et al., 2004). Gadd45β associates
tightly with MKK7 and inhibits its catalytic activity by
contacting crucial residues in the catalytic pocket, including
the ATP-binding residue Lys149 (Moriguchi et al., 1997). It
probably inactivates MKK7 by blocking access of ATP (Papa
et al., 2004). MKK7 is a selective activator of JNK, and its
ablation in fibroblasts completely abolishes JNK induction by
TNF-α (Davis, 2000; Tournier et al., 2001). Τhus, blocking this
MAPKK seems sufficient alone to account for the specific and
near-complete inhibition of the JNK cascade by Gadd45β (De
Smaele et al., 2001; Papa et al., 2004). Studies using peptides
that impede binding of Gadd45β to MKK7 support this notion
and show that, at least in some tissues, the Gadd45β-mediated
targeting of MKK7 is crucial for the protective effects of NF-
κB (Papa et al., 2004). Thus, the Gadd45β-MKK7 interaction
represents an important molecular link between the NF-κB and
JNK pathways (Fig. 1).
In contrast with these findings, a recent report has suggested
that, in MEFs, Gadd45β ablation has no effect on TNF-α-
induced PCD (Amanullah et al., 2003). Whereas this
discrepancy might in part reflect experimental differences
(Zazzeroni et al., 2003b), there could be other explanations.
The mechanism of MKK7 inhibition activated in response to
TNF-α appears to be tissue specific and, at least in MEFs, other
factors (distinct from Gadd45β) contribute to block induction
of this JNK kinase (Papa et al., 2004). Yet, despite the presence
of these factors, experiments with cell-permeable peptides
show that, in these cells, Gadd45β is required for efficient
blocking of TNF-α-induced killing (Papa et al., 2004).
In some systems, overexpression of Gadd45 factors has been
linked to apoptosis (Chung et al., 2003; Takekawa and Saito,
1998; Vairapandi et al., 2000). It is not clear, however, whether
this is physiological, because in many other systems induction
of endogenous Gadd45 polypeptides is associated with cell
survival, and overexpression of these polypeptides triggers no
apparent toxicity (Yang et al., 2001; De Smaele et al., 2001;
Nakayama et al., 1999; Smith et al., 1996; Smith et al., 2000;
Hoffmeyer et al., 2001; Zazzeroni et al., 2003a). These
discrepancies probably reflect tissue-specific effects of these
polypeptides and/or distinct activities of the different family
members: Gadd45α (Gadd45), Gadd45β and Gadd45γ
(OIG37/CR6). For instance, Gadd45β is unable to inhibit cell
growth in many systems (De Smaele et al., 2001; Yang et al.,
2000; Yang et al., 2001; Zazzeroni et al., 2003a) and, whereas
various tumor cell lines and primary cells tolerate high levels
of Gadd45β, they cannot sustain stable overexpression of
Gadd45α (De Smaele et al., 2001; Zazzeroni et al., 2003a;
Yang et al., 2000; Yang et al., 2001) (S.P., F.Z. and G.F.,
Gadd45 proteins and other aspects of MAPK
Numerous studies have now implicated Gadd45 proteins in the
regulation of MAPK signaling at several levels. Gadd45
polypeptides associate not only with MKK7, but also with the
MAPKKK MEKK4/MTK1 (Takekawa and Saito, 1998; Mita
et al., 2002). In the latter case, they might serve as initiators of
p38 and JNK signaling in response to stress (Takekawa and
Saito, 1998; Mita et al., 2002). In keratinocytes, Gadd45α is
seemingly involved in p38 and JNK signaling in response to
UV irradiation (Hildesheim et al., 2002). The Gadd45β- and
Gadd45γ-mediated control of MAPK cascades also appears to
be essential for the differentiation/function of the T helper 1
(Th1) subset of T cells (Yang et al., 2001; Lu et al., 2001; Lu
et al., 2004). Furthermore, knockout studies have placed these
factors upstream of MEKK4 in the TCR- and interleukin (IL)-
12 receptor-induced pathways for p38 activation (Chi et al.,
The basis for the regulation of MAPK signaling by Gadd45
proteins and its function remain, however, somewhat
controversial. Whereas Gadd45β–/–and Gadd45γ–/–Th1 cells
exhibit a severe defect in p38 and JNK activation by both
antigen and cytokine receptors (Lu et al., 2001; Lu et al., 2004),
the signaling impairment in MEKK4-deficient lymphocytes is
confined to the p38 cascade (Chi et al., 2004). This suggests
that, in these cells, regulation of JNK signaling by Gadd45
involves a MEKK4-independent mechanism. Furthermore,
the seemingly global signaling defect in Gadd45β-null and
Gadd45γ-null T cells might be due, at least in part, to a
developmental block – which would explain the unexpected
loss of ERK activation, an event that is not believed to involve
MEKK4 or to be controlled by Gadd45 protein (Davis, 2000;
Takekawa and Saito, 1998).
Other observations complicate things further. Two studies
Journal of Cell Science 117 (22)
Control of apoptosis by NF-κB
have shown that activation of JNK and p38 by stress precedes,
rather than follows, induction of Gadd45 genes (Shaulian and
Karin, 1999; Wang et al., 1999b). Moreover, in several cell
lines, overexpression of Gadd45 polypeptides does not cause
JNK or p38 activation (Wang et al., 1999b; De Smaele et al.,
2001), and a recent study has shown that activation of p38 by
Gadd45α involves direct association with this MAPK rather
than with MEKK4 (Bulavin et al., 2003). In addition to
MEKK4, Gadd45β interacts with the MAPKKK ASK1
(Papa et al., 2004). Nevertheless, association with these two
MAPKKKs does not appear to be relevant to the Gadd45β-
mediated control of JNK activation and PCD induced by TNF-
α, because MEKK4 is not involved in TNFR signaling (Davis,
2000; Takekawa et al., 1997), and ASK1 is seemingly
unaffected by Gadd45β (Papa et al., 2004). Furthermore,
activation of p38 (possibly through interaction of Gadd45β
with MEKK4 or ASK1) would be unlikely to modulate the
apoptotic response to TNF-α (De Smaele et al., 2001), and any
activation of JNK through a similar mechanism would be
overridden by downstream suppression of MKK7 (Papa et al.,
These apparent discrepancies probably reflect the
complexity of the biological functions of Gadd45 factors,
which are probably subject to tissue- and/or signal-specific
regulation that ultimately dictates their output.
Other mechanisms of NF-κB–JNK crosstalk
Additional factors might mediate inhibitory effects of NF-κB
on JNK signaling (Fig. 2). One such factor is XIAP, a member
of the IAP family of caspase blockers (Clem, 2001; Salvesen
and Duckett, 2002). XIAP binds to and inhibits caspase-3 and
caspase-7 through its N-terminal linker and baculovirus IAP
repeat (BIR) 2 domain, respectively, and might prevent
activation of procaspase-9 through a BIR3-containing region
(Takahashi et al., 1998; Chai et al., 2001; Huang et al., 2001;
Riedl et al., 2001) (see also Clem, 2001; Karin and Lin,
2002). It is also a known target of NF-κB (Stehlik et al.,
1998), and its induction by TNF-α is somewhat reduced in
RelA–/–MEFs (Tang et al., 2001). Overexpression of XIAP
inhibits TNF-α-induced cytotoxicity in NF-κB-deficient cells
(Stehlik et al., 1998), and thymocytes from XIAP-transgenic
mice are resistant to apoptosis induced by various triggers
(Conte et al., 2001). This overexpression has been reported
to diminish activation of JNK by TNF-α in RelA–/–cells, but
to have no effect on the p38 and ERK cascades (Tang et al.,
2001). However, the mechanisms by which XIAP blocks this
activation are not clear. One possibility is that this is a
secondary consequence of caspase inhibition (Salvesen and
Duckett, 2002). Nevertheless, like Gadd45β, XIAP can block
both the caspase-dependent phase and caspase-independent
(that is, z-VADfmk-insensitive) phase of JNK induction by
TNF-α (also discussed above) and thus may be a genuine
inhibitor of the JNK cascade. Indeed, XIAP is capable of
interacting with JNK-activating kinases (Yamaguchi et al.,
1999; Sanna et al., 2002). Curiously, however, these
interactions appear to result in activation rather than
inhibition of JNK signaling (Sanna et al., 2002). Furthermore,
XIAP–/–mice exhibit no obvious apoptotic phenotype (Harlin
et al., 2001), and XIAP ablation in MEFs does not affect the
kinetics of JNK induction by TNF-α (Kucharczak et al.,
compensatory mechanisms, further studies are needed to
establish whether XIAP-mediated control of JNK is
Another likely candidate is the zinc-finger protein A20.
It is rapidly induced by TNF-α through a mechanism that
requires NF-κB (Beg and Baltimore, 1996; Kucharczak et al.,
2003). A20-null MEFs exhibit increased apoptosis after
treatment with TNF-α, and this correlates with increased
activation of JNK (Lee et al., 2000) (see also Lademann et al.,
2001). However, overexpressed A20 cannot block PCD in NF-
κB-deficient cells (Beg and Baltimore, 1996). Thus, although
required, it does not appear to be sufficient to mediate the pro-
survival activity of NF-κB. How A20 blunts JNK signaling is
not understood. Nevertheless, A20 can interact with TRAF2
and NEMO and is recruited to the TNFR1-IKK signaling
complex upon stimulation with TNF-α (Song et al., 1996;
Zhang et al., 2000), which suggests that it acts immediately
downstream of the receptor (Lee et al., 2000; Lademann et al.,
2001; Song et al., 1996; He and Ting, 2002). Its upregulation
although this ablation might activate
Fig. 2. The various mediators of the NF-κB suppression of JNK
signaling and their potential modes of action.
also blocks TNF-α-induced NF-κB activation and, in fact, is
an important negative-feedback mechanism controlling this
(Lee et al., 2000; Song et al., 1996) (see also Wajant et al.,
2003). Analyses of A20–/–MEFs suggest that A20 specifically
interferes with activation of NF-κB and JNK signaling in
response to TNF-α, because induction of this signaling by IL-
1 is unaffected in these cells (Lee et al., 2000). This is in line
with an early report proposing that NF-κB acts selectively on
JNK activated by TNFR signaling and not by IL-1R or UV
rays (Tang et al., 2001). Note, however, that a more recent
study has shown that NF-κB negatively regulates JNK
activation regardless of whether the cell stimulus is TNF-α or
IL-1 (Reuther-Madrid et al., 2002), and various biochemical
studies support a more global role for A20 in regulating
MAPKKK activity and cytokine receptor signaling (Zetoune
et al., 2001; Heyninck et al., 1999; Jaattela et al., 1996). Thus,
at the present time, it is not possible to propose a
comprehensive, straightforward model depicting the function
An intriguing new study has shown that NF-κB activation
prevents accumulation of reactive oxygen species (ROS)
produced in response to TNF-α – probably through
upregulation of target genes (Sakon et al., 2003) (C.G.P. and
G.F., unpublished observations). This is relevant since ROS
have been implicated as essential mediators of TNF-α-induced
apoptosis (Wajant et al., 2003) (see also Sakon et al., 2003;
Schulze-Osthoff et al., 1993). Expression of the superoxide
dismutase Mn-SOD – a ROS scavenger and known target of
NF-κB (Bernard et al., 2001; Tanaka et al., 2002; Wong et al.,
1989) – cannot reproduce the effects of NF-κB on ROS
generated in response to TNF-α (Sakon et al., 2003). This
indicates that additional factors are responsible. Because ROS
help to sustain JNK signaling – partly through inactivation of
the ASK1 inhibitor thioredoxin (Matsuzawa et al., 2002) –
their suppression might represent yet another mechanism by
which NF-κB downregulates this signaling.
NF-κB–JNK crosstalk and human disease
TNF-α is a potent activator of NF-κB, which in turn is a
potent inducer of TNF-α (Aggarwal, 2003). This positive
feedback is key to chronic inflammatory conditions such as
rheumatoid arthritis and inflammatory bowel disease (Tak and
Firestein, 2001; Romas et al., 2002). Indeed, the standard
therapy for these conditions includes NF-κB blockers such as
aspirin and glucocorticoids, and neutralizing anti-TNF-α
antibodies represent an effective new tool (Makarov, 2000;
Roshak et al., 2002). Inhibition of NF-κB by either
glucocorticoids or proteasome inhibitors is also beneficial in
certain malignancies, including HL and MM (Tesch et al.,
2001; Lenz, 2003; Richardson, 2003). However, current
compounds can only achieve partial inhibition of NF-κB and
have considerable side effects, which limit their use in
humans. Thus, there is an urgent need for new drugs that
target the downstream anti-apoptotic effectors rather than
The finding that the targeting of JNK signaling by NF-κB is
a key protective mechanism mediated by NF-κB offers a
unique opportunity for developing such drugs. Blocking the
ability of NF-κB to shut down JNK activation should promote
apoptosis of self-reactive and proinflammatory cells at the site
of inflammation, where there are high levels of TNF-α (Tak
and Firestein, 2001; Romas et al., 2002). Experiments using
cell-permeable peptides indicate that compounds that disrupt
binding of Gadd45β to MKK7 might provide an effective new
tool (Papa et al., 2004) (Fig. 3). These compounds or others
that interfere with the NF-κB–JNK crosstalk might enable us
to dissociate the anti-apoptotic and proinflammatory functions
of NF-κB and so avoid the potent immunosuppressive effects
of global NF-κB blockers (Karin et al., 2004; Tak and Firestein,
2001). Indeed, given the apparent cell-type specificity of the
JNK inhibition program activated by NF-κB (Papa et al.,
2004), they might also allow selective targeting of this program
in diseased tissues.
This therapeutic relevance might also extend to cancer
(Franzoso et al., 2003). JNK and NF-κB have seemingly
opposing effects in tumor cells. Whereas NF-κB activation
is required to suppress transformation-associated apoptosis
(Kucharczak et al., 2003), activators of the JNK cascade (e.g.
MKK4, JNK3 and BRCA1) are tumor suppressors (Franzoso
et al., 2003; Kennedy and Davis, 2003). Several oncogene
products, including oncogenic Ras and Her-2/Neu, are potent
inducers of JNK (Davis, 2000; Kennedy and Davis, 2003), and
thus cancerous cells might need constitutively active NF-κB to
suppress JNK-mediated apoptosis induced by these products.
Apoptosis caused by genotoxic agents such as topoisomerase
inhibitors – a desirable effect in anticancer therapy – also
requires JNK (Davis, 2000; Tournier et al., 2000) but is
antagonized by NF-κB (Kucharczak et al., 2003). Thus,
augmentation of JNK signaling by inhibiting selected NF-κB
targets might provide a powerful new adjuvant for cancer
Journal of Cell Science 117 (22)
Global NF-κ κB blockers
(salicylates, proteasome inhibitors,
Fig. 3. Potential therapeutic implications of the NF-κB-mediated
blockade of TNF-α-induced JNK signaling. A positive-feedback
loop between TNF-α and NF-κB drives chronic inflammatory states;
several pharmacological agents can be used to treat these states. The
effects of MKK7-mimicking peptides are also shown (Papa et al.,
2004), which support the therapeutic feasibility of blocking the NF-
κB anti-apoptotic activity without significantly affecting the immune
Control of apoptosis by NF-κB
The NF-κB-mediated attenuation of JNK signaling is crucial
for numerous physiological processes, such as the response of
the liver to injury and the survival of cells during an
inflammatory reaction, as well as for chronic inflammatory
diseases and cancers. In recent years, much progress has been
made in understanding the basis for this attenuation, and it is
now clear that this involves activation of a program of gene
expression. The use of multiple genes might ensure effective
shut down of the JNK cascade. It might also enable the
organism to tailor the response to specific biological contexts
and needs. Undoubtedly, a major future challenge will be to
determine which NF-κB-inducible genes are most crucial in
each context and, ultimately, how their products inhibit JNK
signaling. Analyses of conditional knockout models will be
invaluable to address these issues. Since inappropriate NF-κB-
mediated blockade of apoptosis is key to several human
diseases, these efforts could lead to the development of new
treatment strategies. Initial findings suggest that it might be
possible to achieve tissue-specific inhibition of the NF-κB anti-
apoptotic activity with minimal side effects on the immune
system. Indeed, this represents a major therapeutic goal.
We thank A. Hayes for help with manuscript preparation. This
research was supported in part by NIH grants R01-CA84040 and R01-
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