review

AP-1 as a regulator of cell life and

death
Eitan Shaulian*§ and Michael Karin†‡
*Department of Experimental Medicine and Cancer Research, School of Medicine, the Hebrew University, Jerusalem, 91120, Israel
†Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California San Diego, La Jolla, CA 92093, USA
e-mail: ‡karinoffice@ucsd.edu or §eshaulian@md.huji.ac.il

The transcription factor AP-1 (activator protein-1) is involved in cellular proliferation, transformation and death.
Using mice and cells lacking AP-1 components, the target-genes and molecular mechanisms mediating these
processes were recently identified. Interestingly, the growth-promoting activity of c-Jun is mediated by repression of
tumour suppressors, as well as upregulation of positive cell cycle regulators. Mostly, c-Jun is a positive regulator of
cell proliferation, whereas JunB has the converse effect. The intricate relationships between the different Jun pro-
teins, their activities and the mechanisms that mediate them will be discussed.

P-1 was one of the first mammalian transcription factors to

A be identified1, but its physiological functions are still being

unravelled. AP-1 activity is induced by a plethora of physio-
logical stimuli and environmental insults. In turn, AP-1 regulates a
c-Jun–c-Fos
JunB–c-Fos ?
p53
p21 p16

wide range of cellular processes, including cell proliferation, death,
survival and differentiation. However, despite increasing knowl-
edge regarding the physiological functions of AP-1, the target-genes
mediating these functions are not always obvious. This review is
focused on recent findings, which suggest how AP-1 proteins regu-
late cell proliferation and survival.
The ability of a single transcription factor to control an eclectic
collection of biological processes stems primarily from its structur-
al and regulatory complexity. AP-1 is not a single protein, but a
menagerie of dimeric basic region-leucine zipper (bZIP) proteins
that belong to the Jun (c-Jun, JunB, JunD), Fos (c-Fos, FosB, Fra-1
and Fra2), Maf (c-Maf, MafB, MafA, MafG/F/K and Nrl) and ATF
(ATF2, LRF1/ATF3, B-ATF, JDP1, JDP2) sub-families, which recog-
nize either 12-O-tetradecanoylphorbol-13-acetate (TPA) response
elements (5′-TGAG/CTCA-3′) or cAMP response elements (CRE,
5′-TGACGTCA-3′)2. This review is focused mainly on the functions
of Jun and Fos. c-Jun is the most potent transcriptional activator in
its group3, whose transcriptional activity is attenuated and some-
times antagonized by JunB4,5. The Fos proteins, which cannot
homodimerize, form stable heterodimers with Jun proteins and
thereby enhance their DNA binding activity1. Whereas c-Fos and
FosB contain transcriptional activation domains, Fra1, Fra2 and the
alternative splicing variants of FosB, FosB2 and DFosB, do not.
The regulation of AP-1 activity is complex, and we refer the read-
er to earlier and more comprehensive reviews6,7. Briefly, regulation
occurs through: first, changes in jun and fos gene transcription and
mRNA turnover; second, effects on Jun and Fos protein turnover;
third, post-translational modifications of Jun and Fos proteins that
modulate their transactivation potential; fourth, interactions with
other transcription factors that can either synergize or interfere
with AP-1 activity2. In addition to being a transcriptional activator,
there is increasing evidence that some of the biological effects of
AP-1 are mediated by gene repression8–10. These effects may depend
on the interactions of AP-1 proteins with transcriptional corepres-
sors11 and may also be affected by the nature of the AP-1 target
site5,12.
Signalling pathways that regulate AP-1 activity
AP-1 activity is induced by growth factors, cytokines, neurotrans-
mitters, polypeptide hormones, cell–matrix interactions, bacterial
JunB–JunB ?
JunB–c-Jun ?
Cyclin D1 Proliferation
Cdk
G1 S
Figure 1 A model describing the effects of AP-1 proteins on the major cell
cycle regulators. Putative JunB-containing dimers may account for the ability of
AP-1 to both promote and inhibit cell cycle progression.
and viral infections, and a variety of physical and chemical stresses.
These stimuli activate mitogen activated protein kinase (MAPK)
cascades13 that enhance AP-1 activity through the phosphorylation
of distinct substrates. Serum and growth factors that potently induce
AP-1 do so by activating the extracellular-signal-regulated kinase
(ERK) subgroup of MAPKs, whose members translocate to the
nucleus to phosphorylate, and thereby potentiate, the transcription-
al activity of ternary complex factors (TCFs) that bind to fos pro-
moters14. Furthermore, the ERKs directly phosphorylate Fra1 and 2
in response to serum stimulation, possibly enhancing their DNA
binding in conjunction with c-Jun15. An additional contribution to
AP-1 induction by serum growth factors comes from ERK5-
induced phosphorylation of the transcription factor monocyte-
specific enhancer binding factor 2c (MEF2C), whose activation
increases c-Jun expression16.
The induction of AP-1 by pro-inflammatory cytokines and
genotoxic stress is mostly mediated by the JNK and p38 MAPK cas-
cades13. Once activated, the JNKs translocate to the nucleus17, where
they phosphorylate c-Jun and thereby enhance its transcriptional
activity6. The JNKs also phosphorylate and potentiate the activity
of ATF2, which heterodimerizes with c-Jun to bind divergent AP-1
sites in the c-jun promoter18. Importantly, the induction of c-Jun
expression by certain genotoxic stresses, such as short-wavelength
ultraviolet (UV) radiation, is much more robust and persistent
than the induction seen after mitogenic stimulation10,19.
Constitutive expression of activated oncogenes, such as Ha-ras, also
results in an elevation of AP-1 activity20, mostly through persistent
activation of ERK and JNK21,22. The contribution of p38 to AP-1
induction can be mediated by the direct phosphorylation and acti-
vation of ATF2, MEF2C and TCFs23.

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© 2002 Nature Publishing Group

review
Table 1 AP-1-regulated genes that significantly affect cell cycle progression and apoptosis.
Gene product Activity
Cyclin D1(reviewed, ref. 24) Proliferation ↑
p53 (ref. 8) Proliferation ↓
Apoptosis ↑
p21Cip1 (ref. 10) Proliferation ↓
p16INK4 (ref. 9) Proliferation ↓
Apoptosis ↑
p19ARF (ref. 43) Proliferation ↓
Apoptosis ↑
GM-CSF (ref. 41) Proliferation ↑
KGF (ref. 32) Proliferation ↑
HB-EGF (ref. 53) Proliferation ↑
FL1 (ref. 57) Proliferation ↑
FasL (ref. 24) Apoptosis ↑
Fas (ref. 88) Apoptosis ↑
Bc13 (ref. 98) Apoptosis ↓
AP-1 in cell proliferation and transformation
Initial studies examining the function of AP-1 proteins in cell pro-
liferation and oncogenic transformation, based on tissue culture
models such as rodent and avian fibroblasts, suggested that c-Jun
and the Fos proteins positively regulate cell proliferation, whereas
JunB is thought to be a negative regulator. Recent studies, however,
support a more complicated scenario. Below, we describe some of
the experimental data implicating AP-1 proteins in growth control
and transformation and discuss the possible mechanisms that
mediate these effects.
Inhibition of fos and jun expression in mouse fibroblasts and ery-
throleukaemia cells using antisense RNA demonstrated their
requirement for proliferation and cell cycle progression24. Similarly,
microinjection of antibodies against Fos and Jun prevents serum-
stimulated quiescent mouse fibroblasts from re-entering the cell
cycle25. Interestingly, non-crossreactive antibodies against any Jun
protein, including JunB, inhibit cell cycle entry, whereas simultane-
ous inactivation of several Fos proteins is required to achieve a simi-
lar effect25, suggesting a unique and critical role for each Jun protein,
but a redundant function for the Fos proteins. Studies using fibrob-
lasts derived from fos and jun knockout mice provide partial genetic
support for these conclusions. Fibroblasts deficient in c-Fos or FosB
alone proliferate normally, and only cells lacking both proteins have
a reduced proliferative capacity26,27. Interestingly, c-fos−/−fosB−/− dou-
ble-knockout mice, but not single knockouts, are smaller than their
wild type counterparts26. A similar correlation between reduced
fibroblast proliferation and smaller cell size was made for junD−/−
mice28, or knockin mice that express a phosphorylation-defective
mutant form of c-Jun, in which the major JNK phosphorylation sites
(Ser 63 and Ser 73) were replaced by alanine (c-junAla63/73 mice)29.
The availability of Fos-deficient mice allowed a rigorous exami-
nation of the role of Fos proteins in cyclin D1 induction, thereby
providing a connection to the cell cycle machinery. AP-1 proteins
were shown to bind directly to the cyclin D1 promoter and activate
it in transient transfection experiments24. These results were con-
firmed in vivo with the demonstration that the induction of cyclin
D1 by serum is more efficient in wild type fibroblasts than in c-fos−
/−
fosB−/− double mutants26. Thus, the induction of cyclin D1 pro-
vides one route for AP-1 proteins to stimulate cell proliferation.
Among the different AP-1 deficiencies, mouse embryo fibroblasts
(MEFs) from c-jun−/− embryos have the most severe proliferation
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c-Jun JunB JunD
Up Down –
Down – –
Down – –
Down Up
– – Down
Up Down
Up Down –
Up – –
Up Up Up
Up – –
Down – –
Up – –
defects. These cells can be passed in culture only once or twice
before entering a premature senescence8,30, and even after immor-
talization, they continue to proliferate slower than wild type cells8.
JNK-mediated phosphorylation of c-Jun partially stimulates cell
proliferation, as c-junAla63/73 fibroblasts have a proliferation defect
that is less severe than that of c-jun−/− fibroblasts29. c-Jun induction
is also required for cell cycle re-entry of UV-irradiated fibrob-
lasts10. Although wild type fibroblasts undergo a transient cell cycle
arrest after exposure to UV, c-jun−/− cells undergo prolonged
growth arrest and fail to resume proliferation. By contrast, cells
that constitutively express c-Jun fail to arrest and continue to cycle
after UV exposure10. Other cell types, such as foetal hepatoblasts
derived from c-jun−/− foetuses, also display reduced proliferation31.
More importantly, liver regeneration after partial hepatecotomy is
impaired in the absence of c-Jun (Behrens et al., see note added in
proof) Collectively, these results suggest that AP-1 activity is
important for wound healing responses. Indeed, a recent study
demonstrated a reduced healing rate of skin injuries in mice whose
epidermis was rendered deficient in c-Jun (R. Johnson, personal
communication). A c-Jun deficiency in mouse fibroblasts also
results in a reduced ability to support keratinocyte proliferation in
culture32.
In common with c-fos−/−fosB−/− double knockout fibroblasts, c-
jun−/− MEFs also have reduced expression of cyclin D1 (ref. 33).
However, this deficiency does not fully account for their prolifera-
tive defect, as the defect is only partially suppressed by ectopic
expression of cyclin D1 in c-jun−/− MEFs33. By contrast, the defect is
completely suppressed through loss of the p53 tumour suppressor
protein8. Importantly, c-Jun functions as a direct repressor of p53
gene transcription, and therefore p53 is elevated in c-jun−/− fibrob-
lasts through increased p53 gene transcription8. Furthermore, c-Jun
also decreases the transcriptional activity of p53 itself, down-mod-
ulating its ability to activate the p21Cip1 gene10. p21Cip1 is a CDK
inhibitor (CDI) that is responsible for the antiproliferative activity
of p53 (refs 34,35). Correspondingly, c-jun−/− fibroblasts have lower
levels of G1 CDK activity, not because of a cyclin D1 deficiency, but
because of elevated p21Cip1 expression8. Similarly, v-Jun activates the
cyclin E–CDK complex in chicken embryo fibroblasts (CEF), with-
out inducing expression of cyclin D or E36. Hence, c-Jun can stimu-
late cell cycle progression through two mechanisms: induction of
cyclin D1 transcription and repression of p21Cip1 transcription.
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a even more effectively than wild type cells32. The effects of Jun on
FasL
Bim Apoptosis
JNK
UV c-Jun
Bcl3
Σ Survival
Fas
UV
b
Repaired Cell cycle
c-Jun p53 damage re-entry
Sustained
p21 Apoptosis
damage
G1 S G2 M interpret. Certain findings suggest that JunD is a positive regulator
Figure 2. The effects of c-Jun in apoptosis. a, A model describing the direct
effects of c-Jun on apoptosis through transcriptional regulation of pro- and anti-
apoptotic gene products. c-Jun-mediated induction of pro-apoptotic genes (sur-
rounded by the oval) enhances apoptosis, whereas upregulation of anti-apoptotic
gene products and down-regulation of pro-apoptotic gene products (surrounded by
the square) support cell survival. The sum of all signals (Σ) will determine whether
the cells undergo apoptosis or survive. b, A model describing the indirect effects of
c-Jun on apoptosis. c-Jun activation by UV results in downregulation of p21Cip1
expression to allow growth-arrested cells to proliferate. However, the actual fate of
cells exposed to UV will be determined by the extent of the UV-induced cell damage.
Expression of inducible dominant negative c-Jun in HT1080
fibrosarcoma cells demonstrated that the second mechanism is
more responsive to c-Jun. Elevated p21Cip1 expression and reduced
cell proliferation were obtained by dominant negative levels, which
were insufficient to induce an increase in cyclin D1 expression37.
The antibody microinjection experiments described above may
lead one to conclude that all Jun proteins positively regulate cell
proliferation. However, such a conclusion is inconsistent with earli-
er results demonstrating that JunB antagonizes the transforming
activity of c-Jun4,38. Recent experiments conducted in vivo support
these earlier studies and suggest that JunB is a negative regulator of
proliferation, at least in certain cell types and in the presence of c-
Jun expression. Unlike the slower proliferation of MEFs deficient in
c-Jun or JunD, junB−/− MEFs proliferate normally in culture39.
However, MEFs derived from junB transgenic mice that overexpress
junB had limited proliferative capacity40. Furthermore, after immor-
talization they continued to proliferate slower than wild type fibrob-
lasts, caused by an extended G1 transition time9. Consistent with its
ability to antagonize c-Jun, JunB represses the cyclin D1 promoter40.
In addition, JunB induces transcription of the p16INK4a gene, coding
for another CDI that inhibits Rb phosphorylation by CDKs and
thereby prevents G1 to S phase transition9. p16INK4a is highly
expressed in JunB transgenic fibroblasts and its deletion negates the
inhibitory effect of JunB9. Further support for the anti-proliferative
function of JunB was also obtained by introducing a ubiquitously
expressed JunB transgene into a junB−/− background. The JunB
transgene suppressed the embryonic lethality associated with loss of
JunB, but serendipitous extinction of the JunB transgene in myeloid
cells, which rendered them JunB deficient41, prevented the induction
of p16Ink4a expression associated with terminal differentiation of
granulocytes, resulting in the perpetual proliferation and eventual
transformation of granulocytic progenitors41. Some of the negative
proliferative effects of JunB are not cell-autonomous. Unlike
c-Jun-deficient fibroblasts, which poorly support keratinocyte pro-
liferation, junB−/− fibroblasts support keratinocyte proliferation
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review
keratinocyte proliferation are probably mediated through modula-
tion of granulocyte-macrophage colony stimulating factor (GM-
CSF) and keratinocyte growth factor (KGF) expression, with c-Jun
as a positive regulator and JunB as a negative regulator of their
genes32. These results provide an example of a physiologically rele-
vant antagonism between c-Jun and JunB.
However, new evidence supports the possibility that the differ-
ences in JunB and c-Jun function may be cell-type-specific or
depend on the relative expression levels of these proteins.
Replacement of c-jun by junB prevents most of the developmental
and cellular defects associated with a loss of c-Jun42. These results
suggest that in the absence of c-Jun, JunB may function as a posi-
tive growth regulator. However, in the presence of c-Jun, JunB has
opposite effects. It is possible that the anti-proliferative activity of
JunB requires the formation of growth inhibitory c-Jun–JunB het-
erodimers (Fig. 1).
The effects of JunD on cellular proliferation are even harder to
of cell proliferation: junD−/− MEFs have a proliferation defect which
results in premature senescence that is less severe than that
observed in c-jun−/− MEFs43. This defect correlates with increased
expression of p19ARF, a tumour suppressor gene that enhances p53
activity by sequestering Mdm2 (ref. 44). Immortalized junD−/− cells,
however, display a different phenotype, which includes increased
proliferation and higher levels of cyclin D143. As this phenotype is
reminiscent of fibroblasts in which c-Jun is constitutively
expressed8, c-Jun might be overexpressed in immortalized junD−/−
cells to compensate for the loss of JunD. The tumour suppressor
Menin interacts with JunD and inhibits its transcriptional activity,
whereas tumour-derived mutants of Menin lack this activity45.
Thus, inhibition of JunD might be involved, in some cells, in the
suppression of neoplastic growth. However, other studies have
demonstrated that JunD may partially suppress Ha-Ras-induced
transformation and that its expression decreases in Ha-Ras-trans-
formed fibroblasts46. In conclusion, the role of JunD in the control
of cell proliferation is somewhat nebulous. It is safe to conclude,
however, that JunD does not have as potent pro-proliferative func-
tion as c-Jun.
In light of their ability to regulate cell cycle progression, it is not
surprising that Jun and Fos are also involved in transformation.
Both, c-fos and c-jun are cellular homologues of retroviral onco-
genes47,48. Furthermore, AP-1 activity is induced by various tumour
promoters and activated oncoproteins1. Certain AP-1 proteins can
co-operate with activated oncogenes, such as Ha-Ras, in the trans-
formation of rodent fibroblasts4,49. Interestingly, all Jun proteins,
including JunB, can co-operate with Ha-Ras in rat embryo fibrob-
lasts (REF) transformation, although c-Jun is certainly the most
potent among them49. In addition, c-Jun is required for Ha-Ras-
induced transformation, and c-jun−/− cells are refractory to the
transforming activity of oncogenic Ras50. This oncogenic coopera-
tion may be partially dependent on the ability of c-Jun to be phos-
phorylated by JNK51.
Several genes involved in the transforming activity of Jun pro-
teins in CEF were recently identified. JAC (Jun-activated gene in
CEF) and heparin-binding epidermal growth factor-like growth
factor (HB-EGF) are c-Jun and v-Jun target-genes that are capable
of transforming CEFs52,53. However, their transforming activity is
lower than that of c-Jun52,53 and they can not induce tumorigenici-
ty when expressed individually, suggesting that several c-Jun target-
genes co-operate to exert its full transforming activity. The identity
or the transforming activity of the mammalian homologues of JAC
and HB-EGF have yet to be determined, in order to establish their
possible role in mammalian cell transformation by c-Jun. HB-EGF
is known to exert mitogenic activity on keratinocytes, hepatocytes,
smooth muscle cells and fibroblasts.
Consistent with its effects on DNA binding, c-Fos enhances the
transforming ability of c-Jun4,5 and overexpression of either protein
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transforms immortalized rodent fibroblasts in culture38,54. Fra1 is
induced in response to expression of oncogenic Ha-ras, and togeth-
er with c-Jun, generates stable AP-1 heterodimers that contribute to
Ras-mediated transformation55. c-Fos-induced transformation is
mediated, at least in part, by induction of the enzyme DNA methyl
transferase 1 (DNMT1), which may downregulate the expression of
negative growth regulators through methylation of their promoter
region56. As a c-Jun antagonist, cotransfected JunB attenuates the
ability of c-Jun to participate in REF transformation38.
Furthermore, overexpression of JunB in mouse fibroblasts reduces
transformation by v-ras or v-src9.
The fact that the c-Jun/JunB antagonism is probably context-
dependent42 is also reflected by the fact that both c-Jun and JunB
increase angiogenesis in a cell culture model of fibrosarcoma,
through activation of proliferin (FL1) gene expression. FL1, an
angiogenic factor that is primarily produced by trophoblast giant
cells, is required for the migration of uterine vascular endothelial
cells toward trophoblasts. Interestingly, FL1 expression correlates
with the stage of fibrosarcoma development, suggesting a role for c-
Jun and JunB in tumour progression57.
The importance of the dimerization partner of c-Jun for its
transformation-related activities was also addressed. It seems that
c-Jun–ATF2 heterodimers induce autocrine growth, whereas c-
Jun–c-Fos heterodimers induce anchorage-independent growth58.
However, the differentially regulated target-genes responsible for
these activities remain to be identified.
Transgenic mice expressing c-Fos develop bone lesions as early
as 4 weeks after birth, and after 9–10 months these eventually
progress into bone tumours in 15% of animals59,60. Deletion of c-fos
from mice expressing a v-ras transgene inhibits the development of
fully malignant skin tumours in response to treatment with phor-
bol ester tumour promoters61. Similar inhibition of malignant
transformation is observed in mice expressing a dominant negative
c-jun transgene62. Thus, c-Fos and c-Jun are required for two-stage
skin carcinogenesis. However, transgenic overexpression of c-Jun in
the absence of additional oncogenic stimulation does not increase
tumour incidence63.
Skin carcinogenesis may require JNK-mediated phosphoryla-
tion of c-Jun, because the incidence of skin tumours induced by a
transgene coding for an activated form of the Ras exchange factor
SOS, is reduced in a c-junAla63/73 background51. A recent study sug-
gested that Ras-induced c-Jun phosphorylation synergizes with the
prolyl isomerase Pin1 to augment the induction of cyclin D1 by c-
Jun in breast cancer64. In conclusion, a persistent alteration in AP-1
activity can result in enhanced oncogenic transformation through
deregulated expression of positive and negative growth regulators,
such as cyclin D1, and a number of autocrine growth factors.
AP-1 proteins as regulators of cell death and survival
Apoptosis suppresses oncogenic transformation, and controls
organogenesis and immune responses. AP-1 transcription factors
are involved in both the induction and prevention of apoptosis,
and the exact outcome is highly tissue- and developmental-
stage-specific. The first indication for such an apoptotic function
for AP-1 came from observations linking the induction of c-Fos
and c-Jun to conditions that result in cell death. c-Fos, for
instance, is persistently induced in the brains of mice treated with
kainic acid, a potent activator of glutamate receptors that induces
apoptosis of hippocampal neurons65. c-Fos induction is also
observed during tissue remodelling, such as mammary gland invo-
lution66 or castration-induced prostate gland regression67. The
induction of apoptosis in neuronal and lymphoid cell cultures
through withdrawal of growth factors is preceded by the induction
of AP-1 proteins68–70. Another setting in which robust c-Jun induc-
tion precedes the onset of apoptosis is the exposure of cells to
genotoxic stress, such as alkylating agents (for example, MMS) or
short-wavelength UV radiation10,19,71.
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Such observations, however, do not demonstrate whether Jun or
Fos induction is functionally involved in triggering apoptosis.
Some direct evidence for pro-apoptotic functions was derived from
transient overexpression experiments, in which c-Jun or c-Fos were
found to induce apoptosis in various cell lines69,72,73. However, as the
expression levels achieved in such experiments are unusually high,
and could therefore result in non-specific effects, such results may
have no bearing on the physiological function of the overexpressed
protein. A more relevant way to study the function of AP-1 in apop-
tosis is to examine the sensitivity of animals and cells lacking AP-1
expression or activity to different pro-apoptotic stimuli and geno-
toxins. Antisense oligonucleotides directed against c-fos and c-jun
mRNAs were found to increase the survival of growth-factor-
deprived lymphoid cells70. Similarly, inhibition of c-Jun activity
through the expression of a dominant negative c-Jun mutant or
injection of neutralizing antibodies, can protect neuronal cells from
apoptosis induced by withdrawal of nerve growth factor (NGF) or
chronic depolarization68,69,74–76. In addition, light-induced apoptosis
of retinal photoreceptors is impaired in c-Fos-deficient mice77. The
anti-apoptotic activity of dominant negative c-Jun depends, at least
partially, on its ability to induce the expression of Bim78, a pro-
apoptotic Bcl-2 family member that is critical for neuronal apopto-
sis. It is not clear, however, whether Bim transcription is directly
regulated by c-Jun. A more established AP-1 target is the gene
encoding Fas-ligand (FasL), whose product can promote apopto-
sis24. c-Jun-dependent FasL induction was demonstrated in several
experimental systems. However, it should be noted that the regula-
tion of FasL transcription is complex and may only be promoted by
c-Jun under certain conditions.
JNK-mediated phosphorylation is important for c-Jun-induced
apoptosis in neuronal cells. Expression of c-Jun that has been
mutated in the JNK phospho-acceptor sites, c-JunAla63/73, can block
apoptosis induced by NGF withdrawal74. Most importantly, c-
junAla63/73 mice are resistant to kainic acid-induced cytotoxicity29.
Furthermore, targeting of JNK3, a JNK isoform specifically
expressed in neuronal cells, reduced both AP-1 activation and
kainate-induced apoptosis79. In addition, inhibition of JNK activity
by the products of two NF-κB target-genes, Gadd45β and X-chro-
mosome-linked inhibitor of apoptosis (XIAP), provides partial
protection from tumour necrosis factor (TNF)-α -induced apopto-
sis80,81. However, it should be mentioned that there are many phys-
iological and pathological conditions that result in JNK activation
and c-Jun N-terminal phosphorylation in neuronal cells, but do
not cause apoptosis82–84.
The exact function of AP-1 in cellular responses to genotoxic
stress has not been entirely resolved. Several studies suggest that c-
Jun is involved in the induction of UV-induced apoptosis. c-Jun-
deficient fibroblasts and jnk1−/−jnk2−/− double knockout MEFs are less
sensitive to UV-induced apoptosis10,85. Similarly, c-jun−/− fibroblasts
are resistant to the apoptotic effects of alkylating agents, which may
be mediated by the induction of FasL86. In addition, dominant nega-
tive c-Jun reduces apoptosis in human monoblastic leukaemia cells
exposed to a variety of genotoxins87. However, other studies suggest
that c-Jun protects cells against UV-induced cell death33,88. This pro-
tective activity may be mediated through co-operation with STAT3
to suppress transcription of Fas88. However, the cells used in this
study are likely to be p53-deficient, as they are derived from tumours.
Because p53 is a regulator of Fas expression89, and is required for c-
Jun-induced apoptosis after exposure to UV10, it is expected to have
an important effect on the link between c-Jun, Fas and apoptosis.
The involvement of p53 in UV-induced apoptosis of cells expressing
normal levels of c-Jun is nebulous. Although known as a potent pro-
apoptotic factor, p53 elicits protective effects on mouse fibroblasts
exposed to UV, possibly by participating in nucleotide excision repair
(NER) and arresting cell proliferation until DNA is sufficiently
repaired90,91. The relative resistance of senescent keratinocytes to UV-
induced apoptosis supports the notion that replication is required
for the induction of apoptosis in UV-exposed cells92.
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A clearer example of anti-apoptotic activity of c-Jun is provided
by hepatocytes derived from c-jun−/− embryos, which undergo mas-
sive apoptosis31,93. Surprisingly, a junB transgene can prevent liver
degeneration in c-jun−/− embryos42. The brains of jnk1−/−jnk2−/− dou-
ble knockout embryos have an abnormal morphology caused by
disregulated apoptosis, which is decreased in some areas of the
brain and increased in others94. Increased spontaneous apoptosis is
exhibited by the same c-jun−/− fibroblasts that are resistant to UV-
induced apoptosis10. Furthermore, re-introduction of c-Jun reduces
this spontaneous apoptosis but simultaneously enhances UV-
induced apoptosis10. Some in vitro studies suggests that JNK is not
required for TNF-induced apoptosis95 and even inhibits both TNF-
96
and Fas-induced97 apoptosis. Some of the protective effects of AP-
1 might be mediated through induction of Bcl-3, whose product
functions as a survival factor for growth-factor-deprived T cells98.
Two models can explain the diverse effects of AP-1 on cell death
and survival. The first model (Fig. 2a) suggests that the induction of
AP-1 results in activation of various genes, such as FasL, Bim, or Bcl3,
whose products are either positive or negative regulators of apoptosis.
It is the balance between the pro-apoptotic and anti-apoptotic target-
genes that determines whether the final outcome will be cell survival
or cell death. This balance may vary from one cell type to another, and
may be dependent on the type and duration of stimulus used to acti-
vate AP-1, as well as on the activation of other transcription factors.
According to the second model (Fig. 2b), AP-1 functions as a homeo-
static regulator that keeps cells in a certain proliferative steady state.
Changes in environmental conditions may enhance AP-1 activity.
Robust or persistent activation of AP-1 in cells containing damaged
DNA causes defective replication and may trigger apoptosis through
the same mechanisms that induce cell death after constitutive expres-
sion of oncogenes. However, the activation of AP-1 in cells that are
able to proliferate promotes cell proliferation and survival.
Future prospects
In the last few years, the progress in our understanding of the phys-
iological and pathological activities of AP-1 transcription factors
was highly dependent on the use of genetically altered mouse
strains and cell cultures derived from them. The results obtained
from these experiments have shed light on a few key questions
regarding AP-1 activity and provide some explanations of its role in
cell proliferation. However, other major questions regarding the
activity of individual AP-1 proteins and their specificity remain
unanswered. For example, the ability of c-Jun and JunB to elicit
opposite transcriptional responses in the presence of apparently
similar AP-1 recognition sites found in the control regions of dif-
ferent genes remains enigmatic, as is the ability of JunD to posi-
tively regulate the proliferation of MEFs while negatively regulating
proliferation in immortalized fibroblasts. Furthermore, the molec-
ular mechanisms that underlie the ability of c-Jun and other AP-1
proteins to repress gene transcription have yet to be identified.
Most importantly, an understanding of the network of dynamic
interactions between AP-1 proteins and other transcription factors
is far from complete. It is expected, however, that the generation of
additional mouse mutations, in which the coding regions of one
AP-1 protein are replaced with those of another, together with new
technological advances that should facilitate the identification of a
large number of AP-1 target-genes, should eventually provide us
with answers to many of these questions. Such an analysis should
also be facilitated by the availability of specific pharmacological
inhibitors of the many signalling pathways that modulate the
expression and activity of AP-1 proteins.
Note added in proof: the article by Behrens et al. has subsequently
been published (Behrens, A. et al. Impaired postnatal hepatocyte pro-
liferation and liver regeneration in mice lacking c-Jun in the liver.
EMBO J. 21, 1782–1790 (2002).
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