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Molecular and Cellular Biology, January 2000, p. 575-582, Vol. 20, No. 2
Division of Signal Transduction and Growth
Control1 and Division of Pediatric
Oncology,2 Deutsches Krebsforschungszentrum,
D-69120 Heidelberg, Germany, and Research Institute of
Molecular Pathology (IMP), A-1030 Vienna, Austria3
Received 18 June 1999/Returned for modification 9 August
1999/Accepted 20 October 1999
Mouse 3T3 fibroblasts derived from fetuses lacking c-Jun were used
to define an essential role of c-Jun, a main component of the
transcription factor AP-1, in the cellular response to the alkylating
agent methyl methanesulfonate (MMS). MMS represents the most potent and
selective activator of the stress-induced kinases JNK/SAPK and p38,
resulting in very efficient induction of c-Jun hyperphosphorylation and
c-jun transcription. This agent induced apoptosis
with high efficiency in wild-type cells but not in
c-jun Mammalian cells are exposed to many
environmental cues, including chemical carcinogens, tumor promoters,
and radiation, that commonly induce damage to DNA. Cells respond to
these agents by activating DNA repair enzymes and other protection
functions or by inducing the apoptotic program (for reviews,
see references 16 and 28). A
critical role of the transcription factor AP-1 in the induction of the
genetic programs regulating cell survival and apoptosis was
suggested. For example, transcription of the members of the
jun, fos, and ATF gene families, encoding AP-1 subunits, is highly induced in response to UV irradiation and alkylating agents. The enhanced de novo synthesis and the activation of
preexisting and newly synthesized proteins by phosphorylation are
required for the subsequent induction of the two main types of AP-1
target genes: those regulated by the c-Fos-c-Jun-specific 7-bp
consensus AP-1 sequence 5'-TGAGTCA-3', as found in the
collagenase and stromelysin genes (1, 2), and genes such as
c-jun, harboring the c-Jun-ATF-2-specific 8-bp motive
sequence 5'-TTACCTCA-3' in the promoter (3, 9, 22, 31,
49). However, neither the type of AP-1 target genes nor the
specific function of individual members of the Jun, Fos, and ATF
families in apoptosis and cell survival has been identified conclusively.
The best evidence for a specific function of AP-1 subunits in the
mammalian response to DNA-damaging agents was provided by fibroblasts
lacking c-fos. These cells exhibited an increased rate of
apoptosis and, in consequence, reduced cell survival upon UV
irradiation (44). Thus, c-Fos-regulated genes play a role in
protecting cells from the cytotoxic effects of UV irradiation. On the
other hand, the lack of c-Fos results in the loss of light-induced apoptosis of photoreceptors in retinal degeneration
(21), demonstrating proapoptotic and
antiapoptotic functions of c-Fos, depending on the cell
type and extracellular stimuli. Inhibition of c-Jun either by a
dominant negative mutant or by a neutralizing antibody led to reduced
apoptosis upon nerve growth factor withdrawal in rat sympathetic neurons. Similarly, interference with Jun activity reduced
apoptosis in human monoblastic leukemia cells upon induction of
stress, indicating that c-Jun is required for programmed cell death
(15, 23, 52). Correspondingly, ectopic expression of c-Jun
in 3T3 fibroblasts increased apoptosis (10). The
proposed role of c-Jun as a mediator of apoptosis is further
supported by recent data describing the regulation and function of
components of the mitogen-activated protein kinase (MAPK) cascades
regulating AP-1 activity. Two types of MAPKs, JNK/SAPKs and p38, as
well as common upstream kinases, including MEKK, are activated by
genotoxic agents, such as UV and the alkylating agent methyl
methanesulfonate (MMS), to phosphorylate and thereby activate
transcription factors, including c-Jun and ATF-2 (reviewed in
references 30 and 40). Persistent
activation of JNK/SAPKs has been shown to induce apoptosis (11). Persistent activation of JNK/SAPKs by dominant active MEKK-1 resulted in hyperphosphorylation and activation of c-Jun and
increased apoptosis in PC12 cells (37). Vice versa,
inhibition of JNK/SAPK activity by a transdominant negative mutant
conferred resistance to apoptosis induced by various genotoxic
agents (57). In mice lacking the neuron-specific JNK
isoform, JNK3, stimulation of the glutamate receptors does not result
in excitotoxicity and apoptosis of hippocampal neurons
(56). In line with these data, neuronal apoptosis
induced by the excitatory amino acid kainate is absent in mice
expressing a c-Jun mutant protein which contains amino acid
substitutions at the critical JNK phosphorylation sites (8).
Despite these different lines of evidence suggesting an important role
of AP-1 proteins in cell death, however, a direct link between AP-1
activity and the induction of specific initiators or executors of
apoptosis has not yet been identified by functional means.
Induction of apoptosis may be initiated by activation of the
cell surface receptor CD95 through binding of its ligand, CD95-L. The
subsequent cross-linking of CD95 results in the binding of adapter
molecules, such as FADD and caspase 8, to the intracellular death
domain, leading to the activation of the death-signalling cascade
(5, 20, 34, 41, 46). Interestingly, transient transfection
analyses with human T-lymphocytes showed that the induction of CD95-L
by DNA-damaging agents depends on AP-1 and NF- To elucidate the specific function of c-Jun and c-Jun-regulated target
genes in apoptosis in response to genotoxic agents, we used
immortalized 3T3 fibroblast cell lines with a targeted disruption of
the c-jun gene (45). We analyzed the cellular response to the monofunctional alkylating agent MMS because it represents one of the most potent activators of c-jun
transcription and c-Jun or ATF-2 hyperphosphorylation (38,
50) and the most selective inducer of the stress-induced
signalling pathways involving JNK/SAPK and p38 (38, 50, 54).
We found that c-Jun-deficient cells, in contrast to wild-type cells,
failed to induce the apoptotic program upon MMS treatment. Lack
of apoptosis was accompanied by a strongly reduced induction of
AP-1 target genes, including the CD95-L gene. Apoptosis sensitivity in
mutant cells could be restored upon the addition of recombinant CD95-L,
demonstrating that c-Jun is not required for the expression and
activity of downstream components of the CD95 death-signalling cascade.
Reduction of MMS-induced apoptosis by dominant negative FADD or
by neutralizing CD95-L antibodies further underlined the critical role
of c-Jun-dependent CD95-L expression and CD95 signalling in the
induction of apoptosis by genotoxic agents.
Cell culture.
Wild-type and
c-jun RNA isolation, Northern blot analysis, and Southern blot
analysis.
Total RNA was prepared as described by Chomczynski and
Sacchi (13). Northern blot and Southern blot analyses
were performed as previously described (44). For the
amplification of CD95-L and Analysis of apoptosis and flow cytometry.
Cells were
incubated with various doses of MMS. To measure DNA content
(apoptotic nuclei), cells were harvested, washed with phosphate-buffered saline, and lysed in a hypotonic buffer containing 0.1% sodium citrate, 0.1% Triton X-100, and 50 µg of propidium iodide per ml. The fluorescence intensity of propidium iodide-stained nuclei was determined by flow cytometry (FACScan; Becton Dickinson, Heidelberg, Germany) with Cell Quest software. Segmented
apoptotic nuclei were recognized by subdiploid DNA content.
Early apoptotic changes were identified by staining of cells
with fluorescein thiocyanate-conjugated annexin V (Bender, Vienna,
Austria) and analysis by flow cytometry as described previously
(25).
0270-7306/0/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
c-Jun-Dependent CD95-L Expression Is a
Rate-Limiting Step in the Induction of Apoptosis by Alkylating
Agents
ABSTRACT
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
/ cells. Resistance to
apoptosis was accompanied by impaired expression of CD95 ligand
(CD95-L), a well-known inducer of apoptosis. The addition of
recombinant CD95-L restored apoptosis sensitivity in
c-jun/ fibroblasts. MMS-induced
apoptosis in wild-type fibroblasts or human lymphocytes was
strongly reduced by neutralizing CD95-L antibodies or transdominant
negative FADD, confirming the importance of CD95 signalling in
MMS-induced apoptosis. The loss-of-function approach in
fibroblasts allowed the identification and dissection of
c-Jun-dependent and -independent processes upstream or downstream of
CD95 activation. We have found that c-Jun can act as a
proapoptotic regulator in cells exposed to DNA damage via
induction of CD95-L. Once activated, CD95-induced death signalling is
not affected by the loss of c-Jun, demonstrating that only the
initiation and not the execution of stress-induced apoptosis
depends on c-Jun.
INTRODUCTION
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
B activities
(33). Moreover, a c-Jun-ATF-2-like binding site which
mediates transcriptional activation of CD95-L and apoptosis in
lymphocytes upon overexpression of MEKK1 was defined in the CD95-L
promoter (17).
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
/ 3T3 fibroblasts were cultured in
Dulbecco's modified Eagle's medium containing 10% fetal calf serum.
The following human cell lines (described in reference
26) were used: JURKAT (acute human T-cell leukemia);
JAPO, a JURKAT subclone resistant to antibody to APO-1 (
-APO-1);
BJAB (human B lymphoma); and BJAB-FADD-DN (human B lymphoma transfected
with pcDNA3-FADD-DN). These cell lines were cultured in RPMI medium
containing 10% fetal calf serum, 100 U of penicillin per ml, 100 µg
of streptomycin per ml, 25 mM HEPES, and 2 mM L-glutamine.
-tubulin, the following primers were
used: CD95-L, 5'-CAGCAGTGCCACTTCATCTTGG-3' and
5'-TTCACTCCAGAGATCAGAGCGG-3' (amplified fragment, 550 bp); and -tubulin, 5'-TCACTGTGCCTGAACTTACC-3' and
5'-GGAACATAGCCGTAAACTGC-3' (amplified fragment, 317 bp).
Stimulation of cells.
Recombinant CD95-L was derived from
supernatants of stably transfected 293 cells (27).
Neutralizing CD95-L monoclonal antibodies MFL3 and NOK-1 were purchased
from Pharmingen. Antibody -APO-1 was prepared as previously
described (14).
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RESULTS |
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Reduced expression of AP-1 target genes in fibroblasts lacking
c-Jun.
The interstitial collagenase (collagenase-3) gene and
c-jun represent the most extensively analyzed AP-1
target genes used to measure changes in Jun- Fos- and
Jun-ATF-dependent gene expression, respectively, in response
to phorbol esters and genotoxic agents (1, 2, 9, 29, 31, 44,
49). To confirm the requirement of c-Jun in AP-1-dependent gene
expression, we compared the mRNA levels of both genes in immortalized
3T3 fibroblasts derived from wild-type mouse embryos and embryos
lacking c-Jun (45) in response to well-known inducers of
AP-1 activity, such as the phorbol ester tetradecanoyl phorbol
acetate (TPA), UV, and MMS. In c-jun/
cells, part of the coding sequence of c-jun is replaced by
the neomycin resistance gene, yielding a c-jun-neo fusion
transcript whose expression is controlled by the intact
c-jun promoter (45 and references
therein). Since previous studies have shown that maximal induction of
c-jun is reached after 45 min (for TPA and UV) (3,
47) or 2 h (for MMS) (54), RNA was prepared at these times. In addition, RNA was prepared 6 h posttreatment, representing the time point of maximal induction of collagenase (1, 19, 42). As shown in Fig.
1, the induction of c-jun and
the collagenase gene was very efficient in wild-type cells. Importantly, the absence of c-Jun resulted in a decrease in basal-level expression and a strong reduction or complete loss of induction of the
c-jun and collagenase genes, respectively (Fig. 1).
Induction of the stromelysin-1 gene, representing another
c-Jun-c-Fos-regulated target gene (29, 44), was observed in
wild-type but not mutant cells (data not shown). These data demonstrate
that the induction of both classes of c-Jun target genes regulated by
either c-Jun-c-Fos or c-Jun-ATF-2 heterodimeric complexes is greatly
impaired in c-Jun-deficient cells. Residual induction of the
c-jun promoter in mutant cells might be explained by the
ability of ATF-2 (or ATFa) homodimers to bind to the c-jun
promoter and functionally compensate, at least in part, for c-Jun-ATF
heterodimers (50).
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Reduced apoptosis of c-jun/
fibroblasts after treatment with MMS.
Previously, we have observed
reduced AP-1 DNA binding and transactivation of AP-1 target genes in
fibroblasts lacking c-Fos, leading to increased cell death, in response
to UV irradiation (44). To analyze the consequences of
defects in c-Jun-dependent gene expression for the cellular response to
genotoxic agents, we compared the rate of MMS-induced apoptosis
in wild-type and c-jun/ fibroblasts.
/ cells did not exhibit a
significant increase in apoptosis at 24 h (4%) and
48 h (3%), even at 300 µM MMS (Fig. 2A). Also, at 72 h
following MMS treatment, wild-type cells showed a much higher rate of
apoptosis than c-Jun-deficient cells (data not shown). To
confirm these differences in apoptosis by an independent assay, we measured staining of phosphatidylserine exposed on the outer cell
membrane by flow cytometry. In agreement with the data obtained by
propidium iodide incorporation, annexin V staining showed that at 24, 48 and 72 h following MMS treatment, only wild-type and not mutant
cells exhibited a higher percentage of apoptosis (Fig. 2B). To
rule out the possibility that the reduced rate of proliferation of
c-jun/ cells (45) is responsible
for the reduced rate of apoptosis, we measured
apoptosis 6 days after MMS treatment by propidium iodine
staining. At this late time point, apoptosis in
c-jun/ cells was still below the rate of
apoptosis in wild-type cells measured at any time point after
MMS treatment (data not shown). These data demonstrate that c-Jun is
required for the efficient induction of apoptosis in response
to the alkylating agent MMS.
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) and c-jun
) cells 24, 48, or 72 h posttreatment was measured by annexin V staining and
flow cytometry. Specific apoptosis was calculated as described
previously (Efficient induction of CD95-L expression by MMS in wild-type but
not in c-jun/ cells.
Recently, in
lymphoid cells, the induction of a master regulator of
apoptosis, CD95-L, by DNA-damaging agents was found to depend on the presence of both NF-B- and AP-1-binding sites in the
CD95-L promoter (33). Having found defects in the induction of known AP-1-target genes in c-jun/ cells
(Fig. 1), we compared the expression of CD95-L in wild-type and mutant
cells in response to MMS. For wild-type fibroblasts, we observed a
strong increase in CD95-L expression upon MMS treatment (Fig.
3A) which resembled the
kinetics of induction of collagenase and stromelysin, reaching maximal
levels at 6 h and returning to basal levels or below at 22 h
poststimulation (Fig. 3A and data not shown). In contrast, basal-level
expression of CD95-L in c-jun/ cells was
reduced, and induction by MMS was almost completely absent (Fig. 3A).
Only at late time points after MMS treatment was a small increase
observed. However, the level of CD95-L transcripts in MMS-treated
mutant cells was still below the basal level seen in untreated
wild-type cells (Fig. 3A). In contrast to those of CD95-L, the levels
of expression of its receptor, CD95, were similar in wild-type and
mutant cells (Fig. 3B). These data identify the CD95-L gene as a novel
c-Jun-regulated target gene and open the possibility that the loss of
induction of this gene is responsible for the defects in MMS-induced
apoptosis in c-jun/ cells.
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) or a CD95-specific
antibody (Jo2) (CD95) followed by flow cytometry. (C) Wild-type cells
were treated with supernatant from 293 cells containing recombinant
CD95-L protein in the presence or absence of a neutralizing CD95-L
antibody (NOK-1) (see also Fig. Addition of exogenous CD95-L restores the apoptotic program
in cells lacking c-Jun.
To analyze whether c-Jun-dependent
expression of CD95-L might be a rate-limiting step in MMS-induced
apoptosis that is missing in c-jun/
cells, we examined the rate of apoptosis upon the addition of recombinant CD95-L protein. As shown in Fig. 3C for wild-type fibroblasts, apoptosis was very efficiently induced by
recombinant CD95-L. The apoptotic effect of CD95-L could be
reversed by the addition of neutralizing CD95-L antibodies, which
prevent the binding of the ligand to its receptor (Fig. 3C),
demonstrating the specificity of the recombinant protein. Importantly,
in wild-type and c-jun/ cells, the rate of
apoptosis was greatly increased with similar efficiencies after
the addition of CD95-L (Fig. 3D). These results imply that the
expression or activity of cellular components acting downstream of
activated CD95 is not significantly affected by the lack of c-Jun
expression. The induction of apoptosis in both wild-type and
mutant cells was also observed through agonistic antibody (Jo2) binding
to CD95 (data not shown). Interestingly, neither in wild-type nor in
mutant cells was CD95-induced apoptosis significantly amplified
in the presence of MMS (Fig. 3D), suggesting that CD95 signalling is
the major pathway which mediates MMS-induced apoptosis.
MMS-induced apoptosis can be inhibited by blocking of the
CD95 signalling pathway.
The strong induction of CD95-L by MMS in
wild-type cells and the ability of recombinant CD95-L to induce
apoptosis in c-jun/ cells suggest an
important role of this protein in MMS-induced apoptosis. To
confirm this assumption, we measured the efficiency of MMS-induced
apoptosis in the presence of neutralizing anti-human or
anti-mouse CD95-L-specific antibodies. MMS treatment (200 or 400 µM)
resulted in increased apoptosis in wild-type but not in mutant
cells which was easily detectable by changes in cell morphology (Fig.
4A) or differences in annexin V staining
(Fig. 4B). In wild-type cells, the MMS-induced apoptosis was
strongly reduced by neutralizing CD95-L antibodies (Fig. 4). In
line with the lack of CD95-L expression and induction of
apoptosis in c-jun/ cells, neither
untreated nor MMS-treated mutant cells were significantly affected by
neutralizing CD95-L antibodies (Fig. 4).
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-APO-1) or, to a
lesser extent, by MMS (Fig. 5). A
subclone of JURKAT cells that is resistant to apoptosis induced
by -APO-1 exhibited a decrease in the rate of apoptosis in
response to MMS (Fig. 5). Residual apoptosis in these cells may
be explained by MMS-dependent induction of other death-inducing
ligands, such as tumor necrosis factor alpha (TNF-) and
TNF-related apoptosis-inducing ligand (TRAIL; for reviews, see
references 5, 34, and 41), or
triggering of death receptor-independent pathways.
Correspondingly, BJAB cells stably expressing transdominant negative
FADD (12), which blocks CD95-induced death signalling (Fig.
5), exhibited an almost complete block of MMS-induced apoptosis
(Fig. 5).
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) or a CD95-specific
agonistic antibody (
). Apoptosis was measured
by annexin V staining and flow cytometry 48 h following treatment.
The numbers are averages of three experiments, each performed in
duplicate. Error bars show standard deviations. / fibroblasts very likely is
responsible for the failure of these cells to undergo apoptosis.
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DISCUSSION |
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Abstract
Introduction
Materials and Methods
Results
Discussion
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AP-1 has been suggested to play an essential role in the cellular responses to genotoxic agents. This role includes the regulation of genetic programs associated with protection and survival functions and the induction of apoptosis. Here we have genetically defined the function of a specific subunit of AP-1, c-Jun, in apoptosis induced by alkylating agents, such as MMS. This class of genotoxic agents represents the most potent inducer of c-jun expression and the transactivation function of c-Jun protein (38, 50, 54). Fibroblasts with a targeted null mutation in c-jun exhibit a defect in MMS-induced apoptosis. We provide different lines of evidence that this phenotype is due to reduced expression of a major initiator of apoptosis, CD95-L, whereas events downstream of CD95 signalling function in a c-Jun-independent manner.
First, the expression of the CD95-L gene is highly induced by MMS in
wild-type fibroblasts but is almost completely abolished in
c-Jun-deficient cells, identifying the CD95-L gene as a novel c-Jun
target gene. This conclusion is in line with previous findings showing
strongly reduced CD95-L induction in cells expressing a c-Jun mutant
protein which lacks the critical JNK/SAPK phosphorylation sites in its
transactivation domain (8) and a reduction of apoptosis and CD95-L expression in PC12 cells upon
overexpression of a c-Jun mutant lacking the JNK/SAPK phosphorylation
sites (37). Second, the addition of recombinant CD95-L
induced apoptosis with a high efficiency in both wild-type and
mutant fibroblasts. Upon binding, trimerization of the receptor, CD95,
is induced, leading to the recruitment of adaptor molecules, such as
FADD and procaspase molecules. In turn, a cascade of downstream
caspases is induced, leading to degradation of chromosomal DNA and cell
death (for reviews, see references 20, 34, and
41). Obviously, c-Jun is not absolutely required for
the expression and activity of these cellular components located
downstream of CD95, because we were able to restore CD95-L-induced
apoptosis in mutant cells. In agreement with our
findings, in JURKAT T cells the overexpression of a dominant
negative c-Jun mutant which blocked nonselectively total AP-1 activity
interfered with AP-1-dependent gene expression but not with
CD95-induced apoptosis (36). Induction of the
apoptotic program by recombinant CD95-L demonstrates that the
lack of apoptosis in the mutant cells cannot be explained by a
constitutive upregulation of antiapoptotic genes. We have
found the activity of the transcription factor NF-B, which has been
described to induce the expression of survival genes, depending on the
cell type and treatment (7, 39, 48, 53), even to be slightly
reduced in c-jun/ cells. Moreover, we did
not detect major differences in the expression of members of the Bcl-2
family in wild-type and c-jun/ cells
(unpublished data).
In the presence of neutralizing CD95-L antibodies, MMS-induced
apoptosis is not completely blocked. At present, we cannot exclude the possibility that the activation of other death-inducing ligands, such as TRAIL and TNF-, also contributes to MMS-induced apoptosis. However, when we measured the expression of these
ligands, only very low levels of TRAIL were found in both wild-type and mutant fibroblasts, and these were not further increased upon MMS
treatment. Moreover, neither in wild-type nor in
c-jun/ fibroblasts was the induction of
apoptosis by recombinant TRAIL observed. The amount of TNF-
expressed in wild-type and c-jun/ cells was
below the level of detection, even after MMS treatment (unpublished
data). These data, together with the previous finding that TNF-
treatment of embryonic fibroblasts does not induce apoptosis
(55), strongly suggest that neither TNF- nor TRAIL contributes to MMS-induced apoptosis in fibroblasts. In
contrast, in T (JURKAT) and B (BJAB) cell lines,
apoptosis can be efficiently induced by activation with
TNF-, TRAIL, and CD95-L (26). We found these cells
also highly susceptible to MMS-induced
apoptosis. Whether or not c-Jun is required for
apoptosis in these cells remains to be determined.
Nevertheless, the reduction of MMS-induced apoptosis in cells
expressing a dominant negative mutant of FADD further underlines the
critical role of death receptor-induced signalling in alkylating
agent-induced apoptosis, a role which is not restricted to
fibroblasts but can be extended to lymphoid cells and most likely other
cell types.
What are the mechanisms of MMS-induced expression of CD95-L? Alkylating agents, such as MMS, are very efficient inducers of the JNK/SAPK and p38 pathways in many cells, including fibroblasts and JURKAT cells, but do not affect the growth factor-induced Ras-Raf-MAPKK-MAPK pathway (50, 54; D. Wilhelm, A. Dieckmann, and P. Angel, unpublished data). In the presence of an inhibitor of p38, MMS-induced expression of c-jun is significantly reduced and correlates with a reduced rate of apoptosis (I. Herr, D. Wilhelm, and P. Angel, unpublished data). These data strongly suggest that both JNK/SAPK and p38 MAPKs are required for the full activation of MMS-induced c-jun transcription and c-Jun-dependent CD95-L expression. In fact, numerous reports describe a correlation among JNK/SAPK activation, CD95-L expression, and the induction of apoptosis (8, 18, 24, 33, 35, 56; for a review, see reference 6).
Most likely, the critical transcription factors serving as a substrate
of JNK/SAPKs and p38 to regulate c-jun and CD95-L gene expression are c-Jun and ATF-2. These proteins are most efficiently phosphorylated and, in turn, activated by alkylating agents, and c-Jun-ATF-2 heterodimers have been identified as binding to and activating the c-jun promoter (50). They also
bind to the CD95-L promoter to mediate the induction of CD95-L and
apoptosis in response to MEKK-1 overexpression (17,
18). On the other hand, in the human CD95-L promoter, NF-B and
Jun-Fos recognition sequences have been defined as being required for
induction by genotoxic agents (33). However, in contrast to
c-jun, c-fos was only weakly induced by
alkylating agents (unpublished data). Treatment of cells with
activators of protein kinase C, such as the phorbol ester TPA, which
hardly activate JNK/SAPK and p38 kinase activities (54) and
which induce neither CD95-L expression nor apoptosis in wild-type or c-jun/
fibroblasts (A. Kolbus, I. Herr, and P. Angel, unpublished
data) are very efficient inducers of c-fos expression
(4). These data strongly suggest that c-Jun-ATF-2 rather
than c-Jun-Fos is responsible for JNK/SAPK- and p38-mediated
transcriptional activation of c-jun and, subsequently,
CD95-L in response to alkylating agents.
While JNK/SAPKs and p38 are required for the induction of CD95-L,
consensus has not been reached for the requirement of JNK/SAPK (and
p38) activation downstream of activated death receptors. Depending on
the cell type and death-inducing ligand, data either supporting a
function of JNK/SAPKs in apoptosis or describing a lack of
correlation between JNK activation and cell death have been obtained.
In some cases, JNK activation even interfered with apoptosis
(for a review, see reference 6 and references
therein). When we measured JNK/SAPK activity in wild-type and
c-jun/ cells, no induction was detectable in
response to recombinant CD95-L (unpublished data). Treatment of
wild-type and mutant cells with MMS induced a characteristic transient
activation of kinase activity that was seen in other cell types
(50) and that returned to basal levels after 6 h. No
additional increase in JNK activity was observed at later time points,
when CD95-L induction reached maximal levels and apoptosis
became detectable (unpublished data). These data represent another line
of evidence that JNK/SAPKs activation is required for the initial phase
of the apoptotic program in response to alkylating agents,
transcriptional activation of CD95-L, but is not absolutely required
for the cellular events downstream of activated CD95 leading to cell
death. In agreement with this concept, in thymocytes from JNK2 knockout
mice, apoptosis induced by an agonistic CD95 antibody is not
affected (43).
In addition to MMS, we also observed an almost complete loss of CD95-L
induction in response to UV irradiation, as measured by reverse
transcription-PCR and Western blot analyses. Accordingly, the rate of
apoptosis is reduced in c-jun/
fibroblasts, as determined by measurement of lactate
dehydrogenase release, sub-G1 DNA content, and
annexin V staining (unpublished data). These data are in
agreement with the reduction of UV-induced apoptosis in
fibroblasts expressing a c-Jun mutant which lacks the critical JNK/SAPK
phosphorylation sites (8). Interestingly, others have
observed even enhanced rates of UV-induced apoptosis in primary
fibroblasts from c-Jun-deficient mouse embryos (55), suggesting that c-Jun, like c-Fos (21, 44), can exhibit
either proapoptotic or antiapoptotic
activities, depending on the cell type and intracellular and
extracellular conditions.
Most recently, c-Jun-deficient fibroblasts have been used to establish a critical role of c-Jun in the regulation of cell proliferation (32, 45, 55). Obviously, c-Jun represents an intersection of multiple pathways which regulate cell proliferation and apoptosis, two apparently opposing phenotypes. Some of the specificity of c-Jun function is presumably based on the choice of the heterodimeric partner, dictating sequence specificity and, in turn, the subset of AP-1 target genes to be addressed. Reintroduction of c-Jun mutants that select and sequester a preferred partner subunit (51) may help to identify subgroups of c-Jun target genes involved in either cell growth and/or apoptosis. A shift in the equilibrium of the expression of such distinct classes of c-Jun target genes, in conjunction with alterations in c-Jun-independent pathways, will contribute to the decision of the cell to proliferate, to activate survival factors, or to induce the genetic program of cell death in response to extracellular signals, including genotoxic agents.
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ACKNOWLEDGMENTS |
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We thank Jan-Paul Medema, Christian Behrens, and Klaus Hexel for help with cytometry; Melanie Sator-Schmidt and Sibylle Teurich for technical assistance; Dagmar Wilhelm and Andreas Dieckmann for sharing unpublished data; and Marina Schorpp-Kistner, Axel Behrens, and Kanaga Sabapathy for critical reading of the manuscript.
This work was supported by grants from the Deutsche Forschungsgemeinschaft (He-551/8-2) and the German-Israeli Cooperation in Cancer Research and the TMR and Biomedicine and Health programs (CT96-0044 and CT BMH4-98-3505) of the European Economic Community.
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FOOTNOTES |
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* Corresponding author. Mailing address: Deutsches Krebsforschungszentrum, Abteilung Signaltransduktion und Wachstumskontrolle, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany. Phone: (49)-6221-42-4570. Fax: (49)-6221-42-4554. E-mail: P.angel{at}DKFZ-Heidelberg.de.
Present address: Research Institute of Molecular Pathology (IMP),
A-1030 Vienna, Austria.
Present address: Department of Microbiology and Genetics, Vienna
Biocenter, A-1030 Vienna, Austria.
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REFERENCES |
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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