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Molecular and Cellular Biology, April 2000, p. 2687-2695, Vol. 20, No. 8
Center for Advanced Biotechnology and
Medicine,1 Graduate Programs in
Biochemistry and Molecular Biology and in
Biotechnology,2 and Department of
Biochemistry,3 Robert Wood Johnson Medical
School, University of Medicine and Dentistry of New Jersey, Piscataway,
New Jersey 08854-5638
Received 6 August 1999/Returned for modification 23 September
1999/Accepted 31 January 2000
The transcription factors of the Rel/NF- Apoptosis is an inducible
suicide program that occurs at all stages of multicellular life. It is
required for normal development, immune system function, tissue
remodeling, and prevention of inappropriate cellular proliferation.
Dysregulated cell death is associated with various pathological
conditions, including neurodegenerative disorders, autoimmune diseases,
and cancer (reviewed in reference 17). Experimental
evidence suggests a proactive role for the Rel/NF- Consistent with the notion that NF- The Bcl-2 family of cell death regulators is critical for determining
cell fate in the apoptotic pathway. Bcl-2 and its mammalian homologs
Bcl-xL, Bfl-1 (also called A1), and Mcl-1 block cell death,
while Bax, Bcl-xS, Nbk (also called Bik), Bak, and Bad promote apoptosis (reviewed in reference 1). Each of
these factors influences the cleavage-mediated activation of caspases, which act as the ultimate downstream effectors of the suicide program.
While little is known about the signaling pathways that control the
expression of Bcl-2-related factors and of the transcription factors
involved in their regulation, exogenous expression of prosurvival
Bcl-2-related proteins was shown to block apoptosis in lymphoid cells
under conditions in which NF- Here, we show that NF- Plasmids.
The human c-rel gene
(hc-rel, a gift from N. Rice, ABL-NCI, Frederick, Md.) was
stably expressed in a Tet-OFF system, under the control of a minimal
cytomegalovirus (CMV) promoter and seven tetracycline operator sites
from plasmid pUHD10-3-hygro (13) (pUHD10-3-hygro-hc-rel). In transient transfection assays,
hc-rel was expressed from the CMV promoter of pJDCMV19SV
(pCMV-hc-rel). Vectors expressing the death antagonists
Bcl-2 and Bcl-xL from the CMV promoter of pcDNA3.0
(Invitrogen) were a gift from C. Labrie (CHUL, Québec, Canada).
pCMV- Cell culture and endogenous NF-
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
The Rel/NF-
B Family Directly Activates
Expression of the Apoptosis Inhibitor Bcl-xL
ABSTRACT
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
B family are key
regulators of immune and inflammatory responses and contribute to lymphocyte proliferation, survival, and oncogenesis. The absolute correlation between the antiapoptotic and oncogenic activities of the
Rel/NF-B oncoprotein v-Rel emphasizes the importance of characterizing the death antagonists under NF-B control. Our recent
finding that the prosurvival Bcl-2 homolog Bfl-1 (also called A1) is a
direct transcriptional target of NF-B raised the issue of whether
NF-B is a specific or global regulator of death antagonists in the
Bcl-2 family. Here, we demonstrate that NF-B differentially
regulates the expression of particular Bcl-2-related death inhibitors
and that it directly activates the expression of Bcl-xL.
While Bcl-xL was significantly upregulated by c-Rel and
RelA, Bcl-2 was not. Importantly, stimuli that activate endogenous NF-B factors also upregulated bcl-x gene expression and
this effect was antagonized by an inhibitor of NF-B activity. The expression of bcl-x suppressed apoptosis in the presence or
absence of NF-B activity. Functional analysis of the
bcl-x promoter demonstrated that it is directly controlled
by c-Rel. These results establish that NF-B directly regulates the
expression of distinct prosurvival factors in the Bcl-2 family, such as
Bcl-xL and Bfl-1/A1. These findings raise the possibility
that some of these factors may contribute to oncogenesis associated
with aberrant Rel/NF-B activity.
INTRODUCTION
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
B family of
transcription factors in the inhibition of programmed cell death, as
shown by the following observations. (i) Homozygous inactivation of
RelA in mice led to extensive apoptosis in the liver (6).
(ii) Inactivation of endogenous Rel/NF-B factors by superrepressor
forms of the inhibitory protein IB
sensitized cells to
stimulus-induced apoptosis (32, 54, 57, 62). (iii) Lymphoid
cells transformed by the Rel/NF-B oncoprotein v-Rel required
continuous expression of v-Rel for survival. v-Rel inactivation by a
temperature-sensitive mutation or through tetracycline-regulated control resulted in the rapid onset of apoptosis (59, 68). (iv) Transcriptionally competent Rel/NF-B factors (v-Rel, c-Rel, and
RelA) blocked apoptosis induced by tumor necrosis factor alpha (TNF-), whereas those defective for transactivation did not (5, 13, 32, 67).
B regulates the expression of
genes that antagonize cell death, its protective activity is dependent
on RNA and protein synthesis (reviewed in reference 55). Candidate target genes recently identified
include those encoding the caspase inhibitors c-IAP1, c-IAP2, and
X-IAP, the TNF receptor-associated factors TRAF1 and TRAF2, and the
zinc finger protein A20 and the immediate-early response gene
IEX-1L (15, 30, 50, 58, 63, 66). Thus, in
addition to regulating the expression of genes important for immune and
inflammatory responses, Rel/NF-B also controls the transcription of
genes that confer resistance to death-inducing signals.
B activity was inhibited
(62). This raised the possibility that some of these factors
may lie downstream of NF-B in the survival cascade. The recent
demonstration that the prosurvival Bcl-2 homolog Bfl-1 is
transcriptionally controlled by Rel/NF-B is consistent with these
results (23, 31, 56, 69). It is therefore important to
determine whether NF-B is a general or specific regulator of death
antagonists in the Bcl-2 family.
B can differentially regulate the expression
of prosurvival Bcl-2 family proteins. Whereas c-Rel and RelA had no
effect on Bcl-2 expression in HT1080 and HtTA cells, they strongly
upregulated the expression of Bcl-xL. bcl-x
promoter activation was dependent on an NF-B DNA site, and its
protective activity was correlated with that of c-Rel. These results
indicate that NF-B activates distinct prosurvival Bcl-2 family
proteins and suggest a role for these factors in the inhibition of cell death by Rel/NF-B.
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
-gal expressed the -galactosidase gene
(-gal) from a CMV promoter (69).
B activation.
Human HT1080
fibrosarcoma cells, HeLa cervical carcinoma cells, Jurkat T lymphocytic
leukemia cells, CEM T cells, and 293 embryonal kidney cells were
obtained from the American Type Culture Collection. Jurkat T cell lines
expressing wild-type IB (IB-wt) or a constitutive IB
inhibitor (IB
N) were a gift from D. W. Ballard
(Vanderbilt University, Nashville, Tenn.) (15). The cell
line RC-K8, derived from a diffused large cell lymphoma, was a gift
from N. Zeleznik-Le (University of Chicago, Chicago, Ill.)
(33).
B activity was induced upon treatment with TNF-
(1,000 U per ml; Sigma) for 2 h (CEM) or with phorbol 12-myristate 13-acetate (PMA) (50 ng per ml) plus ionomycin (concentration, 1 µM
in 0.05% dimethylsulfoxide) for 2 h (Jurkat).
B1) under tetracycline-regulated control were previously described (67, 69). Human HT1080-tTA fibrosarcoma cells stably expressing the tTA (tetracycline-regulated transactivator) protein were generated by cotransfecting HT1080 cells
with pUHD15-1 (21) and pSV2Neo, using SuperFect (Qiagen). Neomycin-resistant HT1080-tTA cell clones were selected with G418 (200-µg potency units) in the presence of tetracycline-HCl (2 µg
per ml) and screened for luciferase gene activation following transient
transfection of the pUHD13-3 luciferase expression plasmid (21). The HT1080-hc-rel cell line that
conditionally expressed hc-rel under tetracycline control
was obtained by transfecting HT1080-tTA cells with
pUHD10-3-hygro-hc-rel. Cell clones were selected in the
presence of hygromycin B (400 µg per ml; Calbiochem) and screened for
inducible expression of hc-Rel by immunoblotting. HT1080-hc-rel cells were maintained in minimum essential
medium supplemented with 10% fetal bovine serum, 2 mM glutamine,
Earle's balanced salt solution containing sodium bicarbonate (1.5 g
per liter), 1× nonessential amino acids, 0.1 mM sodium pyruvate, and antibiotics (100 U of penicillin per ml and 100 µg of streptomycin per ml). Cells were maintained at 37°C in an atmosphere of 5% CO2. All cell clones were maintained in the presence of
tetracycline (2 µg per ml) and refed every other day.
Immunoblotting.
Cells were induced to express the c-Rel,
RelA, or p50 protein upon removal of tetracycline from the cell culture
medium. Extracts were prepared in lysis buffer (50 mM Tris HCl [pH
7.5], 150 mM sodium chloride, 1% sodium deoxycholate, 1% Triton
X-100, 10 µg of leupeptin per ml, 10 µg of pepstatin per ml, 20 µg of aprotinin per ml, 10 mM sodium pyrophosphate, 50 mM sodium
fluoride, and 0.5 mM sodium orthovanadate) (42) and
quantitated by the method of Bradford (10). Proteins (20 µg) were resolved by sodium dodecyl sulfate-polyacrylamide gel
electrophoresis (SDS-PAGE) and transferred to nitrocellulose membranes.
Immunoblotting was performed by enhanced chemiluminescence (ECL;
Amersham). Processing of procaspase 3 and procaspase 8 in
HT1080-hc-rel cells was induced by treatment with TNF- (5 ng per ml) plus cycloheximide (CHX; 5 µg per ml) before or after a
48-h induction of c-Rel expression. The hc-Rel protein was detected
with rabbit polyclonal antibody SC-272 (Santa Cruz Biotechnology).
Antibodies to caspase 3, Bcl-xL/S, and Bcl-2 were purchased
from PharMingen. The anti-caspase 8 antibody was from Zymed
Laboratories. An antiactin antibody (Sigma) was used as a control.
Northern blot analysis.
Total RNA (20 µg) extracted with
RNAzol B (TEL-TEST) was fractionated in 1% agarose-formaldehyde gels
and transferred onto Hybond-NX membranes (Amersham). Membranes were
baked for 10 min at 80°C under vacuum and UV cross-linked with a
Stratalinker (Stratagene). Probes were generated by random priming with
Klenow DNA polymerase in the presence of [-32P] dCTP
and [-32P] dGTP (19). A 28S oligonucleotide
probe (5'-AAGGATCAGAGTAGTGGTATTTCACC-3') was labeled
with [
-32P]ATP and T4 polynucleotide kinase.
Membranes were hybridized in ExpressHyb (Clontech) according to the
manufacturer's recommended procedure, or in 5× SSC (0.75 M NaCl plus
75 mM Na citrate [pH 7.0]), 5× Denhardt's solution, 0.5% SDS, and
sheared salmon sperm DNA (100 µg per ml) at 65°C overnight.
Membranes were washed twice in 2× SSC-0.1% SDS and twice in 1×
SSC-0.1% SDS at 65°C, followed by autoradiography.
Apoptosis assays.
Cell resistance to TNF-- or anti-Fas
antibody-induced apoptosis in transient assays was examined as
described previously (60). HT1080 cells (2 × 105) were cotransfected with pCMV--gal (0.5 µg) together with pCMV vectors expressing Bcl-xL or
hc-Rel (1.5 µg), using SuperFect reagent (Qiagen). An empty pCMV
vector was used as a control. After 30 h, the cells were treated
with CHX either alone (30 µg per ml) or together with TNF- (10 ng
per ml; Sigma) or with anti-Fas antibodies (1 µg per ml; Calbiochem)
for 14 h. After fixation and staining with
5-bromo-4-chloro-3-indolyl--D-galactopyranoside (X-Gal),
cells were counted from a minimum of 10 fields chosen at random.
Quantitation of cell survival represents the ratio of the number of
cells expressing -gal in wells treated with TNF- or
anti-Fas plus CHX over that in wells treated with CHX alone. In assays
of cell death performed in the absence of cycloheximide, HeLa cells
(3 × 106) were coelectroporated using a Bio-Rad Gene
Pulser (220 V, 960 µF) with pCMV--gal (3 µg), an
empty CMV vector, or pCMV-IBM (12 µg) to constitutively repress
NF-B, alone or together with pCMV-bcl-xl (6 µg). Cells
were then distributed equally into two 35-mm wells and treated 24 h later with TNF- (10 ng per ml) for 16 h. Cells were counted
from a minimum of 10 fields chosen at random.
Cloning of the human bcl-x promoter region and
transient CAT assays.
The human bcl-x promoter region
was isolated by nested PCR amplification using a Genome Walker
PromoterFinder kit (Clontech) and cloned in a promoterless vector
expressing a chloramphenicol acetyltransferase (CAT) reporter gene
(pCAT-basic; Promega). bcl-x promoter activity was analyzed
by transient transfection of HT1080 cells with bcl-x-CAT
reporter plasmids (0.8 µg) in the presence of a CMV-hc-rel
expression vector (1.2 µg) or an empty pCMV vector as a control.
Assays were performed with 20 µg of protein for 1.5 h. The
relative CAT activity represents the average of three independent
experiments. The bcl-x promoter region (from positions 
298
to +22) cloned in pAlter-1 was subjected to site-directed mutagenesis
to inactivate the NF-B motif (mutated bases are underlined) at
position 232 (TTTACTGCCC; 298/+22 mB;
Altered Sites Mutagenesis System [Promega]). Mutation of the NF-B
site was confirmed by sequencing.
DNA-binding assays.
The binding of Rel/NF-B factors to
the B DNA site found in the bcl-x promoter was assayed in
human 293 cells transiently transfected with CMV expression vectors for
p50, p65, or c-Rel. Nuclear extracts (3 µg) were incubated with a
double-stranded 32P-labeled NF-B oligonucleotide probe
derived from the bcl-x promoter region
(5'-AGTGGGGGCGGGGGGGACTGCCCCCTCTCCTT-3') or a control
interleukin 6 (IL-6)-B oligonucleotide probe (4 × 104 cpm) (64) in 12.5 mM HEPES (pH 7.9), 12%
glycerol, 5 mM MgCl2, 60 mM KCl, 0.2 mM EDTA, 1 mM
dithiothreitol, bovine serum albumin (1 µg per µl), poly(dI-dC) (2 µg) and analyzed on 5% native polyacrylamide gels as described
previously (64). Where indicated, nuclear extracts were
prepared from HT1080-hc-rel cells induced to express c-Rel
for 0, 24, 48, 72, or 96 h following the removal of tetracycline. Extracts (3 µg) were analyzed for binding to the bcl-x
B DNA oligonucleotide probe in gel retardation assays, as described above.
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RESULTS |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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c-Rel and RelA promote the expression of Bcl-xL in
HT1080 and HtTA cells but have no effect on Bcl-2.
To investigate
whether NF-B is a specific or global regulator of death antagonists
in the Bcl-2 family, we examined the effect of c-Rel on the
steady-state levels of endogenous Bcl-2 and Bcl-xL proteins
in human HT1080-hc-rel cells that conditionally expressed the human c-rel gene under tetracycline-regulated control.
Similar to the HeLa-derived HtTA-CCR43 cell line that we previously
characterized (67), HT1080-hc-rel cells showed
significant protection from TNF-- or anti-Fas antibody-induced
apoptosis following induction of c-Rel expression upon withdrawal of
tetracycline (data not shown). Interestingly, expression of c-Rel in
these cells was accompanied by a four- to sixfold increase in
Bcl-xL protein levels (Fig.
1A, lanes 1 to 5). The 29-kDa protein
doublet that was detected with anti-Bcl-x antibodies is typical of
Bcl-xL (28). In contrast to the strong induction
of Bcl-xL, the steady-state levels of Bcl-2 remained
unchanged following c-Rel expression (Fig. 1A, lanes 1 to 5).
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B site-containing promoters failed
to show any increase in Bcl-xL protein levels (Fig. 1B,
lanes 6 to 9). Together, these results suggested a correlation between
the expression of transcriptionally competent Rel/NF-B proteins and
the specific accumulation of the prosurvival factor Bcl-xL.
The increased accumulation of Bcl-xL protein correlated
with an increase in the steady-state levels of bcl-xl
transcripts in c-Rel-expressing cells. Northern blots showed a strong
enhancement in bcl-x gene expression in
HT1080-hc-rel cells induced to express c-Rel (14-fold
increase) (Fig. 1C, compare lanes 2 and 3). On the contrary,
bcl-2 mRNAs were virtually undetectable in
HT1080-hc-rel cells and remained unaffected by the
expression of c-Rel (Fig. 1C, lanes 2 and 3). Similarly,
bcl-xl was found to be highly expressed in human RC-K8 cells
in comparison to the low levels of bcl-2 transcripts (Fig.
1C, lane 1). These cells are derived from a human diffused large cell
lymphoma associated with overexpression of a rearranged
c-rel gene (33).
Consistent with these results, bcl-x gene expression was
also strongly induced by p65. Northern blot analysis showed a ninefold increase in bcl-x transcript levels 48 h after the
removal of tetracycline from the HeLa-derived HtTA-RelA cell line to
induce expression of p65 (Fig. 1D, compare lanes 4, 5, and 6). As
anticipated, p50 failed to promote bcl-x gene expression
(Fig. 1D, lanes 1 to 3). These data indicated a selective effect of
transcriptionally competent Rel/NF-B subunits on bcl-xl
expression but not on bcl-2 expression.
Stimuli that activate NF-B also upregulate bcl-x
gene expression.
To further investigate the functional regulation
of Bcl-xL, we verified the effects of endogenous NF-B
activation on bcl-x gene expression. The basal levels of
bcl-x transcripts were significantly increased upon
stimulation of human CEM T cells with TNF- (Fig. 2A, lanes 1 and 2). The participation of
NF-B in bcl-x gene expression was further substantiated
by the analysis of human Jurkat T cells stimulated with PMA plus
ionomycin to activate endogenous NF-B factors. Basal levels of
bcl-x transcripts were increased threefold following
PMA-plus-ionomycin treatment of both parental Jurkat T cells and Jurkat
T cells expressing IB-wt in comparison to untreated cells (Fig.
2B, lanes 1 to 4). This enhanced expression correlated with the
induction of mRNAs for IL-2 receptor alpha (IL2R), a known target
gene for NF-B. Importantly, the constitutive repression of NF-B
in Jurkat-IBN cells by a mutant of IB that is resistant
to proteolytic degradation (15) markedly decreased the
response of bcl-x (Fig. 2B, compare lanes 5 and 6).
Together, these data indicated that the activation of NF-B enhances
bcl-x gene expression.
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The protective activity of Bcl-xL is correlated with
that of c-Rel and can substitute for NF-B to block TNF--induced
cell death.
We investigated the protective activities of
Bcl-xL and c-Rel in transient transfection assays. HT1080
cells were cotransfected with a CMV--gal reporter plasmid
together with pCMV vectors expressing either Bcl-xL or
c-Rel or an empty vector as a control. Cells were treated with CHX
either alone or together with TNF- or anti-Fas antibodies. Cell
survival represents the ratio of the number of cells expressing
-gal in wells treated with TNF- plus CHX or anti-Fas
plus CHX to that in wells treated with CHX alone. The cotransfection of
pCMV-hc-rel with CMV--gal significantly
suppressed cell killing induced either by TNF- or by Fas receptor
cross-linking with an anti-Fas antibody (Fig.
3A). c-Rel increased cell survival 10-fold following addition of TNF- and 5.5-fold following treatment with anti-Fas antibodies. Consistent with the protective activity of
c-Rel in this assay, bcl-xl also efficiently repressed
apoptosis induced by either stimulus (eightfold for TNF- and
fivefold for anti-Fas [Fig. 3A]). The correlation between the
protective activities of c-Rel and Bcl-xL is consistent
with the possibility of a functional relationship between these
factors.
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-plus-CHX treatment (Fig. 3B).
HT1080-hc-rel cells maintained in the presence of
tetracycline to block c-Rel expression underwent significant processing
of procaspase 3 within 6 h of TNF--plus-CHX treatment, as shown
by the disappearance of the procaspase 3 band (Fig. 3B, compare lanes 7 and 9 to lane 1). The 17-kDa cleavage product of procaspase 3 processing was detected only after long exposure times and is shown in
the middle panel. In contrast, the caspase 3 proenzyme was
significantly more resistant to cleavage in cells induced to express
c-Rel following the removal of tetracycline (Fig. 3B, lanes 8 and 10).
Interestingly, the induction of c-Rel expression also suppressed the
cleavage-mediated activation of FADD-like IL-1 convertase enzyme
(FLICE; also known as procaspase 8), the apical caspase in the death
receptor caspase cascade (Fig. 3C, compare lanes 8 and 10 to lanes 7 and 9). While Bcl-xL was reported to function downstream of
FLICE (8), others showed that it can prevent the
oligomerization of FADD and the recruitment of FLICE coincident with
the inhibition of apoptosis (38). Although more studies are
needed to establish the extent to which Bcl-xL contributed to this activity, the conditional expression of c-Rel in
HT1080-hc-rel cells conferred a protective activity similar
to that provided by Bcl-xL, consistent with the
upregulation of bcl-xl transcripts by Rel/NF-B factors.
Importantly, Bcl-xL also suppressed TNF--induced killing
in cells in which endogenous NF-B activity was suppressed by a serine-to-alanine mutant of IB that is resistant to
signal-induced degradation (IBM) (54). While the
expression of IBM sensitized HeLa cells to killing induced by
TNF- in the absence of CHX, the cotransfection of Bcl-xL
rescued the cells from apoptosis (Fig. 3D). Together, the results
support a role for Bcl-xL as one of several death
antagonists that function in the NF-B pathway for cell survival.
c-Rel directly regulates the bcl-x promoter.
To
clarify the nature of the response of bcl-xl to Rel/NF-B,
we isolated and characterized the regulatory sequences that lie
upstream of the bcl-x cDNA. Nested PCR amplification of an adapter-ligated human genomic library generated a product of 435 bp
with a 3' end derived from the 5' end of the bcl-xl cDNA and extending 5' into adjacent genomic sequences (Genome Walker
PromoterFinder kit; Clontech). The sequence was identical to that
previously reported (DDBJ, EMBL, and GenBank accession no. D30746). A putative NF-B DNA binding site was identified at position 232 relative to the first nucleotide in the human bcl-xl cDNA
sequence (DDBJ, EMBL, and GenBank accession no. L20121;
GGGACTGCCC; position 77 relative to the transcription
start site) and is conserved in the mouse bcl-x promoter
region (22).
B
oligonucleotide probe was used as a control for Rel/NF-B protein
expression (Fig. 4A, lanes 3 to 5). A time course gel shift analysis
was then used to monitor the binding of Rel factors to this site in
induced HT1080-hc-rel cells and to see its relationship to
endogenous Bcl-xL expression (Fig. 4B). In this assay, Rel
factor binding to the bcl-x B DNA site was correlated
with the time course for the induction of Bcl-xL in these
cells (Fig. 1A).
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298/+22 bcl-x-CAT reporter
construct showed little activity on its own, but the cotransfection of
CMV-hc-rel increased the construct's expression 16-fold
(Fig. 5B). Progressive deletions removing
5' sequences from the bcl-x promoter region rapidly
interfered with its response to c-Rel. Importantly, a mutant promoter
with a deletion endpoint mapping only 10 nucleotides downstream of the
NF-B motif showed a 65% reduction in activity in comparison to the
wild-type promoter construct (222/+22 bcl-x-CAT) (Fig. 5B). These results are consistent with our data showing increased expression of Bcl-xL in response to Rel/NF-B factors.
Site-directed mutagenesis was used to inactivate the NF-B site at
position 232 to confirm its role in the Rel-mediated induction of the bcl-x promoter (TTTACTGCCC; 298/+22
mB). While this mutation slightly decreased the basal activity of
the bcl-x promoter, it greatly reduced its responsiveness to
c-Rel (Fig. 5C). The response of the 298/+22 mB
bcl-x-CAT mutant promoter construct to c-Rel was decreased
down to 3.5-fold, in comparison to the 16-fold induction observed with
the wild-type 298/+22 bcl-x-CAT reporter plasmid. Together, these results demonstrate a direct role for Rel/NF-B in
the regulation of bcl-xl expression.
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DISCUSSION |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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The strong correlation that exists between the antiapoptotic and
oncogenic activities of Rel/NF-B factors has elicited a fervent
search for the target genes that participate in the NF-B survival
pathway. Recent work from members of our group and others demonstrated
that NF-B directly regulates expression of the prosurvival Bcl-2
family protein Bfl-1 and its mouse homolog A1 (23, 31, 56,
69). The positioning of one member of the important Bcl-2 family
of death antagonists in the NF-B survival pathway raised the
question of whether NF-B also controls other death inhibitors from
the Bcl-2 family. Here, we demonstrate that Bcl-xL is also a transcriptional target of NF-B. We show that ectopically expressed and endogenous Rel/NF-B factors specifically upregulated the expression of bcl-xl. This effect was dependent on NF-B
activity, as a mutant form of IB that can physiologically inhibit
NF-B antagonized bcl-x gene induction. Functionally, both
c-Rel and Bcl-xL exhibited similar antiapoptotic activities
toward cell death induced by TNF- or by Fas receptor cross-linking.
This agrees with studies indicating that expression of either
Bcl-xL or Rel/NF-B factors antagonizes apoptosis in
response to various death-inducing stimuli (2, 8, 14, 32, 43, 49,
54, 57, 62, 67). The mapping of a functional B DNA site in the
human bcl-x promoter region confirmed its Rel-dependent
response. Together, these data demonstrate the direct participation of
NF-B in the transcriptional control of the prosurvival factor
Bcl-xL.
Our finding that NF-B is an important inducer of bcl-xl
is consistent with recent reports showing the NF-B-dependent
upregulation of bcl-xl upon CD40-mediated activation of B
lymphocytes, in primary neurons stimulated with TNF, and in mouse T
cells expressing human T-cell leukemia virus type 1 (HTLV-1) Tax
(31, 51, 52). However, the regulation of bcl-xl
expression appears to be quite complex and the contribution of NF-B
to this process may depend on cell type, differentiation stage and/or
activating stimuli. For instance, while the studies described above
point to a proactive role for NF-B in inducing bcl-xl,
other analyses looking for death antagonists under NF-B control
failed to reveal alterations in bcl-xl transcript levels
(23, 58, 63). Similarly, no change in bcl-xl
expression was observed in IL-3-dependent mouse B cells expressing
HTLV-1 Tax (34). Understanding of the relationship between
NF-B and Bcl-xL is also complicated by data implicating NF-B as a negative regulator of Bcl-xL in
double-positive thymocytes (24) and by reports pointing to
the ability of Bcl-xL to interfere with NF-B activation
upstream of IB degradation (3). Additional work is
thus needed to sort out the functional and regulatory relationships
between NF-B and Bcl-xL and the conditions under which
they take place.
Our findings do not exclude the possibility that NF-B may function
in conjunction with other transcription factors to regulate bcl-x gene expression. Similarly to NF-B, transcription
factors Stat1, Stat5, and Ets2 were also recently implicated in the
regulation of bcl-xl expression (20, 45, 47) and
multiple binding sites for other transcription factors were identified
in the bcl-x promoter (22). The regulation of
bcl-xl induction by multiple transcription factors may thus
explain why significant levels of bcl-xl transcripts have
been observed in the absence of NF-B activation. In this respect, it
is noteworthy that the response of bcl-x to endogenous NF-B activation differed somewhat from the response that our group
and others previously described for its homolog bfl-1/a1 (31, 69). Whereas cells that lack nuclear NF-B activity
failed to show any expression of bfl-1/a1, a basal level of
endogenous bcl-x gene expression was observed in several
cell lines, which was further induced upon NF-B activation. These
data are consistent with a model in which NF-B may act in concert
with other transcription factors to control the expression of
bcl-xl depending on cell type and/or activating stimuli.
Nevertheless, the results described herein indicate that NF-B is one
of several important inducers of bcl-xl.
As a result of alternative splicing, bcl-x encodes two death
regulators that exhibit opposing activities (7).
Bcl-xL exerts a protective effect, whereas the shorter
form, Bcl-xS, is proapoptotic. The 29-kDa protein doublet
detected in our immunoblots with anti-Bcl-x antibodies is typical of
Bcl-xL (Fig. 1A) (28). No change was observed at
the position for its proapoptotic isoform, Bcl-xS. Our
results therefore highlight the participation of NF-B in the control
of bcl-x gene activation to block cell death through upregulation of the prosurvival Bcl-xL factor. In a recent
study, Tsukahara et al. also observed NF-B-mediated induction of
bcl-xl but not bcl-xs in CTLL-2 cells expressing
Tax (52). It will be interesting to investigate the
mechanism underlying the selective induction of the bcl-x
promoter by NF-B that leads to production of the antiapoptotic long
form rather than the proapoptotic short form.
The ability of c-Rel to transcriptionally regulate bcl-x and
its homolog bfl-1/a1 is in contrast with its failure to
induce bcl-2 gene expression in our cells. While NF-B has
been implicated in the induction of bcl-2 in certain cells
(51) but not others (52), the absence of a
bcl-2 response in our system implies that NF-B is able to
selectively regulate particular prosurvival genes in the Bcl-2 family
in defined cellular environments. This differential regulation is
consistent with the fact that Bcl-xL and Bcl-2 can display
different patterns of expression in various hematopoietic cells and
tissues. For instance, bcl-2 is intensely expressed in naive
and memory B cells but is mostly absent from germinal center B cells.
In contrast, bcl-xl is weakly expressed in naive and memory
B cells but is abundant in germinal center B cells where
c-rel is constitutively expressed (12, 28, 35). Thus, despite the sequence and functional homology between
Bcl-xL and Bcl-2, their different modes of regulation
enable them to exhibit complementary protective activities in
hematolymphoid tissues by allowing them to participate in distinct
survival programs in different cells and at different stages of
differentiation (reviewed in references 41 and
65).
In experiments not shown here, we observed that transcripts for the
Bcl-2-related protein Mcl-1 were also upregulated by c-Rel and NF-B
activation and that mcl-1 mRNAs were abundantly expressed in
immune tissue where NF-B is active (data not shown). However, we
have so far been unable to demonstrate that NF-B activity is
required for mcl-1 gene expression. While NF-B activation in Jurkat T cells treated with PMA plus ionomycin efficiently promoted
mcl-1 gene expression, a similar degree of induction was
observed in Jurkat-IBN cells in which endogenous NF-B activity was constitutively repressed (data not shown). This is in
contrast to the results that members of our group obtained with
bcl-xl and bfl-1/a1 (Fig. 2B) (69).
Further work is therefore needed to characterize the mcl-1
promoter region and to assess the role of NF-B in its regulation.
Taken together, our findings indicate that NF-B can specifically
regulate particular cell death inhibitors in the Bcl-2 family.
Dysregulated Rel/NF-B activity has been implicated in several
hematopoietic and solid tumors (reviewed in references
34 and 40). For example,
c-rel is amplified in human extranodal diffuse large cell
lymphomas and constitutive NF-B/Rel activity was observed in
Hodgkin's lymphoma and in breast, colon, and prostate carcinoma
(4, 9, 11, 16, 25, 29, 39, 48, 61; F. Payvandi,
W. X. Zong, C. Gélinas, P. Amenta, and A. B. Rabson, unpublished data). Although the mechanisms involved remain to be
clarified, the ability of NF-B to promote cell survival is likely to
contribute to malignancy. Interestingly, bcl-xl is
overexpressed in lymphoid and hematopoietic tumors as well as in a high
proportion of colorectal, prostate, and primary breast carcinomas
(26, 27, 37, 44, 53). While Bcl-xL is unlikely
to be the only antiapoptotic factor responsible for the protective
activity of NF-B, these observations suggest that the dysregulated
expression of Bcl-xL, Bfl-1, and other prosurvival factors
under NF-B control may be important for the oncogenic process.
Future challenges will be to elucidate the pathways responsible for the
differential regulation of death antagonists controlled by NF-B and
to establish their respective contribution to tumors associated with
aberrant Rel/NF-B activity.
| |
ACKNOWLEDGMENTS |
|---|
We are very grateful to D. W. Ballard (HHMI, Vanderbilt
University) for Jurkat-IB-wt and Jurkat-IBN cells, C. Labrie (CHUL) for bcl-2, bcl-xl, and
mcl-1 cDNAs, D. Perez and E. White (HHMI, CABM, Piscataway,
N.J.) for anti-Bcl-2 antibodies, N. Rice (ABL-NCI) for
hc-rel cDNA, H. Bujard (Zentrum fur Molekulare Biologie der
Universitat Heidelberg, Heidelberg, Germany) for the gift of pUHD
vectors, and to N. Zeleznik-Le (University of Chicago) for the RC-K8
cell line. We thank P. Lizzul, A. Rabson, B. Rayet, E. White, and W.-X.
Zong for helpful comments on the manuscript.
This work was supported by a grant from the National Institutes of Health (CA54999) and by the New Jersey Commission on Science and Technology to C.G. C.C. was a postdoctoral fellow of the New Jersey Commission on Cancer Research and The Foundation of UMDNJ. L.C.E. was partially supported by NIH Biotechnology predoctoral training grant GM08339 and by NIH predoctoral training grant in Biochemistry and Molecular Biology GM08360.
| |
FOOTNOTES |
|---|
* Corresponding author. Mailing address: CABM, 679 Hoes Ln., Piscataway, NJ 08854-5638. Phone: (732) 235-5035. Fax: (732) 235-5289. E-mail: gelinas{at}cabm.rutgers.edu.
Present address: The R. W. Johnson Pharmaceutical Research
Institute, Johnson & Johnson Co., Springhouse, PA 19477.
| |
REFERENCES |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Mineva, N. D., Rothstein, T. L., Meyers, J. A., Lerner, A., Sonenshein, G. E.
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Chiu, G. N.C., Edwards, L. A., Kapanen, A. I., Malinen, M. M., Dragowska, W. H., Warburton, C., Chikh, G. G., Fang, K. Y.Y., Tan, S., Sy, J., Tucker, C., Waterhouse, D. N., Klasa, R., Bally, M. B.
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Liu, Y., Smith, P. W., Jones, D. R.
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Mao, X., Moerman-Herzog, A. M., Wang, W., Barger, S. W.
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Djavaheri-Mergny, M., Amelotti, M., Mathieu, J., Besancon, F., Bauvy, C., Souquere, S., Pierron, G., Codogno, P.
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Nyakern, M., Cappellini, A., Mantovani, I., Martelli, A. M.
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Collett, G. P., Campbell, F. C.
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Li, Y. C., Park, M. J., Ye, S.-K., Kim, C.-W., Kim, Y.-N.
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Kim, K. M., Song, J. J., An, J. Y., Kwon, Y. T., Lee, Y. J.
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Demicco, E. G., Kavanagh, K. T., Romieu-Mourez, R., Wang, X., Shin, S. R., Landesman-Bollag, E., Seldin, D. C., Sonenshein, G. E.
(2005). RelB/p52 NF-{kappa}B Complexes Rescue an Early Delay in Mammary Gland Development in Transgenic Mice with Targeted Superrepressor I{kappa}B-{alpha} Expression and Promote Carcinogenesis of the Mammary Gland. Mol. Cell. Biol.
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Sanjabi, S., Williams, K. J., Saccani, S., Zhou, L., Hoffmann, A., Ghosh, G., Gerondakis, S., Natoli, G., Smale, S. T.
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Hu, W.-H., Pendergast, J. S., Mo, X.-M., Brambilla, R., Bracchi-Ricard, V., Li, F., Walters, W. M., Blits, B., He, L., Schaal, S. M., Bethea, J. R.
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Takahashi, N., Kobayashi, S., Kajino, S., Imai, K., Tomoda, K., Shimizu, S., Okamoto, T.
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(2005). Blockade of Histone Deacetylase Inhibitor-Induced RelA/p65 Acetylation and NF-{kappa}B Activation Potentiates Apoptosis in Leukemia Cells through a Process Mediated by Oxidative Damage, XIAP Downregulation, and c-Jun N-Terminal Kinase 1 Activation. Mol. Cell. Biol.
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Li, Y., Schwabe, R. F., DeVries-Seimon, T., Yao, P. M., Gerbod-Giannone, M.-C., Tall, A. R., Davis, R. J., Flavell, R., Brenner, D. A., Tabas, I.
(2005). Free Cholesterol-loaded Macrophages Are an Abundant Source of Tumor Necrosis Factor-{alpha} and Interleukin-6: MODEL OF NF-{kappa}B- AND MAP KINASE-DEPENDENT INFLAMMATION IN ADVANCED ATHEROSCLEROSIS. J. Biol. Chem.
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Takahashi, A., Hanson, M. G. V., Norell, H. R., Havelka, A. M., Kono, K., Malmberg, K.-J., Kiessling, R. V. R.
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Bai, J., Sui, J., Demirjian, A., Vollmer, C. M. Jr., Marasco, W., Callery, M. P.
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Mandal, M., Borowski, C., Palomero, T., Ferrando, A. A., Oberdoerffer, P., Meng, F., Ruiz-Vela, A., Ciofani, M., Zuniga-Pflucker, J.-C., Screpanti, I., Look, A. T., Korsmeyer, S. J., Rajewsky, K., von Boehmer, H., Aifantis, I.
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Moreaux, J., Legouffe, E., Jourdan, E., Quittet, P., Reme, T., Lugagne, C., Moine, P., Rossi, J.-F., Klein, B., Tarte, K.
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Kerstan, A., Hunig, T.
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Yoshida, Y., Kumar, A., Koyama, Y., Peng, H., Arman, A., Boch, J. A., Auron, P. E.
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Molestina, R. E., Payne, T. M., Coppens, I., Sinai, A. P.
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Chawla-Sarkar, M., Bauer, J. A., Lupica, J. A., Morrison, B. H., Tang, Z., Oates, R. K., Almasan, A., DiDonato, J. A., Borden, E. C., Lindner, D. J.
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Kotelkin, A., Prikhod'ko, E. A., Cohen, J. I., Collins, P. L., Bukreyev, A.
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Hatada, E. N., Do, R. K. G., Orlofsky, A., Liou, H.-C., Prystowsky, M., MacLennan, I. C. M., Caamano, J., Chen-Kiang, S.
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Sayers, T. J., Brooks, A. D., Koh, C. Y., Ma, W., Seki, N., Raziuddin, A., Blazar, B. R., Zhang, X., Elliott, P. J., Murphy, W. J.
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Hundal, R. S., Gomez-Munoz, A., Kong, J. Y., Salh, B. S., Marotta, A., Duronio, V., Steinbrecher, U. P.
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Whyburn, L. R., Halcomb, K. E., Contreras, C. M., Pappu, R., Witte, O. N., Chan, A. C., Satterthwaite, A. B.
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Chen, X., Kandasamy, K., Srivastava, R. K.
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