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Is a Component of the Growth Hormone-Regulated Network of Liver Transcription Factors1
Hormone and Metabolic Research Unit, Université Catholique de Louvain and Christian de Duve Institute of Cellular Pathology, Brussels 1200, Belgium
Address all correspondence and requests for reprints to: Dr. Frédéric P. Lemaigre, avenue Hippocrate 75, Box 7529, 1200 Brussels, Belgium. E-mail: lemaigre{at}horm.ucl.ac.be
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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(C/EBP)
binds to the hnf6 gene and inhibits its expression. This
inhibitory effect involved an N-terminal subdomain of C/EBP and two
sites in the hnf6 gene promoter. Using liver nuclear
extracts from GH-treated hypophysectomized rats, we found that GH
induces a rapid, transient decrease in the amount of C/EBP protein.
This GH-induced change is concomitant with the transient stimulatory
effect of GH on the hnf6 gene. Stimulation of the
hnf6 gene by GH therefore involves lifting of the
repression exerted by C/EBP in addition to the known GH-induced
stimulatory effects of STAT5 (signal transducer and activator of
transcription-5) and HNF-4 on that gene. Our data provide further
evidence that GH controls a network of liver transcription factors and
show that C/EBP participates in this process. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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HNF-6, HNF-3ß, and HNF-4 belong to a network in which
CCAAT/enhancer-binding protein- (C/EBP), the prototype of a
fourth family of liver-enriched transcription factors called bZIP (13, 14), also participates. The aim of this work was to investigate the
possibility that C/EBP could mediate the effects of GH on gene
transcription. As shown here, we found that the hnf6 gene
promoter binds C/EBP. We therefore investigated whether the activity
of C/EBP was GH sensitive and, if so, whether C/EBP could, by
controlling the hnf6 gene, participate in the hormonal
modulation of the hepatic network of transcription factors. Our data
demonstrate that GH treatment of hypophysectomized rats leads to a
rapid decrease in the amount of liver C/EBP protein at a time when
the liver HNF-6 messenger RNA (mRNA) concentration is known to increase
in response to GH. This is followed by an increase in the amount of
C/EBP mRNA and protein, which is concomitant with the reported
decrease in HNF-6 mRNA. Consistent with this, we found that C/EBP
represses the activity of the hnf6 gene promoter. The data
presented show that both C/EBP mRNA and protein levels are
controlled by GH. They also add a new loop to the regulation of the
hepatic network of transcription factors.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Cell cultures and transfections
COS-7 cells (6 x 105 cells/6-cm
plates) cultured in DMEM supplemented with 10% FCS were transfected
for 6 h in DMEM without FCS using
N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-triethyl-ammonium
methyl-sulfate (DOTAP, Roche Molecular Biochemicals,
Indianapolis, IN) and 10 µg C/EBP expression vector. Forty-eight
hours after transfection, the cells were washed with PBS and harvested
in 1 ml 40 mM Tris-Cl (pH 7.5), 1 mM EDTA, and
150 mM NaCl. The cells were pelleted and resuspended in 50
mM Tris-Cl (pH 7.9), 500 mM KCl, 0.5
mM EDTA, 2.5 µg/ml leupeptin, 1 mM
dithiothreitol, 0.1% (vol/vol) Nonidet P-40, 1 mM
phenylmethylsulfonylfluoride, and 20% (vol/vol) glycerol. After three
freeze-thaw cycles, the lysates were centrifuged, and supernatants were
collected for electrophoretic mobility shift assays (EMSA) or
deoxyribonuclease I (DNase I) footprinting. Rat hepatoma FTO-2B cells
were grown in DMEM/Ham’s F-12 medium supplemented with 10% FCS. Cells
(1 x 105 cells/well on 24-well plates) were
transfected in medium without FCS using Lipofectamine Plus (Life Technologies, Inc., Gaithersburg, MD), 400 ng of the indicated
reporter constructs, the amount of the expression vectors
indicated, and 30 ng pRL-138 as internal control. After 6 h, the
cells were washed with PBS and further incubated for 45 h in
DMEM/Ham’s F-12 medium supplemented with 10% FCS before measuring the
luciferase activities with the Dual-Luciferase kit (Promega Corp., Madison, WI) and a Promega Corp. TD20/20
luminometer. Luciferase activities were expressed as the ratio of
reporter activity (firefly luciferase) to internal control activity
(Renilla luciferase).
DNase I footprinting and EMSA
For DNase I footprinting on the HCI promoter region, a
BamHI-ClaI (-44 to +161) fragment of the rat
hnf6 gene promoter was labeled on the sense strand at the
ClaI site with [-32P]deoxy-GTP.
For DNase I footprinting on the HCII region, a
SacI-BamHI (-323 to -44) fragment of the rat
hnf6 gene promoter was labeled on the sense strand at the
BamHI site with [-32P]dGTP. The
incubations, which contained 15 µg rat liver nuclear protein or 15
µl COS-7 cell extracts and the probe, were carried out as previously
described (15) and were followed by analysis on 6% polyacrylamide-8
M urea sequencing gels. For EMSA, nuclear
extracts from rat liver (5 µg protein) or from COS-7 cells (5 µl
cell extract) were incubated on ice for 20 min in a final volume of 20
µl containing 10 mM HEPES (pH 7.6), 1
mM dithiothreitol, 1 mM
MgCl2, 0.5 mM EGTA, 50
mM KCl, 10% (vol/vol) glycerol, 4 µg
poly(dI-dC), and the 32P-labeled probe (30,000
cpm). The samples were loaded on a 6.5% acrylamide gel (29:1,
acrylamide/bisacrylamide ratio) in 0.25 x Tris-borate-EDTA buffer
and electrophoresed at 200 V. The following double stranded
oligonucleotides were used: C/EBP, 5'-GATCAATTCAATTGGGCAATCAGGAATT-3'
(16); HCI, 5'-CACGGATCCTTTTTGGAAATTAATATT-3' (-48 to -22 of the rat
hnf6 gene promoter); HCII,
5'-ACAGTCTGCAACAGTAACCGAGCCATGGCTCGA-3' (-224 to -192 of the rat
hnf6 gene promoter); and Sp1, 5'-ATTCGATCGGGGCGGGGCGAGC-3'
(Promega Corp.). The anti-C/EBP antibody (Santa Cruz Biotechnology, Inc., Santa Cruz, CA; sc-61-G, provided by
A. Bailly) was added to the incubations on ice 20 min before addition
of the labeled probe. Incubation was then allowed to proceed for 20 min
on ice before electrophoresis.
Expression vectors and reporter constructs
pcDNA-C/EBP and pcDNA-CHOP10 (both provided by D. Ron)
contain the C/EBP and CHOP-10 complementary DNA (cDNA) cloned into
the pcDNA-I expression vector. pCMV-C/EBPß was constructed by
inserting a 1.4-kb cDNA fragment (provided by V. Poli) into the
EcoRI site of pCMV-NH. Expression vectors for C/EBP
mutants were gifts of E. Ziff. The reporter construct pNF/0.75 luc,
which contains 752 bp of the rat hnf6 gene promoter upstream
of the firefly luciferase reporter gene, has been described previously
(17). pRL138, used as an internal control, contains the rat
6-phosphofructo-2-kinase gene liver promoter (-138 to +86) cloned in
pRLnull (Promega Corp.). To prepare the pNF/0.75 (HCI mut)
luc construct, two PCR reactions were carried out (the mutated
nucleotides are underlined). The first PCR was performed
with the following primers: TAC-M,
5'-CCCAACAGCACGGATCCTTTTAGGCCTTTAATATTAAAAAAG-3'
(-56 to -15 of the rat hnf6 gene promoter, sense strand);
and GL primer 2, 5'-CTTTATGTTTTTGGCGTCTTCC-3' (standard primer of pGL3
basic vector of Promega Corp.). In the second PCR the
amplified fragment from the first PCR was used as a primer with 3'SAC,
5'-CTACCGAATCTCAGCCACAG-3' (-240 to -221 of the rat hnf6
gene promoter, sense strand). The product of this PCR was digested with
XhoI and cloned in pNF/0.75 luc opened with XhoI.
pNF/0.75 (HCII mut) luc was made by PCR amplification with two sets of
primers: GAHC-s,
5'-AAAAGTACTGTCCTCCGGG-CTCGAGCTGGCGGGCGGCAC-3' (the
3'-end corresponds to -176 of the rat hnf6 gene promoter,
sense strand); and GL primer 2, as well as GAHC-as,
5'-AAAAGTACTCCGGCAGACTGTGGCTGAGATTGC-3' (the 3'-end
corresponds to -236 of the rat hnf6 gene promoter,
antisense strand); and PH6IIs, 5'-CCGCTGCCCACCCTCACGCCC-3' (-273 to
-253 of the rat hnf6 gene promoter, antisense strand). The
first fragment was digested with HindIII and
ScaI, and the second fragment was digested with
SacI and ScaI. The digested fragments were
gel-purified and ligated with pNF/0.75 luc opened at the
HindIII and SacI sites. In this way the HCII site
was replaced with a GAL4-binding site. For preparation of pNF/0.75
(HCI+HCII mut) luc, a BamHI-HindIII fragment of
pNF/0.75 (HCI mut) luc and a BamHI-SacI fragment
of pNF/0.75 (HCII mut) luc were ligated with pNF/0.75 luc opened at the
HindIII and SacI sites.
Immunoblotting
Liver nuclear extracts (20 µg protein) from hypophysectomized
male rats that had received a single injection of GH as indicated were
loaded on an 8% SDS-polyacrylamide gel. After electrophoresis, the
proteins were transferred to a polyvinylidene fluoride membrane
(Amersham Pharmacia Biotech, Aylesbury, UK) that was
incubated overnight with the anti-C/EBP antibody (Santa Cruz Biotechnology, Inc.; 1:5000) used for EMSA or with an anti-HNF-4
antibody (1:5000), provided by M. Pontoglio. Protein-antibody complexes
were visualized using the Enhanced Chemiluminescence Detection System
of Roche Molecular Biochemicals, Inc. (Mannheim,
Germany).
Northern blot analysis
Total RNA (20 µg) from the liver of hypophysectomized male
rats that had received a single injection of GH as indicated was
size-fractionated on a denaturing 1% agarose gel and transferred to a
nylon membrane (Hybond-N, Amersham Pharmacia Biotech) by
overnight vacuum blotting (VacuGeneXL, Pharmacia Biotech,
Uppsala, Sweden). After UV cross-linking (Stratalinker,
Stratagene, La Jolla, CA), the membrane was hybridized to
a rat C/EBP cDNA probe labeled by random priming with
32P. The membrane was rehybridized with a
32P-labeled oligonucleotide specific for 18S
ribosomal RNA to correct for variations in RNA concentration.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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binds to the hnf6 gene promoter
). Consistent with
this, the HCI region was protected by rat liver nuclear extracts in
DNase I footprinting experiments (Fig. 2A). To identify the DNA-binding proteins
involved, we performed EMSA with a probe corresponding to the HCI
region (Fig. 2B). Such experiments conducted with rat liver nuclear
extracts showed that the proteins that bind to site HCI belong to the
C/EBP family. Indeed, the specific complexes were prevented by addition
of a C/EBP-binding oligonucleotide, but not of a Sp1-binding
oligonucleotide (Fig. 2B, lanes 3–6). Pretreatment of the extracts at
80 C for 5 min showed that the complexes are heat stable (Fig. 2B, lane
8), as expected for C/EBP. The liver contains several C/EBP isoforms
that bind to DNA as homodimers or heterodimers (14, 18). Preincubation
with an antibody directed against the C/EBP isoform retarded the
migration of the main complex (Fig. 2B, lane 7). EMSA with extracts
from COS-7 cells transfected, or not, with a C/EBP expression vector
confirmed that C/EBP binds to the HCI site (Fig. 2B, lanes 1 and
2).
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binding to the hnf6 gene is inhibited by GH via a
posttranscriptional mechanism is involved in this control. We first
investigated by EMSA whether C/EBP binding to the HCI site in the
hnf6 gene promoter is influenced by GH treatment. We used
liver nuclear extracts from hypophysectomized rats that had received a
single injection of GH. As shown in Fig. 3A, the binding activity of C/EBP in
these extracts decreased 1 h after the injection of GH, almost
disappeared after 3 h, and returned to normal after 6 h. To
investigate the mechanism of this GH effect, we determined whether the
GH-induced changes in C/EBP-binding activity were due to changes in
the amount of C/EBP protein. Immunoblotting of the liver nuclear
extracts used for EMSA with a specific antibody against C/EBP showed
a clear correlation between binding activity and quantity of the two
isoforms of C/EBP, with an obvious decrease after 1 h, a strong
decrease after 3 h, and a return to normal after 6 h (Fig. 3B). These fluctuations were not due to differences in the amount of
total liver protein, as controlled by detection in the same immunoblots
of HNF-4, the amount of which did not change under these conditions
(12). The two C/EBP isoforms originate from a single mRNA by
differential usage of two translation initiation codons (19, 20). We
therefore investigated the possibility that the decrease in liver
C/EBP protein concentration seen within 3 h of GH injection
resulted from a decrease in liver C/EBP mRNA concentration. The data
presented in Fig. 3C discounted this hypothesis. Liver C/EBP mRNA,
measured by Northern blotting, actually increased with time after the
injection of GH. We concluded from these experiments that GH treatment
leads to 1) a rapid decrease in the amount of C/EBP in liver,
presumably by a posttranscriptional mechanism; and 2) a delayed
increase in C/EBP gene expression.
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inhibits hnf6 gene promoter activity concentration in liver described here. Thus, if C/EBP is
involved in the control of the hnf6 gene promoter, it should
not stimulate, but, rather, inhibit, its activity. To test this, rat
hepatoma FTO-2B cells were cotransfected transiently with a luciferase
reporter gene under the control of the hnf6 gene promoter
and with a C/EBP expression vector. Consistent with our model,
C/EBP strongly inhibited the activity of the hnf6 gene
promoter (Fig. 4). This inhibition
required binding of C/EBP to DNA, as it was prevented by CHOP-10,
which is a natural dominant negative isoform of C/EBP that prevents
its binding to DNA (21). Moreover, overexpression of C/EBPß did not
influence the activity of the hnf6 gene promoter (Fig. 4),
thereby demonstrating that the inhibitory effect of C/EBP is specific
to the C/EBP isoform. We next investigated whether inhibition of the
hnf6 gene promoter by C/EBP resulted from the binding of
C/EBP to its HCI site in the promoter. To do so, we repeated these
cotransfection experiments with a reporter construct in which the HCI
site had been destroyed by mutagenesis (Fig. 1
). EMSA experiments
demonstrated that the mutation abolished C/EBP binding (data not
shown). However, this mutation did not prevent C/EBP from inhibiting
the activity of the hnf6 gene promoter, and again, CHOP-10
blocked this inhibition (Fig. 4). We concluded that site HCI is not
involved, or is not the only region involved, in the inhibitory effect
of C/EBP on the hnf6 gene promoter.
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, we performed DNase I
footprinting experiments with regions of the hnf6 gene
promoter located further upstream by using as a source of protein
extracts from COS-7 cells transfected, or not, with the C/EBP
expression vector. As shown in Fig. 2C, a hypersensitive site appeared
at -196 with extracts from C/EBP-transfected cells. This
hypersensitive site was prevented by addition of an oligonucleotide
that binds C/EBP. Examination of the corresponding region (HCII), which
is perfectly conserved between rat and mouse, showed that it contains
several sequences that fit the C/EBP binding consensus (Fig. 1). All of
these sequences were mutated, as indicated in Fig. 1, to evaluate by
transfection the role of the HCII region in the inhibitory effect of
C/EBP. As shown in Fig. 4, mutation of the HCII region did not
prevent this inhibitory effect. However, the concomitant destruction of
C/EBP-binding sites in both the HCI and HCII regions abolished the
effect of C/EBP (Fig. 4).
Delineation of the transcription inhibitory domain in C/EBP
The experiments described above showed that C/EBP inhibits the
activity of the hnf6 gene promoter and that this effect
requires the integrity of both the HCI- and HCII-binding sites. C/EBP
belongs to the bZIP family of transcription factors, which contain a
basic DNA-binding domain and a leucine zipper dimerization domain in
the carboxyl-terminal region (16). The trans-activation
domain has been delineated by several groups (22, 23, 24), and it consists
of three elements, called TE-I, TE-II, and TE-III. To determine which
part of the C/EBP molecule mediates the inhibitory effect described
here, we performed transient cotransfection experiments with C/EBP
deletion mutants. These experiments showed that the inhibitory effect
of wild-type C/EBP was only mimicked by the mutant that contains the
TE-I subdomain. Mutants that contain only TE-II or TE-III did not exert
this inhibitory effect (Fig. 5). These
data show that the TE-I subdomain of C/EBP is required for the
inhibitory activity on the hnf6 gene promoter.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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inhibits the
expression of the hnf6 gene and that GH controls C/EBP.
This action of GH involves both a rapid, transient decrease in the
amount of C/EBP protein and a slow increase in C/EBP mRNA
concentration. The role of C/EBP in the GH control of the
hnf6 gene is understood when considering the kinetics of
hnf6 gene induction by GH. Indeed, hnf6 gene
expression is maximally induced 3 h after administration of GH and
is deinduced between 3 and 6 h after hormone treatment (12). This
profile is a mirror image of the DNA binding of C/EBP, which is
maximally decreased between 1 and 3 h after GH administration and
returns to normal levels 6 h after GH administration. GH-mediated
stimulation of the hnf6 gene is therefore associated with
the loss of a repressive effect exerted by C/EBP. We showed
previously that GH stimulates transcription of the hnf6 gene
by promoting the binding of STAT5 (signal transducer and activator of
transcription-5) and by increasing the binding of HNF-4 to the
hnf6 gene promoter (12). The regulation by GH of
hnf6 gene transcription therefore involves an increased
promoter activity mediated by a combination of stimulation and
derepression, followed by a decreased activity mediated by a repressive
mechanism.
How C/EBP protein levels are controlled by GH is not known. The
rapid decrease in C/EBP protein concentration after GH
administration points to the possibility that GH controls C/EBP mRNA
translation. A previous report (25) has shown that C/EBP translation
is negatively regulated by a short open reading frame located at the
5'-end of C/EBP mRNA. The effect of this open reading frame is
controlled, as it is weaker in liver compared with other tissues. Based
on these observations, we speculate that extracellular signals, such as
GH, may participate in the control of C/EBP translation by
modulating the activity of the upstream open reading frame.
C/EBP is generally known as a transcriptional stimulator. Our data
show that C/EBP inhibits hnf6 gene transcription. A
similar negative effect of C/EBP has been reported for the gene
coding for the ß2-adrenergic receptor (26). The
negative effect of C/EBP on the hnf6 gene requires two
cis-acting elements located between -22 and -44 and
between -192 and -224. As both sites need to be destroyed to abolish
the negative effect of C/EBP on the promoter, their activity can be
considered redundant. Although the proximal site shows up as a
footprint in DNase I protection experiments and detectably binds
C/EBP in the EMSA, the distal site was only found as a
C/EBP-induced DNase I-hypersensitive site in footprinting
experiments. Despite several attempts, we failed to detect C/EBP
binding to the distal site in EMSA experiments (data not shown). Our
current interpretation is that binding of C/EBP to the distal site
occurs in a complex of proteins that is unstable under the conditions
used in EMSA. An alternative interpretation would be that C/EBP
binds to the proximal site and to another site, distinct from the HCII
site, in the hnf6 gene promoter. C/EBP binding to this
unidentified site would then induce changes in the binding of other
factors to HCII.
Three subdomains, called TE-I, -II, and –III, have been identified in
C/EBP and are responsible for its transcriptional stimulation
properties. Here we show that subdomain TE-I is required for the
inhibitory effect of C/EBP. This subdomain is therefore
bifunctional, and we speculate that its activity is dependent on the
interaction with transcriptional coactivators or corepressors, the
recruitment of which is context dependent. A similar context-dependent
transcriptional stimulatory or inhibitory effect has been shown for the
NK-4 factor (27).
In the liver, transcription factors make up a regulatory network with
cross-regulatory and autoregulatory loops (13, 28). In this network
HNF-6 stimulates the hnf-3ß and hnf-4 genes
(11), and HNF-4, in turn, stimulates the hnf-6 gene (12).
C/EBP is also known to stimulate the hnf3ß gene (29),
which controls the hnf4 gene (28). In addition, the
autoregulation of the c/ebp, hnf-3ß, and
hnf-4 genes has been well documented (30, 31, 32) (Fig. 6). C/EBP has been shown to
participate in the liver-specific expression of genes regulated by GH
(33, 34) without being directly involved in mediating the effect of GH
on these genes. To our knowledge, the present study shows for the first
time that C/EBP is controlled by GH in the liver. We showed
previously that GH stimulates the expression of hnf6,
hnf3ß, and hnf4 in liver (7, 12). The GH
stimulation of the hnf3ß and hnf4 genes could
be mediated by HNF-6 and/or another mechanism. How the
c/ebp gene is controlled by GH is not known. Still, the
data presented here provide further evidence that GH modulates a
network of liver-specific transcription factors and demonstrate that
C/EBP is involved in this process. This network is schematized in
Fig. 6. Previous reports have shown that GH-regulated nuclear
factor (34), the GAGA factor (35, 36), and STAT1 and -3 (37)
also mediate the effects of GH in the liver. Whether these factors are
implicated in the network outlined in Fig. 6 remains to be
determined.
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Acknowledgments |
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and anti-HNF-4
antibodies, D. Ron for the C/EBP and CHOP-10 expression vectors, V.
Poli for the C/EBPß cDNA, and E. Ziff for plasmids encoding C/EBP
mutants. |
Footnotes |
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2 Senior Research Associate of the National Fund for Scientific
Research (Belgium).
Received December 2, 1999.
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References |
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) gene promoter involves autoregulation and several
ubiquitous transcription factors. Nucleic Acids Res 21:1735–1742This article has been cited by other articles:
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