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Growth and Development Section Molecular and Cellular Endocrinology Branch National Institute of Diabetes and Digestive and Kidney Diseases National Institutes of Health Bethesda, Maryland 20892
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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and HNF-1ß in H4-II-E extracts bind to the palindromic HNF-1
site. Both half-sites are required. Overexpression of HNF-1ß enhances
dexamethasone-stimulated promoter activity. Both the HNF-1 site and the
GRE must be intact for stimulation to occur. By contrast,
overexpression of HNF-1 does not enhance dexamethasone-stimulated
promoter activity, although, as also observed with overexpression of
HNF-1ß, it inhibits basal promoter activity. Thus, the synergistic
effects of HNF-1ß and the GR on dexamethasone-stimulated promoter
activity require that they are bound to the HNF-1 site and the GRE,
respectively, and may involve protein-protein interactions between the
transcription factors, or between them and the basal transcription
machinery or a steroid receptor coactivator. Synergy between the
ubiquitously expressed GR and HNF-1, which is developmentally regulated
and expressed in a limited number of tissues, provides a possible
mechanism for tissue- and development-specific regulation of
glucocorticoid action. |
INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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5ß1 integrin), as described in Chinese
hamster ovary (CHO) (24) and vascular smooth muscle (25) cells, may
contribute to this potentiation. Glucocorticoids are important physiological and pathological regulators of IGFBP-1. Plasma IGFBP-1 is increased after cortisol infusion in human volunteers (7). Glucocorticoid deficiency after adrenalectomy reduces the dramatic increase in hepatic IGFBP-1 mRNA seen in insulin-deficient diabetic rats, suggesting that glucocorticoids play a permissive role in the regulation of the IGFBP-1 gene by insulin (26). Administration of glucocorticoids to 4-week-old rats increased hepatic IGFBP-1 mRNA (13), and dexamethasone treatment of pregnant rats increased IGFBP-1 mRNA in fetal liver in association with severe fetal growth retardation (27). Glucocorticoids also increased IGFBP-1 in cultured human bone cells (28).
We have studied the mechanism of glucocorticoid regulation of rIGFBP-1 promoter activity in the H4-II-E rat hepatoma cell line in which the synthetic glucocorticoid, dexamethasone, stimulates rIGFBP-1 gene transcription (10) and promoter activity (14, 29). Of the three sites in the proximal rIGFBP-1 promoter that bind recombinant human glucocorticoid receptor (GR) (29), the site at nucleotides (nt) -91/-77 with respect to the transcription initiation site corresponds to a consensus glucocorticoid response element (GRE) that must be intact for dexamethasone stimulation to occur (14, 29). Although this single GRE is necessary for dexamethasone stimulation of rIGFBP-1 promoter activity, maximal stimulation also requires the participation of one or more additional cis-elements (30). These include: nt -62/-50, which closely resembles the consensus binding sequence for hepatocyte nuclear factor-1 (HNF-1) (31); nt -108/-99, an insulin response element (IRE) that is necessary for the inhibition of promoter activity by insulin; and the region between nt -252/-236. Under most circumstances, maximal stimulation by glucocorticoids can occur with different combinations of these accessory sites, suggesting that the rIGFBP-1 promoter uses these accessory sites to compensate for the low affinity of its single functional GRE as proposed by Schüle et al. (32). The transcription factors binding to the three accessory sites in the rIGFBP-1 promoter have not been identified.
To begin to elucidate the mechanism by which transcription factors
binding to these accessory sites might act synergistically with the
glucocorticoid receptor (GR) bound to the GRE, we have focused, in this
study, on the putative HNF-1 site. The HNF-1 consensus binding sequence
is found in many genes that are preferentially expressed in liver (31)
and binds the related homeodomain-containing transcription factors,
HNF-1 and HNF-1ß, as homodimers or heterodimers (33, 34, 35). In the
present study, we demonstrate that HNF-1 and -ß are present in
H4-II-E extracts, and that they bind to the HNF-1 site. Overexpression
of HNF-1ß enhances dexamethasone-stimulated promoter activity in
plasmids in which the HNF-1 site and the GRE are intact, whereas
overexpression of HNF-1 does not affect dexamethasone-stimulated
promoter activity.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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) that has been shown to bind two related
transcription factors, HNF-1 and HNF-1ß, both of which occur in at
least three isoforms (36). HNF-1 and HNF-1ß have similar
DNA-binding domains and bind to the canonical HNF-1 sequence with
comparable affinity (31, 33, 34, 35).
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). As seen in lane 2, a predominant DNA-protein
complex was observed when untreated H4-II-E cell nuclear extract was
incubated with an oligonucleotide probe corresponding to nt -72/-40
of the wild type rIGFBP-1
promoter.1 [The pattern was
unchanged when nuclear extracts prepared from dexamethasone-treated
H4-II-E cells were used (results not shown).] Complex formation was
inhibited competitively by coincubation with unlabeled wild type probe
added at 20- or 100-fold molar excess (lanes 2 and 3), but not by a
nonspecific oligonucleotide (nt -135/-92 of the rIGFBP-1 promoter,
lanes 11 and 12).
Both half-sites of the putative HNF-1 site (nt -62/-50) were required
for DNA-protein complex formation (Fig. 1B). Oligonucleotides, in which
all six nucleotides in either the 5'-half-site (ML-6, lanes 4 and 5) or
the 3'-half-site (MR-6, lanes 8 and 9) of the putative HNF-1 site were
substituted, failed to inhibit the formation of complexes with the wild
type oligonucleotide probe even when added at 100-fold excess.
Oligonucleotide ML-3, used in earlier studies by us (30) and by Powell
and colleagues (37, 38), in which only three of the nucleotides in the
5'-half-site were mutated, retained some affinity for the H4-II-E
nuclear proteins (lanes 6 and 7). The presence of an MR-6 substitution
mutation in a nt -327/+79 probe fragment also abolished protection of
the nt -62/-50 region by H4-II-E nuclear extract in deoxyribonuclease
I (DNase I) protection assays (results not shown). Thus, both
half-sites of the HNF-1 consensus sequence must be intact for the
observed complex to form.
HNF-1 and HNF-1ß in H4-II-E Nuclear Extracts Bind to the
Putative HNF-1 Site
To determine whether the protein(s) in H4-II-E extracts that bound
to the wild type nt -72/-40 oligonucleotide probe were related to
HNF-1 or HNF-1ß, gel shift assays were performed after
preincubation of H4-II-E nuclear extract with nonimmune rabbit serum,
or antiserum to HNF-1 or HNF-1ß (Fig. 2). Incubation with nonimmune serum did
not affect complex formation (lanes 2 and 3). By contrast, incubation
with either antiserum to HNF-1 (lane 4) or antiserum to HNF-1ß
(lane 5) decreased the abundance of these DNA-protein complexes, in
part due to the formation of multiple supershifted complexes. Thus, the
observed DNA-protein complexes contain both HNF-1 and HNF-1ß.
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Enhances Dexamethasone
Stimulation of rIGFBP-1 Promoter Activity or -ß on
dexamethasone-stimulated rIGFBP-1 promoter activity, H4-II-E cells were
cotransfected with reporter plasmid p327 containing the nt -327/+79
fragment of the rIGFBP-1 promoter, together with an HNF-1 expression
plasmid, an HNF-1ß expression plasmid, or a control plasmid. When
cotransfected with control plasmid, the promoter activity of the p327
construct was stimulated about 17-fold by dexamethasone (shown as 100%
in Fig. 3) relative to the promoter
activity in cells not treated with hormone. Overexpression of HNF-1
by cotransfection of the HNF-1 expression plasmid did not affect
dexamethasone stimulation, whereas overexpression of HNF-1ß by
cotransfection of the HNF-1ß expression plasmid enhanced
dexamethasone stimulation of p327 by 230% compared with cotransfection
of the control plasmid (Fig. 3, left panel).
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had no effect on dexamethasone
stimulation, we wanted to verify that functional HNF-1 was
expressed. Overexpression of HNF-1 (37) or HNF-1ß (39) had been
reported to enhance basal activity of the human (h)IGFBP-1 promoter in
several human cell lines, irrespective of whether the cells expressed
HNF-1. We examined the effect of HNF-1 overexpression on basal
promoter activity of the rIGFBP-1 gene in H4-II-E cells (Fig. 3, right panel). In H4-II-E cells, overexpression of HNF-1
or HNF-1ß decreased basal promoter activity of p327 by 73%, compared
with the basal promoter activity of p327 cotransfected with the control
plasmid.2 These results indicate that: 1)
the HNF-1 expression vector is functional in H4-II-E cells; 2) the
effects of HNF-1 and HNF-1ß on dexamethasone-stimulated and basal
promoter activity are different; and 3) the functional interaction of
overexpressed HNF-1ß with the GR that results in enhanced
dexamethasone stimulation of rIGFBP-1 promoter activity is not seen
with overexpression of HNF-1.
Both the HNF-1 site and the GRE must be intact for overexpression of
HNF-1ß to enhance dexamethasone stimulation of rIGFBP-1 promoter
activity (see Figs. 4 and 5). When H4-II-E cells were cotransfected
with p327 and an HNF-1ß expression plasmid, dexamethasone stimulation
was increased by 220%, compared with contransfection with a control
vector (Fig. 4). By contrast, when
HNF-1ß was overexpressed in H4-II-E cells transfected with an HNF-1
construct containing an MR-6 mutation in the 3'-half site (p327HNF-1
m), dexamethasone stimulation was not enhanced. Thus, the HNF-1 site
must be intact for HNF-1ß to enhance dexamethasone-stimulated
promoter activity.
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).
H4-II-E cells were cotransfected with the HNF-1ß expression vector
and a reporter plasmid containing either a wild type IGFBP-1 promoter
fragment (p327) or a fragment containing a mutation in the 3'-half-site
of the GRE (p327GREm). Overexpression of HNF-1ß increased
dexamethasone-stimulated promoter activity of p327 by 230%, but did
not enhance promoter activity in p327GREm. Binding of the activated GR
to the functional GRE of the rIGFBP-1 promoter was required for
HNF-1ß to enhance dexamethasone stimulation of rIGFBP-1 promoter
activity. |
DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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The HNF-1 site is required for optimal dexamethasone stimulation of
rIGFBP-1 promoter activity (30). Dexamethasone-stimulated promoter
activity was reduced to 54% of wild type levels when a stringent HNF-1
mutation (MR-6) was introduced into plasmid p327 containing the nt
-327/+79 promoter fragment (Fig. 4). This promoter fragment contains
the other two accessory sites, indicating that they cannot fully
substitute for the requirement of an intact HNF-1
site.3
Two related transcription factors, HNF-1 and HNF-1ß, bind to
the HNF-1 site as homodimers or heterodimers (31, 33, 34). HNF-1 and
HNF-1ß have similar NH2-terminal dimerization and central
DNA-binding domains (43), but differ in their COOH-terminal
transactivation domains (34). Consistent with the binding of HNF-1
and HNF-1ß as homodimers or heterodimers, both half-sites of the
HNF-1 element in the rIGFBP-1 promoter are required for dexamethasone
stimulation. Electrophoretic mobility shift assays using antisera to
HNF-1 and HNF-1ß demonstrated that both factors are present in
H4-II-E nuclear extracts, consistent with previous studies using rat
hepatoma cell lines related to H4-II-E; these earlier studies showed
that both HNF-1 and HNF-1ß are expressed in differentiated liver
cell lines such as H4-II-E, whereas only HNF-1ß is expressed in
undifferentiated cells (35). Both transcription factors form
DNA-protein complexes with an oligonucleotide corresponding to nt
-72/-40 of the rIGFBP-1 promoter that contains the HNF-1 site.
To study the effect of HNF-1 on glucocorticoid stimulation of the
rIGFBP-1 promoter, H4-II-E cells were cotransfected with plasmid p327
and with expression plasmids for HNF-1 or HNF-1ß. Overexpression
of HNF-1ß enhanced dexamethasone stimulation of rIGFBP-1
promoter activity. This increased stimulation required that both the
GRE and HNF-1 sites on the rIGFBP-1 promoter were intact, indicating
that the synergistic effects of HNF-1ß on dexamethasone-stimulated
promoter activity involved the interaction of transcription factors
binding to the two nearby sites.
By contrast, overexpression of HNF-1 did not enhance
dexamethasone-stimulated rIGFBP-1 promoter activity. This was not due
to a failure to express the HNF-1 plasmid, since overexpression of
HNF-1 inhibited basal promoter activity.
Differences in transcriptional activity between HNF-1 and HNF-1ß
probably reflect differences in their transactivation domains (34). For
the human C-reactive protein promoter (35), HNF-1ß was more active
than HNF-1 in HeLa cells, whereas HNF-1 was more active than
HNF-1ß in Fr3T3 cells; neither cell expresses HNF-1 or ß.
Although overexpression of HNF-1 and HNF-1ß previously have been
reported to increase the basal activity of many promoters (33, 35, 37, 39, 44), little information has been available suggesting possible
participation of HNF-1 in gene regulation by glucocorticoids. Despite
intensive study of sites involved in glucocorticoid stimulation of
phosphoenolpyruvate carboxykinase promoter activity in liver-derived
cells (45, 46), and although HNF-1 synergistically stimulated basal
activity of the phosphoenolpyruvate carboxykinase promoter in a mouse
hepatoma cell line cotransfected with a CAAT/enhancer binding
protein- expression plasmid (47), HNF-1 involvement in
glucocorticoid stimulation has not been reported. While the present
manuscript was in preparation, Faust et al. (48) reported
that HNF-1 and the GR participated in dexamethasone stimulation of the
mouse phenylalanine hydroxylase (PAH) promoter. The presence of a
3.8-kb enhancer region from the PAH gene in reporter plasmids
containing either the PAH promoter or a heterologous thymidine kinase
promoter enabled dexamethasone to induce promoter activity in a cell
line closely related to H4-II-E. Full inducibility was localized to a
360-bp fragment that contained three GREs and two HNF-1 sites.
Dexamethasone stimulation of the thymidine kinase promoter was greatly
decreased by mutation of one of the HNF-1 sites.
The mechanism by which HNF-1 bound to the HNF-1 site and the GR bound
to the GRE act synergistically to increase dexamethasone-stimulated
rIGFBP-1 promoter activity is unknown. Possibilities include 1)
protein-protein interactions between HNF-1 and the GR while both
factors are bound to their respective cis-regulatory
elements, or 2) interaction of one or both factors with the basal
transcription machinery or with a coactivator for steroid hormone
receptors. Direct protein-protein interactions with the GR have been
described for c-jun (49), CREB (50), and other transcription
regulatory proteins. The only protein other than HNF-1 that is known to
interact with HNF-1 is an 11-kDa dimerization cofactor for HNF-1 (DCoH)
(43). DCoH binds to the N-terminal regions of HNF-1 and HNF-1ß,
stabilizing HNF-1 dimers and increasing their transactivation
potential.
Direct protein-protein interactions between HNF-1ß and the GR may occur despite the fact that the HNF-1 site and the GRE must be intact for optimal dexa-methasone-stimulated promoter activity. In the ICAM-1 (intercellular adhesion molecule-1) gene, which is synergistically activated by Stat1 (signal transducer and activator of transcription) and the transcription factor Sp1, the cis-elements that bind both factors are required for functional activity despite the fact that Stat1 and Sp1 can be coimmunoprecipitated from solution (51). The binding of either factor to its respective cis-element may induce a conformational change that facilitates its binding to the other protein.
Activated steroid receptors may contact the basal transcription machinery directly or indirectly by forming complexes with coregulatory proteins (52). Synergistic interactions of HNF-1 may arise by regulating the interaction between the GR and one of its coactivators. As precedent for this model, the retinoblastoma protein directly interacts with the steroid receptor coactivator hBrm to up-regulate GR-mediated transcriptional activation (53).
In contrast to the stimulatory effect of HNF-1ß overexpression on
dexamethasone-stimulated rIGFBP-1 promoter activity, overexpression of
HNF-1 or HNF-1ß inhibited basal rIGFBP-1 promoter activity, as
previously described for the ApoCIII, ApoAI, and HNF-1 genes (54).
The reason for this inhibition is unclear. It appears to be, at least
in part, an indirect effect on the rIGFBP-1 promoter since some partial
inhibition is observed even when the HNF-1 site is mutated (results not
shown).4
Synergistic interactions between HNF-1 and HNF-1ß, transcription
factors that are developmentally regulated and expressed in only a
limited number of tissues (31, 35, 40, 41), and the GR, a nuclear
receptor that is capable of acting at many tissues, provide a potential
mechanism for a ubiquitously expressed hormone to exert
tissue-selective actions.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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or HNF-1ß were raised to amino acids 541–561 in the COOH
terminus of HNF-1 (33) and to amino acids 66–94 in the amino
terminus of HNF-1ß (34) and were kindly provided by Drs. Cereghini
(Institut Pasteur, Paris, France) and Crabtree (Stanford University,
Palo Alto, CA), respectively. Expression plasmids for HNF-1 (55)
and HNF-1ß (34) were graciously provided by Dr. Crabtree. A control
plasmid (pcDL-SR296) for cotransfection experiments containing the
same promoter and vector sequence, but lacking a cDNA insert encoding
HNF-1 or HNF-1ß, was kindly provided by Drs. S. Najjar and S.
Taylor (NIDDK).
Plasmid Construction
Plasmid p327LUC (abbreviated p327) contains a nt -327/+79 (with
respect to the transcription initiation site, +1) fragment of the
rIGFBP-1 promoter ligated into plasmid pA3LUC (kindly provided by Dr.
William M. Wood, University of Colorado, Denver, CO) in the sense
orientation relative to a promoterless firefly luciferase reporter gene
(14). Plasmid p327GREm, previously designated p327M6 (14), contains a
substitution mutation in the 3'-half of the GRE.
The 3'-half of the HNF-1 site (-62 GACAATCATTAAC -50) was mutated in a nt -327/+79 promoter fragment by PCR amplification of two fragments overlapping at the BamHI site (nt -82/-77) using the conditions previously reported (30). The 3'-fragment was amplified using a 5'-primer that began at the BamHI site and included the mutated HNF-1 site (-62 GACAATCcggcca -50). The two PCR fragments were annealed and ligated into pA3LUC. The resulting construct contains the MR-6 mutation and was designated p327HNF-1 m.
All plasmids used in transfection studies were prepared using a Qiagen plasmid extraction kit (Qiagen, Inc, Chatsworth, CA), and were quantitated by absorbance at 260 nm. The sequence of the IGFBP-1 promoter insert was confirmed using PRISM Ready Reaction DyeDeoxy Terminator Cycle Sequencing Kit and 370A DNA Sequencer (Applied Biosystems, Foster City, CA).
Transfection and Luciferase Assay
Stock cultures of the H4-II-E cell line, established from the
well differentiated Reuber H35 rat hepatoma (56), were grown as
monolayer cultures (14) and were transfected using
diethylaminoethyl-dextran as previously described (30). Each 60-mm
culture dish of H4-II-E cells received 5 µg plasmid DNA containing
rIGFBP-1 fragments and 1.4 µg of plasmid pXGH5 expressing human GH to
control for transfection efficiency (14). [For cotransfection
experiments, 2 µg of HNF-1 or HNF-1ß expression plasmid or 2
µg of the control plasmid were added at the same time]. The medium
was replaced with serum-free DMEM containing 0.1% BSA and the cells
were incubated overnight. Some of the media were collected before
dexamethasone addition for quantification of GH using a solid phase RIA
kit (Allegro HGH, Nichols Institute Diagnostics, San Juan Capistrano,
CA), after which the medium was replaced with serum-free DMEM
containing 0.1% BSA with or without dexamethasone (1 µM)
as indicated. After 24 h incubation, the cells were lysed and
luciferase activity was assayed in cell lysates as previously described
(30).
Electrophoretic Mobility Shift Assay
Nuclear extracts were prepared from confluent H4-II-E cells as
described by Hennighausen and Lubon (57) with minor modification of the
buffers (30). Oligonucleotides corresponding to nt -72/-40 and nt
-135/-92 of the rIGFBP-1 promoter were synthesized. Equimolar
quantities of complementary strands were annealed by heating at 100 C
for 5 min and cooled to room temperature. The annealed fragments were
labeled with [
-32P]ATP (>7000 Ci/mmol) using T4
polynucleotide kinase. H4-II-E cell nuclear extract (6.7 µg) was
incubated with the oligonucleotide probe (2–4 fmol, 20,000 cpm) for 30
min at room temperature in a reaction mixture (20 µl, final volume)
consisting of 2 µg of poly(dI-dC)·poly(dI-dC) acid buffer [1
mM Tris, pH 7.4, 5% glycerol, 1 mM
MgCl2, 1 mM EDTA, and 1 mM
dithiothreitol]. In competition studies, unlabeled double-stranded
oligonucleotides were added immediately before the probe. The reaction
mixtures were then loaded onto a 4% nondenaturing polyacrylamide gel
that had been preelectrophoresed at 150 V for 1 h at 4 C. The gel
and electrophoresis buffer contained 1 x and 0.5 x TBE
(1 x TBE = 44.5 mM Tris-borate, 1 mM
EDTA, pH 8.3), respectively. Electrophoresis was carried out at 10 mA
for 2 h. Gels were dried and autoradiographed at -70 C using
intensifying screens. In studies designed to immunologically identify
the protein component of the protein-DNA complexes, 1 µl of antiserum
against HNF-1 or HNF-1ß was incubated with the nuclear
extract for 30 min at room temperature, after which the probe was added
for an additional 30 min (final volume 20 µl).
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Although only a single complex is evident in
Fig. 1b, multiple DNA-protein complexes could be distinguished when
gels with better resolving power were used (results not shown). These
may arise from different combinations of the three isoforms of HNF-1
and HNF-1ß generated by alternative splicing (33 36 ). 
2 Inhibition of basal rIGFBP-1 promoter activity
by overexpression of HNF-1 or HNF-1ß was observed when
transfections were performed with various amounts (0.01 µg to 3 µg)
of HNF-1 or HNF-1ß expression plasmids (results not shown). No
significant inhibition of basal promoter activity was observed after
overexpression of HNF-1 or HNF-1ß in constructs in which the HNF-1
site was mutated (results not shown).
3 We previously reported that an intact HNF-1 site
only was required for optimal stimulation of rIGFBP-1 promoter activity
by dexamethasone under some, but not all, experimental conditions (30 ).
In plasmid p92, in which the HNF-1 site was the only accessory site
present in addition to the GRE, the HNF-1 site was necessary. By
contrast, in plasmid p327 containing the nt -327/+79 promoter
fragment, which includes all three accessory sites (the HNF-1 site, the
IRE, and the nt -252/-236 site), the presence of any two sites was
sufficient for optimal dexamethasone-stimulated promoter activity,
suggesting that the sites were interchangeable. The HNF-1 mutation
(ML-3) used in these experiments (30 ), however, retained some affinity
for the HNF-1 site (Fig. 1B). When the more stringent MR-6 mutation was
introduced into plasmid p327 and used in transfection assays,
dexamethasone-stimulated promoter activity now was reduced to 54% of
wild type levels despite the presence of the other two accessory sites
(Fig. 4).
4 The effect of overexpressing a particular
isoform of HNF-1 or HNF-1ß might differ from the activity of
endogenous HNF-1. Inhibition might occur if endogenous HNF-1 dimers (or
particular isoforms) stimulate basal promoter activity, whereas
overexpression of a particular isoform of either protein favors the
formation of inactive dimers.
Received for publication June 20, 1997. Revision received August 14, 1997. Accepted for publication August 19, 1997.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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5 ß1 integrin
by means of its Arg-Gly-Asp sequence. Proc Natl Acad Sci USA 90:10553–10557 and HNF-1ß (vHNF-1) share dimerization and homeo domains,
but not activation domains, and form heterodimers in vitro.
Genes Dev 5:1042–1056-fetoprotein promoter and enhancer. Biochem J 301:49–55
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