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Unité d’Expression des Gènes Eucaryotes (P.M.F., F.B., M.M.Z.) and Unité de Neurobiologie Moleculaire (M.A.J.), Institut Pasteur, 75724 Paris; INSERM, U-369, Faculté de Médecine Laennec (J.M.S.), 69372 Lyon; and INSERM, U-423, Hôpital Necker (S.C.), 75015 Paris, France
Address all correspondence and requests for reprints to: Dr. Mario M. Zakin, Unité d’Expression des Gènes Eucaryotes, Institut Pasteur, 28 rue du Dr. Roux, 75724 Paris Cedex 15, France. E-mail: mzakin{at}pasteur.fr
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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CRH, the main physiological regulator of ACTH secretion and synthesis, is synthesized in the hypothalamus by the parvicellular neurons. These cells secrete CRH, which is delivered to the anterior pituitary gland, and through the cAMP pathway stimulates the secretion of the preformed ACTH. The CRH-induced increase in cAMP also stimulates the expression of the POMC gene and synthesis of a 30-kDa prohormone. Proteolytic cleavage of this protein leads to ACTH and ß-lipotropin production. ACTH, together with the octapeptide angiotensin II (AngII), control adrenal steroidogenesis in vivo. ACTH is the physiological regulator of the synthesis and secretion of glucocorticoids by the adrenal cortex, whereas AngII regulates the synthesis and secretion of mineralocorticoids. However, ACTH is also able to stimulate mineralocorticoid secretion, and AngII can stimulate glucocorticoid secretion as well. The parvicellular neurons, together with the pituitary corticotroph cells and adrenals, constitute the hypothalamo-pituitary-adrenal (HPA) axis that mediates the stress response.
The expression of Nur77 in the cells of this system suggests that the Nur77 protein performs signaling functions at all levels of the HPA axis. Indeed, Nur77 transcription has been shown to be induced in CRH neurons (10). In pituitary-derived cells, CRH-induced Nur77 activates transcription of the POMC gene through formation of protein homodimers that interact with the NurRE sequence present in the POMC promoter region (9). In adrenal glands, in vitro and ex vivo experiments have shown that this nuclear receptor acts as a mediator of ACTH-induced gene expression, resulting in increased steroidogenesis. The promoter sequences required for the synthesis of ACTH-regulated steroidogenic enzymes, such as the 21-hydroxylase (P450c21), contain NBRE-binding sites that are recognized and activated by Nur77 (11).
However, studies of adrenocortical function and regulation of the steroid P450c21 gene in the Nur77-deficient mouse demonstrated that the adrenal gland functions normally in these animals, indicating that Nur77 is not essential for HPA axis function (12). This result suggests that other members of the same subfamily of nuclear receptors are sufficient to maintain normal steroidogenesis in vivo by a compensatory mechanism.
Nor1 is the latest cloned member of the NGFI-B/Nur77 subgroup (1), and most of its properties are still unknown. In this report, the trans-activation and DNA-binding properties of the Nor1 protein, and the physiological effectors involved in its gene regulation were examined. The results are compared with those obtained for NGFI-B and indicate that the two proteins may play similar, albeit distinct, roles in adrenal cell function.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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N are constructs in which
nucleotides from the 5'-end of Nor1 cDNA were deleted, and pC are
constructs in which nucleotides from the 3'-end were deleted. The
resulting plasmids included the following deletions in the
corresponding products: pN7–32, amino acid residues 7–32;
p7–118, amino acid residues 7–11; pN7–210, amino acid residues
7–210; pC1–408, amino acid residues 409–628; and pC1–532, amino
acid residues 533–628. Some of these deletion mutants were generated
by PCR and ligation of amplified fragments using pSG5-Nor1 as a
template. pN7–32, pN7–118, and pN7–210 were generated using
oligonucleotides 5'–CCCGACTATGCCAAGCTG, 5'-ATTCCTCCTCCCTCTGGCC, and
(5'-CACCTGGGCTATGACCCC as forward primers, respectively, and
oligonucleotide 5'-GGCTTGCACGCAGGGCAT as the reverse primer. To
generate the plasmid pC1–532, pSG5-Nor1 was digested with
EcoRV and BglII; the BglII site was
then blunt ended, and the DNA was religated. pC1–408 was obtained
using the Gene-Editor In Vitro Site-Directed Mutagenesis System
(Promega Corp., Madison, WI), by introducing a stop codon
into the triplet encoding Leu408. The
oligonucleotide (5'-AGATCTTGCGTCTGTTTAAGCTCGGAC) was used to introduce
this latter mutation. The chloramphenicol acetyltransferase (CAT)
reporter plasmid, p3NBRE-TK-CAT, contains three copies of the NBRE site
cloned into pBLCAT5 upstream of the herpes simplex virus thymidine
kinase promoter (13). The p-72/65 P450c21-TK-CAT contains two copies
of the -65 element of the P450c21 5'-region cloned into pBLCAT5
upstream of the thymidine kinase promoter. The p5'-P450c21-luc or CAT
contains the -150/+9 region of cytochrome P450c21 cloned into the
pGL3-basic vector or into the pCAT3-basic vector, respectively
(Promega Corp.).
RNA extraction and Northern blots
Total cellular RNA was isolated by the guanidinium thiocyanate
procedure (14). RNA integrity was verified by denaturing formaldehyde
agarose gel electrophoresis and quantified by measuring absorbance at
260 nm. Total RNA (24 µg) was first denatured in 2.2 M
formaldehyde and 50% formamide at 55 C for 15 min and then run on a
1.5% formaldehyde agarose gel. RNA was blotted onto a nylon membrane
(Hybond-N, Amersham Pharmacia Biotech, Aylesbury, UK) by
capillary transfer. The membranes were hybridized with
32P-labeled Nor1 or NGFI-B probes at 42 C in a
buffer containing 50% formamide, 5 x SSC (standard saline
citrate), 4 x Denhardt’s solution, 0.1% SDS, and 10 µg/ml
salmon sperm DNA. A ß-actin probe was used to normalize RNA loading
between lanes. The Nor1 probe was a 409-bp fragment containing the
sequences between nucleotides 1908–2317. This fragment was obtained by
PCR, using rat Nor1 cDNA as a template.
In situ hybridization
The method used was essentially that previously described (15).
Oligodeoxynucleotides complementary to nucleotides 1191–1238 and
1272–1319 of the Nor1 sequence were 3'-end labeled to a specific
activity of 200–600 kBq/pmol, using
[33P]deoxy-ATP (NEN Life Science Products, Boston, MA) and terminal deoxynucleotidyl transferase
(Roche, Indianapolis, IN) following the manufacturer’s
specifications. Frozen adrenal glands from adult Sprague Dawley rats
(250–350 g) were cryostat sectioned (14 µm), thaw-mounted on
poly-L-lysine-coated slides, and stored at -80 C for 1–3
days. Experiments were performed according to the methods of Young
et al. (16), with the modifications described by Zoli
et al. (17). Probes were added to a concentration of 0.55
nM (corresponding to 
15 fmol/section).
Controls with nonradioactive oligonucleotides were performed as
previously described (17).
Cell culture
COS cells were grown in DMEM containing 4.5 g/liter glucose
supplemented with 10% FBS, penicillin (100 U/ml), streptomycin (100
µg/ml), fungizone and amphotericin (2.5 µg/ml),
L-glutamine (2 mM), and sodium pyruvate (10
mM) at 5% CO2 in 95% air. Y1 cells
were grown in DMEM/F-12 nutrient mix (1:1) supplemented with 10% FBS,
penicillin (100 U/ml), streptomycin (100 µg/ml), fungizone and
amphotericin (2.5 µg/ml), and L-glutamine (2
mM) at 5% CO2 in 95% air. Cells
were stimulated with forskolin (2 x 10-6
M; Sigma),
12-O-tetradecanoylphorbol 13-acetate (TPA; 2 x
10-7 M;
Sigma) or ACTH (10-8
M; Sigma) for various durations as
indicated below. Bovine fasciculata adrenal cells were prepared by
sequential treatment of adrenal cortical slices with trypsin (0.15%)
and cultured as previously described (18). Cells were stimulated with
ACTH (10-8 M), AngII
(10-7 M), forskolin
(2 x 10-6 M), or TPA
(2 x 10-7 M) for
various durations. The human epithelial carcinoma C33 cells were
cultured as previously described (19).
Transient expression assays
Twenty-four hours before transfection, 5 x
105 cells were plated in 3-cm dishes, then the
culture medium was changed 3 h before transfection. Plasmids
(prepared with the QIAGEN plasmid kit
(QIAGEN, Hilden, Germany) were introduced into cells using
the FuGENE 6 Transfection Reagent (Roche) according to the
manufacturer’s instructions or by the calcium phosphate precipitation
technique (19). Each dish was transfected with 5 fmol p3NBRE-TK-CAT,
p2NBREc21-TK-CAT, or p5'-450c21-CAT; 50 fmol pRSV-ß-galactosidase; 25
fmol expression vector (pSG5-Nor1 or pSG5-Nur77 or the pSG5-Nor1
mutants); or control plasmid (pSG5); and 25 fmol carrier plasmid DNA
(pBluescript KS+, Stratagene, La
Jolla, CA), which corresponded to about 2.0 µg/dish. Seventy-two
hours posttransfection, cells were washed, collected by centrifugation,
resuspended in 250 mM Tris-HCl and 15% glycerol (pH 7.5),
and lysed by four freeze-thaw cycles. Protein concentrations were
determined by the Bradford assay, and CAT activity was measured by
incubating 20 µg protein with 0.2 µCi
[14C]chloramphenicol (20 µCi/mmol) and 250
µM butyryl-coenzyme A in 100 ml 250 mM
Tris-HCl, pH 7.5, for 1.5 h at 37 C. Acylated chloramphenicol was
extracted using a mixture of 200 µl 2,6,10,14-tetramethylpentadecane
and xylene (2:1) and counted in a scintillation counter (20). The
relative CAT activities were normalized to ß-galactosidase
activity.
Gel mobility shift assays
Canonical NBRE
(5'-GATCGAGTTTTAAAAGGTCATGCTCAATTT-3'), -72/-65
P450c21
(5'-GCTCTAGAAGCAAAGGTCAGAGCTC-TAGAGC-3'), NurRE
(5'-TCCTAGTGATATTTACCTCCAAATGCCAGGA-3')
and MATE (5'-ATTAGAAAAGAGGAAGGAAATT-3')
oligonucleotides were 5'-end labeled with T4
polynucleotide kinase and purified on MicroSpin G-25 columns
(Pharmacia Biotech). The oligonucleotide MATE contains a
binding site for the transcription factor PU.1, present in the promoter
of the receptor Fc
gene. The DNA binding motifs are
underlined. Cell protein extracts and DNA-protein mobility
shift assays were performed as previously described (21, 22). The
anti-NGFI-B 2E1 monoclonal antibody was used in the supershifting
experiments (11). In this case, the antibody was preincubated with the
protein extracts for 10 min at room temperature before probe
addition.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). As in fetal and adult brain (1, 23),
a predominant 6.5-kb transcript was observed, as well as a second 5- to
5.5-kb transcript. In situ hybridization experiments showed
that the nuclear receptor was expressed in the adult mesoderm-derived
adrenal cortex (Fig. 1b), suggesting a role for Nor-1 in adrenocortical
function. This result is consistent with mRNA expression previously
observed in the adrenal cortex of embryonic day 16.5 rat embryos
(8).
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). Nor1 mRNA
synthesis was also rapidly induced, with an induction peak being
reached within 2 h of treatment. Expression of the Nor1 gene
clearly precedes that of the steroidogenic enzymes, such as cytochrome
P450c17 and 3ß-hydroxysteroid dehydrogenase (Fig. 2a). In addition,
the expression of P450c21 was significantly induced after 24 h of
hormonal treatment (data not shown). AngII is another hormone that
controls in vivo adrenal steroidogenesis, and its effect on
the steroidogenic responsiveness of cultured bovine adrenal fasciculata
cells is well documented (24). When these cells were treated with AngII
(10-7 M), cortisol
synthesis was rapidly stimulated, although to a lower extent than with
ACTH treatment. AngII treatment also induced Nor1 mRNA synthesis, but
in this case transcription of Nor1 began later than in the case of
ACTH, and P450c17 expression followed immediately this transcription
(Fig. 2b). These results clearly show that both hormones induce Nor1
expression in primary cultures of fasciculata cells and also indicate
that the Nor1 nuclear receptor may function as an intermediate in the
long-term effects of these hormones on adrenal steroidogenesis and cell
differentiation.
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indicate that Nor1 contains at
least two distinct regions, which when coupled to its DNA-binding
domain, promote transcription from NBRE sites. These regions correspond
to the two main trans-activation domains, AF-1 and AF-2,
previously described in several nuclear receptors including Nur77 (26).
In Nor1, AF-1 is localized between amino acid residues 1–118, at the
amino-terminus of the protein, whereas AF-2 is located between amino
acid residues 532–628, at the carboxyl-terminus. These results and a
comparison of the amino acid sequences indicate that the overall
structural and functional organization of Nor1 is similar to that of
Nur77.
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). Two protein-DNA complexes were
observed that were specifically competed by an excess of cold NBRE
oligonucleotide, but not by a heterologous oligonucleotide. Similar
protein-DNA complexes were detected when nuclear extracts from adrenal
glands were used (Fig. 4b); in the latter case, a faster migrating
complex was also observed. As the band corresponding to this complex
was partially supershifted when antibodies specifically directed to
Nur77 were used, we concluded that at least part of this complex
corresponds to Nur77 bound to NBRE.
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Recently, it was reported that Nur77 interacts as a homodimer with a
novel response element called NurRE, present in the POMC promoter. This
site is composed of two octamers loosely related to NBRE and arranged
in an inverse orientation separated by 6 bp (9). As shown in Fig. 4c
, Nor1 did not interact as a homodimer with this palindromic DNA motif,
even after the nuclear extract concentration was increased to a
3.5-fold excess. Two DNA-protein complexes similar to those observed
for Nor1 and NBRE were detected only after overexposure of the gel to
autoradiographic film (data not shown). Thus, Nor1, like Nur77,
interacts with DNA as a monomer through its interaction with NBRE
sequences. In contrast to Nur77, Nor1 failed to form homodimers capable
of interacting with the palindromic NurRE, but did bind weakly to the
NBRE-like sequences present in each half-site of the NurRE site.
Nor1 activates the expression of a reporter gene under the control
of the P450c21 promoter
Analysis of the promoter elements of genes involved in
steroidogenesis identified sequences containing the nuclear receptor
half-site AGGTCA. In particular, the -72/-65 sequence of the P450c21
promoter contains a canonical NBRE site (31). Gel retardation assays
showed that protein extracts from COS cells transfected with Nor1
interact with an oligonucleotide containing the P450c21 NBRE site (Fig. 5a). This indicated that Nor1 could also
participate in the induction of P450c21 gene expression, consistent
with the mRNA expression profile of both genes (see above). To further
explore the role of Nor1 in the transcriptional regulation of the
P450c21 promoter we analyzed first the ability of the protein to affect
the enhancing capacity of the -72/-65 element. Y1 cells were
transfected with the p-72/-65 P450c21-TK-CAT vector containing two
copies of the -72/- 65 element (see Materials and
Methods), and coexpression of Nor1 augmented significantly the
activity of the reporter gene (Fig. 5b). Having established that Nor1
activates transcription from the -72/-65 sequence, we investigated
its effect on the -150/+9 promoter region of the P450c21 gene.
Cotransfection experiments with different concentrations of the Nor1
expression vector were performed in Y1 (data not shown) or C33 cells
and showed that Nor1 increased the activity of a reporter gene under
the control of the P450c21 promoter (Fig. 5c). Thus, Nor1 binds
directly to the -72/-65 promoter element of the P450c21 gene and is
able to activate this promoter in a dose-response manner.
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), and this induction was additive in
the presence of both compounds. In all cases, the induction peak was
attained within 2 h of treatment, indicating that expression of
Nor1 in adrenal cells depends on protein kinase A (PKA) and protein
kinase C (PKC) pathways.
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), Nor1 expression was not induced by
ACTH, (Bu)2cAMP, forskolin, or TPA in the
adrenocortical tumor cells Y1. Its expression was strongly induced only
when these cells were treated with combinations of
(Bu)2cAMP and TPA, or forskolin and TPA (Fig. 6b). Thus, the mechanisms of transcriptional activation of Nor1 and
Nur77 appear to be different in Y1 cells. The differences observed between the induction of Nor1 transcription in primary cultures of normal fasciculata adrenal cells vs. the tumor cell line Y1, strongly suggest that in the latter case, factors essential for transcription are activated only when adenyl cyclase agonists and TPA act simultaneously.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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ACTH stimulates the transcriptional activation of steroidogenic enzymes and regulates glucocorticoid synthesis. Its effects are indirect and are mediated by the cAMP pathway and proteins, which are most likely transcription factors (32). ACTH rapidly induces Nur77 mRNA synthesis in adrenal glands, and it has been shown that, in transfected cells, the receptor increases the activity of the P450c21 promoter through its interaction with the NBRE sequence. This DNA motif is also present in the promoters of genes encoding other steroidogenic enzymes (31, 33). These observations strongly implicate Nur77 as an intermediary in ACTH activity that ultimately results in increased steroidogenesis (11). In this report, we determine that ACTH can also induce the transcriptional activation of Nor1 in primary cultures of adrenal fasciculata cells. AngII is another hormone that controls adrenal steroidogenesis in vivo. It has been demonstrated that, in addition to regulating aldosterone production in glomerulosa cells, AngII has a direct stimulatory effect on cortisol synthesis in cultured fasciculata cells and a trophic effect on ACTH receptor number and ACTH responsiveness (24, 25). Here we show that AngII also induces the expression of Nor1 in cultured cells. We further demonstrate that Nor1, through its interaction with NBRE sequences, increases the activity of the P450c21 promoter in transfected cells. These data and the analysis of the time-course effects of ACTH and AngII on the expression of genes encoding steroidogenic enzymes, strongly suggest that Nor1 acts as an intermediate in the action of both hormones and is involved in their long-term effects.
Sequence homology demonstrates that these nuclear receptors share a modular structure composed of several regions, named A/B, C, D, E, and F (26); the last one is absent in some receptors, including Nur77. The evolutionary conserved regions, C and E, contain the central zinc finger structure of the DNA-binding domain and the carboxyl putative ligand-binding domain, respectively. Two trans-activation functions have been attributed to region AF-1, located in the hypervariable N-terminal domain A/B, and to AF-2, located in region E (26). Our results indicate that an important activation domain is present in the amino-terminus of the Nor1 protein (amino acid residues 1–118). It has been shown that the sequence in the Nur77 A/B region that is important for its transcriptional activity, corresponds to N-54STFMDGYTGEFDTFLYQ70-C, a motif called TAB-1, enriched in hydrophobic and serine/threonine residues (34). The Nor1 sequence shows only 25% identity over its entire A/B region compared with the same region of Nur77 (1). Interestingly, the only sequence of Nor1 that is homologous to the Nur77 A/B region corresponds to TAB-1 (i.e. N-55STFMEGYPSSCELKPSCLYQ74-C). This finding strongly suggests that a TAB-I like sequence must also be important for Nor1 transcriptional activity. A region containing 14 histidines, 4 glutamines, and 1 proline, located between amino acid residues 99–118, link the AF-1 trans-activation domain of Nor1 to the rest of the molecule (1). Deletion analysis has also revealed that the profile of transcriptional activity mediated by the Nor1 carboxyl-terminal domain is also similar to that of Nur77 (34). Indeed, deletion of sequence 532–628 results in a significant decrease in transcriptional activity. However, deletion of sequence 409–532 partially restores the activity, suggesting that either the latter deletion is accompanied by a conformational change in the truncated protein or that the 409–532 sequence interacts with an inhibitory protein, and deletion of this region partially restores Nor1 activity. These results in addition to the 91% identity observed in their DNA-binding domains, strongly suggest that the overall structural and functional organization of Nor1 is similar to that of Nur77.
In contrast to Nur77, it has been previously demonstrated that Nor1 is unable to form heterodimers with RXR (8), whereas a mechanism for Nur77 action was recently reported that involves formation of homodimers and interaction with a DNA palindromic motif called NurRE (9). Both halves of the NurRE site are required for the responsiveness to physiological signals in pituitary-derived cells. In the present report we show that Nor1 fails to bind as a homodimer to the palindromic motif present in the POMC promoter.
In conclusion, the induction of Nor1 expression by ACTH and AngII, and its interaction with NBRE sequences present in the gene promoters of steroidogenic enzymes indicate that, like Nur77, Nor1 participates in the induction of the genes encoding these enzymes in adrenal cortex cells. In contrast, the inability of the protein to interact with the palindromic NurRE site by forming homodimers, may indicate that Nor1 cannot substitute for Nur77 function in the pituitary gland. During the submission of this manuscript, Maira et al. (35) indicated that the NurRE site of the POMC promoter is preferentially bound and activated by Nur77 homodimers. They also proposed that Nor1 may participate in the activation of the POMC gene essentially by a mechanism involving protein-protein interactions with Nur77. All of these data suggest that Nor1 has functions in the HPA axis that, compared with those of Nur77, are partly unique and partly redundant.
In primary cultures of fasciculata cells, both forskolin and TPA can induce Nor1 expression. The effect of this induction is additive when the cells are treated with the two compounds together. ACTH also induces Nor1 expression in the same cells, and its action is known to be mediated by an increase in cAMP levels. AngII also stimulates Nor1 expression and may exert its effects through the activation of both branches of the phosphoinositide pathway, PKC and Ca2+/calmodulin (36, 37, 38). Recent experiments show that the stimulatory effect of AngII on early-immediate gene mRNA levels in fasciculata adrenal cells is mainly exerted through the action of PKC (39). In Y1 tumor cells, Nor1 expression was strongly induced when cells were treated with combinations of (Bu)2cAMP and TPA, or forskolin and TPA. Therefore, Nor1 expression in adrenal cortex cells also appears to depend on the PKA and PKC pathways.
It is well established that activation of the cAMP-dependent PKA pathway by adenyl cyclase agonists results in phosphorylation and activation of the cAMP response element-binding protein and its subsequent binding to a promoter and the corresponding gene expression. It is also well known that the AP-1 complexes, which are induced by TPA, activate TPA-responsive elements. We can thus hypothesize the existence of TPA- and cAMP-responsive elements in crucial DNA regulatory regions of Nor1 that require the presence of activated AP1 and/or CREB to induce its specific gene expression. Indeed, isolation and characterization of the 5'-flanking region of the Nor1 gene will provide more insight into the mechanisms responsible for its regulation.
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Acknowledgments |
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Footnotes |
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2 Supported by a Saint-Exupery (CROUS) fellowship and the Faculty of
Chemistry, Biochemistry, and Pharmacy of the Universidad Nacional de
San Luis, Argentina.
Received October 19, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-hydroxylase, and
3ß-hydroxysteroid-dehydrogenase messenger ribonucleic acid and
proteins and on steroidogenic responsiveness to corticotropin and
angiotensin-II. J Clin Endocrinol Metab 78:1212–1219[Abstract]
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A. N. McEVOY, B. BRESNIHAN, O. FITZGERALD, and E. P. MURPHY Corticotropin-Releasing Hormone Signaling in Synovial Tissue Vascular Endothelium Is Mediated through the cAMP/CREB Pathway Ann. N.Y. Acad. Sci., June 1, 2002; 966(1): 119 - 130. [Abstract] [Full Text] [PDF]
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K.-H. Song, K. Lee, and H.-S. Choi Endocrine Disrupter Bisphenol A Induces Orphan Nuclear Receptor Nur77 Gene Expression and Steroidogenesis in Mouse Testicular Leydig Cells Endocrinology, June 1, 2002; 143(6): 2208 - 2215. [Abstract] [Full Text] [PDF]
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 A. N. McEvoy, E. A. Murphy, T. Ponnio, O. M. Conneely, B. Bresnihan, O. FitzGerald, and E. P. Murphy Activation of Nuclear Orphan Rece |
