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Molecular Endocrinology Section, Department of Chemical Endocrinology, St Bartholomew’s and the Royal London School of Medicine, and Dentistry, London EC1A 7BE, United Kingdom
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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The most probable explanation for this phenomenon could be the existence of tissue-specific regulatory elements in the ACTH-R promoter. Of particular relevance to ACTH-R expression are several factors that have been shown to be involved in steroidogenic or adrenal-specific expression. The orphan nuclear receptor steroidogenic factor 1 (SF1) is probably the best characterized (11, 12) and has been shown to be involved in steroidogenic cell-specific expression of several genes (13, 14, 15, 16, 17, 18, 19) and in the development of the adrenal and gonad (20, 21, 22). An adrenal-specific nuclear protein (ASP) has also been shown to be involved in the human CYP21B gene expression (23, 24). Disruption of the orphan nuclear receptor DAX-1 has been implicated in X-linked adrenal hypoplasia congenita, suggesting a specific role in adrenal and gonadal development (25). Furthermore, some ubiquitous factors such as NGFI-B (26) and AP1 (27) have been shown to be involved in the regulation of adrenal-specific gene expression.
We have previously reported the cloning and expression of the mouse ACTH-R (28, 29). In this report we describe the characterization of the mouse ACTH-R gene structure and the cloning of its promoter. This promoter has been functionally analyzed in the well characterized Y1 mouse adrenocortical cell line, which has been shown to express the ACTH-R and respond to ACTH (30, 31). Our data indicate the existence of two important regions that regulate tissue-specific expression of the gene. One of these regions suggests a role for SF1, or a closely related protein, in the determination of steroidogenic cell specificity of ACTH-R expression.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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). This was subcloned, sequenced, and
shown to comprise the ACTH-R coding sequence and a 5'-untranslated
sequence of 241 bp (Fig. 1B). Comparison between this cDNA fragment and
the ACTH-R genomic sequence indicated that the mouse ACTH-R gene
consisted of at least two exons with an intron/exon junction 96 bp
upstream of the translation start codon (Fig. 1B). The exonic nature of
the sequence was confirmed using S1 nuclease protection assay (32) with
mouse adrenal mRNA and a genomic probe spanning the putative
intron/exon junction in which only the predicted exonic sequence was
protected against S1 nuclease digestion. Another probe derived from the
5'-RACE cDNA product was fully protected against digestion (data not
shown).
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, the ACTH-R mRNA was relatively abundantly expressed
in adrenal tissue. However, low expression of this gene was also
apparent in abdominal adipose tissue. Expression could not be detected
in spleen, testis, liver, lung, heart, whole brain, or kidney.
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). The restriction fragments marked with
arrows in the figure were subcloned and sequenced. In this
way the 5'-untranslated region was shown to consist of two separate
exons. Exon 1 overlapped the 5'-end of the RACE clone by 33 bp. Exon 2
consisted of 112 bp, which together with the 96 bp at the 5'-end of
exon 3, encode the 5'-untranslated region of this gene. The genomic
clones 4 and 5 contained exon 2 while clones 1, 2, and 3 contained exon
1. The NcoI-positive fragment from clone 1, containing exon
1, was subcloned, sequenced, and shown to contain 1.8 kb upstream
sequence expected to be the mouse ACTH-R promoter. This fragment was
therefore analyzed further.
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). There was a second
protected fragment corresponding to an exon of 109 bp implying that
there were two major start sites for transcription separated by 4 bp.
The intensity of these two protected fragments was similar, indicating
that both transcription start sites are used with equivalent
efficiency.
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) did
not reveal any of the classic promoter features such as a TATA box,
CAAT box, or GC-rich region. However, there is an initiator-like
sequence overlapping the transcription start site (dashed
underlining in Fig. 5), and there are a number of consensus
response elements as depicted in Fig. 5 including an OctB site, an Sp1
site, a glucocorticoid response element, an AP2 site, an AP1 site, and
two SF1-like sites at positions -897 bp and -25 bp, respectively.
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), showing the expected cell-specific
activity of this promoter.
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. Figure 6A summarizes the effect of
these deletions on luciferase reporter activity in the three cell
lines. There was no significant difference between the full length
[p(1808)] construct and all the other deletions up to -113 bp in Y1
cells. No significant luciferase activity was detected for any of the
constructs in L cells. In TM3 cells no luciferase activity was detected
after transfection with the full length construct or the two constructs
p(1590) and p(1236). In contrast, when the deletion constructs p(908),
p(717), p(641), and p(113) were transfected, they all showed luciferase
activity in TM3 cells at a significantly lower level than in Y1 cells
with the exception of p(113), which appeared to induce transcription at
an equivalent level to the minimal promoter in Y1 cells.
Identification of a Binding Site for SF1
Of the transcription factor consensus binding motifs
identified, the SF1-like sequence at position -25 bp was of particular
interest in connection with ACTH-R tissue-specific expression because
it is the only recognized site in the construct p(113) that showed
promoter activity specifically in Y1 cells and TM3 cells. We therefore
used site-directed mutagenesis to alter the -25 SF1 consensus sequence
in the p(113) construct at two critical nucleotides’ SF1 binding site
(AAGGTT 
ATTGTT). The results of an
independent series of experiments performed in Y1 cells are shown in
Fig. 6B and indicate a highly significant loss of promoter activity in
p(113)mutant to 38% of that of p(113) itself (P <
0.01).
Further evidence for the involvement of SF1 at the -25-bp site was
sought using gel shift analysis. A 46-bp fragment surrounding the
SF1-like binding site at position -25 bp was used as the labeled probe
(see Fig. 7A). A DNA/protein complex (CI) was found to
be formed using cellular extracts from Y1 cells. A similar complex was
apparent when a cellular extract from TM3 cells was used. However, no
such complex was observed with extracts from L cells (Fig. 7B),
although a certain amount of very slowly migrating nonspecific material
was present. In Y1 cell extracts a second complex (CII) was also
formed. Specificity of the interaction was confirmed by displacement of
the DNA/protein complexes by a 200-fold molar excess of an unlabeled
consensus SF1- binding site derived from the rat CYP17 gene
(19), providing further evidence that the protein involved in these
complexes was SF1 (Fig. 7B).
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), and do not have any ACTH-R promoter activity (Fig. 6A).
Heterologous expression of SF1 in these cells resulted in significant
induction of ACTH-R promoter activity (P < 0.05)
whereas no effect was observed using a promoterless construct (Fig. 8), lending support to the hypothesis that SF1 is an
essential factor for ACTH-R expression.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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The knowledge of this structure has enabled us to use RT-PCR as a
highly sensitive method of mRNA detection with intron-skipping primers
followed by Southern blotting. As shown in Fig. 3, ACTH-R mRNA is
relatively abundantly expressed in the adrenal gland, as is well
recognized. However, there is also low expression in abdominal adipose
tissues. This site has already been shown to express ACTH-R by binding
studies, and recently this has been confirmed by Northern blot analysis
(9) and has been proposed to mediate the lipolytic action of ACTH.
Thus, our data confirm the tissue-specific nature of ACTH-R gene
expression, and it is the molecular mechanism of this regulation,
especially at the level of the adrenal cortex, that has been the focus
of our further studies. It is of interest that an abstract recently
presented by another group (34) indicated the existence of a fourth
alternatively spliced exon lying between exons 1 and 2. This is
probably an uncommon splice variant that we have been unable to
identify but may be represented by the weak higher molecular weight
band in the adrenal RT-PCR shown in Fig. 2B.
Sequence analysis of the 5'-untranslated flanking region of the ACTH-R
gene indicated that the region immediately upstream of exon 1 does not
show any typical characteristics of promoter regions such as a TATA
box, CAAT box, or GC-rich region. However, there is an initiator-like
site overlapping the transcription start site. The initiator element
(Inr), first identified for viral transcriptional regulation (for
review see 35 , has been shown to be involved in transcription
initiation of a growing number of TATA box-containing and TATA-less
promoters. In addition to this Inr-like sequence, there are several
putative sites for transcription factors as shown in Fig. 5. Of
particular interest is the presence of a partial consensus sequence at
position -25 bp for binding of the mouse transcription factor SF1,
which has been shown to be involved in tissue-specific expression of
several steroidogenic enzymes (11, 12, 13, 20) as well as
Mullerian-inhibiting substance (15), and the glycoprotein hormone
-subunit (16). SF1 has also been shown to be involved in the cAMP
responsiveness of the cytochrome P450c17 enzyme expression (19).
Therefore, this sequence motif represents a strong candidate for
regulation of ACTH-R gene expression. Recently, Naville et
al. (33) have reported the promoter sequence for the human ACTH-R
gene revealing that it also contains an Inr element and an SF1-like
site at position -35.
The presence of a glucocorticoid response element in the ACTH-R promoter is also important because glucocorticoids have been shown to induce a significant increase of ACTH-R expression in ovine adrenocortical cells (36). The molecular mechanism of this effect is not yet known but may occur at the transcriptional level. It is noteworthy that the ACTH-R promoter does not contain any consensus cAMP response element (CRE) despite the fact that ACTH is recognized to stimulate ACTH-R expression via cAMP (31, 37). However, this lack of a consensus CRE is a common feature for the cAMP-regulated steroidogenic enzymes and may suggest the existence of a yet uncharacterized cAMP-dependent regulatory factor. In the case of CYP17, this function has been shown to be fulfilled by SF1 (19), but that does not seem to be the case for the other steroidogenic enzymes. The functional importance of both of these regulatory elements will be addressed in our future work. In contrast, the human ACTH-R contains seven CRE-like elements in the proximal 700 bp of this promoter, although these have not yet been shown to be functional (33).
The promoter activity of the ACTH-R 5'-untranslated region was assessed
after insertion upstream of the luciferase coding sequence in the pGL3
basic vector. It has been shown that this DNA fragment is necessary and
sufficient to drive expression of a heterologous gene in a
cell-specific manner, since the signal was detectable in Y1 cells but
not in TM3 or L cells. Deletion studies allowed us to define two
important regions for cell-specific expression. Promoter activity
became detectable in TM3 cells when sequences upstream of position
-908 bp were removed, despite remaining undetectable in L cells (Fig. 6A). These results suggest that the ACTH-R promoter is potentially
active in steroidogenic tissues other than the adrenal, but is totally
inhibited by the binding of a factor between position -1236 bp and
-908 bp that would act as a repressor of expression in nonadrenal
steroidogenic cells such as the Leydig cell. The existence of such
transcriptional repressors or silencers responsible for tissue-specific
expression of genes has been reported for several genes. However, our
results are the first evidence for a repressor restricting gene
expression in the adrenal gland.
In Y1 and TM3 cells, the minimal promoter extended to -113 bp, which includes the putative SF1-like binding site described earlier. This suggests that SF1 might be a strong candidate for determining steroidogenic-specific expression of the ACTH-R as it does for several other genes. Our data lend support to the notion that SF1 or an SF1-like factor is involved in ACTH-R cell-specific regulation since 1) Mutation of the SF1 site leads to significant loss of promoter activity; 2) it binds specifically to this site as shown by gel shift analysis; and 3) expression of SF1 in a cell line that normally does not have any ACTH-R promoter activity leads to an induction of its activity. However, the level of promoter activity obtained in these conditions is low, indicating that SF1 may be essential to induce the promoter in an "active conformation" whereas other factors are probably necessary for full promoter activity. In keeping with this, it is noteworthy that mutation of the SF1 site leads only to a significant reduction of activity and not complete loss of promoter function. The role of the second SF1-binding site at position -897 bp has not been extensively studied. However, it seems that SF1 binding at this site of the promoter may be more critical in TM3 cells than in Y1 cells because its absence in both constructs p(717) and p(641) resulted in a significant decrease of promoter activity in TM3 cells whereas it was almost without effect in Y1 cells. The significance of these results will need further investigation.
In conclusion, the tissue-specific expression of the ACTH-R gene appears to be mainly under the control of two factors, with SF1, or an SF1-like factor, responsible for steroidogenic cell specificity, and another as yet unknown factor binding between position -1236 bp and -908 bp silencing the promoter in nonadrenal steroidogenic cells. It might be postulated that binding of such a repressor protein upstream of the SF1-binding site prevents the formation of an SF1-dependent transcriptionally active complex.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Rapid Amplification of cDNA Ends
The Marathon cDNA Amplification kit (Clontech, Cambridge, UK)
was used following the manufacturer’s protocol. The mouse ACTH-R gene
antisense primer was 5'-GACCTGGAAGAGAGACATGTAG3-'. RNA was extracted
from mouse adrenal tissues using RNazolB (Biogenesis, Poole, Dorset,
UK), and mRNA was purified using a Sephadex oligo-dT column (Pharmacia,
Herts, UK). One microgram of this mRNA was used per reaction. The PCR
product was subcloned directly in the pGEM-T vector (Promega,
Southampton, UK) and sequenced using sequenase 2.0 (Amersham).
RT-PCR
Ten micrograms of total RNA from the following frozen mouse
tissues were analyzed: whole brain, kidney, lung, spleen, abdominal
adipose tissue, lung, adrenal, heart, and testis. One hundred nanograms
of oligo-dT were used to prime the Superscriptase (GIBCO BRL) for
1 h at 42 C in a 20-µl reaction mixture. One microliter was used
as template for PCR with: mouse ACTH-R exon 1 sense primer:
(5'-CTTGCCGAGAAAGATCCT-3') and exon 3 antisense primer:
(5'-AGCGATGTGAAGGTGAGC-3'), or the ß-actin sense primer:
(5'-GTAACCAACTGGGACGAT-3') and antisense primer
(5'-GACCACACCCCACTATGG-3').
Reaction conditions were 30 sec at 94 C and 30 sec at 56 C for ACTH-R or 58 C for ß-actin and 1 min at 72 C for 30 cycles.
In the case of the ACTH-R, PCR products were run on a 1% agarose gel,
transferred to nitrocellulose membrane, and hybridized in 50%
formamide, 5 x NaCl-sodium citrate, 0.05 M sodium
phosphate buffer (pH 6.8), 0.3 mg/ml herring sperm DNA, 5 x
Denharts solution, 0.05% SDS, with approximately 106cpm
-32P-labeled ACTH-R probe at 42 C for 16 h. The
filters were washed under stringent conditions (1 x NaCl-sodium
citrate, 0.1% SDS) at 65 C and exposed to Kodak XAR-5 film (Eastman
Kodak, Rochester, NY) at -80 C for 3 h or overnight for the long
exposure.
S1 Nuclease Protection Assay
The reaction conditions were as described previously (32). PCR
was performed with a biotinylated sense primer MP237S:
5'-TACAACCTTCACAATCTGC-3' designed in the putative promoter region and
a phosphorylated antisense primer at the 3'-end of exon 1:
5'-CTGAAGTAGGATCTTTCTCG-3'. Fifty micrograms of total mouse adrenal RNA
were hybridized with this probe overnight at 43 C.
Plasmid Constructs
For the full-length construct p(1808), PCR was performed using
Vent polymerase (New England Biolabs., Beverly, MA) with a sense
primer: 5'-GACCATTAACTTTGAATTAGG-3' at the 5'-end of the
NcoI fragment and an antisense primer complementary to exon
1: 5'-CTGAAGTAGGATCTTTCTCG-3' using the genomic positive clone 1 as
template. This was subcloned into the SmaI site of the
pGL3-basic luciferase reporter vector (Promega, Madison, WI), and PCR
artefacts were excluded by sequencing. For the promoter deletions,
p(1808) was digested with specific enzymes as follows: -1590 bp,
KpnI; -1236 bp, NheI; after separation of the
insert and the backbone, the plasmid was religated on itself. For the
following deletions, p(1808) was cut with KpnI and another
specific enzyme, the ends were filled using Klenow fragment, and the
plasmid was religated: -908 bp, Bsg1; -717 bp,
TthIII.1; -641 bp, ApaI; -113 bp,
BstX1. The constructs or at least their 5'- extremities were
checked by sequencing.
Cell Culture and Transfection Experiments
Mouse Y1 adrenal cells were maintained in 50% DMEM and 50%
Ham’s F10 supplemented with 12.5% horse serum and 2.5% FCS. Mouse
TM3 cells (kindly provided by Dr Ray Iles) were grown in 50% DMEM and
50% Ham’s F12 supplemented with 5% horse serum, 2.5% FCS, and 20
mM HEPES (pH 7.4). Mouse L cells (kindly given by Prof. Tom
MacDonald) were grown in RPMI containing 5% FCS. Approximately
106 cells were washed and resuspended in HEPES- buffered
saline and 500 µl were used per electroporation at 300 V and 1000
milliFarads in 2-mm wide cuvettes with 5 µg of the ACTH-R gene
construction and 10 µg of RSV-CAT plasmid. Cells were left 1 min at
room temperature and then resuspended in their respective growth medium
in 60-mm plates for 72 h. Five micrograms of SF1 expression vector
were cotransfected with 5 µg of the p(908) construct in L cells in
the conditions described above. Because the transfection efficiency was
constant, RSV-CAT was not used systematically in all experiments.
Luciferase Activity and Chloramphenicol Acetyltransferase (CAT)
Protein Measurement
The luciferase assay kit (Promega) was used for this purpose.
The cells were washed twice at room temperature with PBS, covered with
400 µl lysis reporter buffer for 20 min at room temperature, scraped,
recovered in Eppendorf tubes, and snap frozen at -70 C. The cell
debris was pelleted and 100 µl of the supernatant were used for
luciferase activity measurement with 400 µl lysis reporter buffer and
100 µl luciferase substrate solution. One hundred fifty microliters
of the supernatant were used for measurement of CAT protein level
according to the CAT ELISA protocol (Boehringer Mannheim, Lewes, UK).
Mutagenesis of the -25 bp site in the p(113) plasmid was accomplished
using the QuikChange technique (Stratagene Ltd., Cambridge, UK) with
Pfu polymerase. The identity of mutated clones was
determined by DNA sequencing.
Electrophoretic Mobility Shift Assay
To prepare the probe an antisense ACTH-R primer,
5'-GACAGCTACTTGTTATCC-3', was labeled with [
32P]ATP
using T4 polynucleotide kinase (New England Biolabs.) and used for PCR
with an unlabeled ACTH-R sense primer, 5'-CCGTTTATTTCTAGTGAC-3'
producing a 46-bp fragment surrounding the SF1-like site, which was
purified with microcentrifuge 5000 tubes (Sigma). Binding reactions of
10 µl were carried out in buffer containing 15 mM HEPES,
75 mM KCl, 9 mM MgCl2, 0.075
mM EDTA, 12.5% glycerol, 1 mM dithiothreitol,
0.1 mg/ml sperm DNA, approximately 5 x 103cpm of
radiolabeled probe, and 30 mg of cellular extracts proteins for the
three cell lines prepared as described previously (36). The reactions
were incubated for 15 min at 30 C. Competitor was added 15 min before
the probe and incubated at 30 C. Free and bound DNA were separated on a
4% nondenaturing polyacrylamide gel in 0.5 x Tris-borate-EDTA at
4 C. The gels were dried and analyzed by autoradiography.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Present address: IGBMC, BP163, C.U. de Strasbourg, 67404 Illkirch,
France. 
Received for publication August 7, 1996. Revision received February 17, 1997. Accepted for publication February 28, 1997.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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D. Lopez, T. W. Sandhoff, and M. P. McLean Steroidogenic Factor-1 Mediates Cyclic 3',5'-Adenosine Monophosphate Regulation of the High Density Lipoprotein Receptor Endocrinology, July 1, 1999; 140(7): 3034 - 3044. [Abstract] [Full Text]
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A. J. Reinhart, S. C. Williams, B. J. Clark, and D. M. Stocco SF-1 (Steroidogenic Factor-1) and C/EBP{beta} (CCAAT/Enhancer Binding Protein-{beta}) Cooperate to Regulate the Murine StAR (Steroidogenic Acute Regulatory) Promoter Mol. Endocrinol., May 1, 1999; 13(5): 729 - 741. [Abstract] [Full Text]
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 K.-i. Morohashi, H. Tsuboi-Asai, S. Matsushita, M. Suda, M. Nakashima, H. Sasano, Y. Hataba, C.-L. Li, J. Fukata, J. Irie, et al. Structural and Functional Abnormalities in the Spleen of an mFtz-F1 Gene-Disrupted Mouse Blood, March 1, 1999; 93(5): 1586 - 1594. [Abstract] [Full Text] [PDF]
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R. Qiu, C. Frigeri, and B. P. Schimmer A Role for Guanyl Nucleotide-Binding Regulatory Protein {beta}- and {gamma}-Subunits in the Expression of the Adrenocorticotropin Receptor Mol. Endocrinol., December 1, 1998; 12(12): 1879 - 1887. [Abstract] [Full Text]
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 P. A. Crawford, C. Dorn, Y. Sadovsky, and J. Milbrandt Nuclear Receptor DAX-1 Recruits Nuclear Receptor Corepressor N-CoR to Steroidogenic Factor 1 Mol. Cell. Biol., May 1, 1998; 18(5): 2949 - 2956. [Abstract] [Full Text]
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 Y. Sadovsky and P. A. Crawford Developmental and Physiologic Roles of the Nuclear Receptor Steroidogenic Factor-I in the Reproductive System Reproductive Sciences, January 1, 1998; 5(1): 6 - 12. [Abstract] [PDF]
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A. L. Jacob, J. Lund, P. Martinez, and L. Hedin Acetylation of Steroidogenic Factor 1 Protein Regulates Its Transcriptional Activity and Recruits the Coactivator GCN5 J. Biol. Chem., September 28, 2001; 276(40): 37659 - 37664. [Abstract] [Full Text] [PDF]
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A. H. Baig, F. M. Swords, L. A. Noon, P. J. King, L. Hunyady, and A. J. L. Clark Desensitization of the Y1 Cell Adrenocorticotropin Receptor. EVIDENCE FOR A RESTRICTED HETEROLOGOUS MECHANISM IMPLYING A ROLE FOR RECEPTOR-EFFECTOR COMPLEXES J. Biol. Chem., November 21, 2001; 276(48): 44792 - 44797. [Abstract] [Full Text] [PDF]
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