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(Received for publication, March 20, 1995; and in revised form, July 12, 1995) From the
Most of the known effects of aldosterone are mediated by the
mineralocorticoid receptor, an intracellular receptor belonging to the
steroid/thyroid hormone/retinoic acid receptor superfamily. We
determined the genomic structure of the human MR (hMR) and identified
10 exons in the gene, including two exons (1
Molecular cloning of a cDNA encoding the human renal
mineralocorticoid receptor (hMR)( The adrenal steroids aldosterone
and cortisol both bind to the mineralocorticoid receptor (type I
corticosteroid receptor); cortisol also binds to the glucocorticoid
receptor (type II receptor). Specificity is conferred by the enzyme
11 Recent studies have reported the presence
of multiple variants of the rat mineralocorticoid receptor mRNA, which
encode for the same protein but diverge in their 5`-untranslated
sequences(10) . These mineralocorticoid receptor mRNAs are
expressed in a tissue-dependent manner and are very likely to be under
the control of different promoter sequences, allowing thus an
independent regulation of each mRNA isoform. The hMR gene has been
localized to chromosome 4q31.1-4q31.2(11, 12) .
We have characterized the structure of the hMR gene and determined the
location of the hMR splice sites. Two different 5`-untranslated exons
were identified which splice into a common translated region.
Expression of these mRNA species is controlled by two distinct
promoters.
Alternative 5` variants of the
mineralocorticoid receptor mRNA were searched for by RACE using reverse
primers located in exon 2 at position 311 and 280 for the first and
second round of amplification, respectively. After subcloning PCR
fragments, colonies which did not hybridize to an exon 1 Nucleotide sequences were
analyzed using the suite of programs provided by the Australian Genomic
Information Service and by CITI 2.
Figure 1:
Structure of the hMR gene. A,
schematic representation of the hMR mRNA including the two alternative
5`-exons (1
Figure 2:
DNA sequence of the region upstream of
exon 1
The transcription
initiation site of hMR
Figure 3:
DNA sequence of exon 1
In the present study we have determined the genomic
organization of the hMR gene. The two different mRNA 5`-ends isolated
by RACE suggested the existence of alternative promoters in the hMR
gene, as has been reported for the mouse glucocorticoid receptor (34) and suggested for the rat mineralocorticoid
receptor(10, 32) . The expression of the two mRNAs is
not mutually exclusive, since the two transcripts were both found in
the kidney. Alternative transcription initiation from exon 1 It is interesting to
compare the genomic structure of the hMR, hGR, hAR, and
hPR(20, 23, 24) , all belonging to the same
steroid receptor subfamily(3, 5) . Although in these
genes the same exon-intron organization is used to assemble functional
domains of the receptor protein (eight exons), no structural
conservation is found for 5`-untranslated exons and regulatory regions.
hGR has a unique 5`-untranslated exon, whereas only eight exons
compose the hAR gene. The expression of both is driven by a unique
promoter, whereas the hPR gene (24, 35) contains two
different hormone-inducible promoters (Fig. 4).
Figure 4:
Comparison of the genomic organization of
hMR, hGR, hAR, and hPR. The locations of the translational start and
stop codons are
indicated(20, 23, 24) .
The DNA
surrounding the transcription initiation site of hMR As with the promoters
directing expression of other steroid receptors (20, 24, 34, 35, 38, 39) ,
including the rat mineralocorticoid receptor (32) , both P1 and
P2 do not contain any TATA box or CCAAT motifs within the first 100 bp,
though several potential Sp-1-binding sites are present. Promoters with
these features are found primarily in housekeeping genes and usually
contain several transcription initiation sites as well as several
potential binding sites for the transcription factor
Sp-1(36) . The hMR gene is thus regulated by alternative
promoters(40, 41) . This mechanism allows more
flexibility in the control of expression and generally, alternative
promoters are associated with tissue- and/or developmental-specific
gene expression. In the rat, MR Although
mineralocorticoid receptor is known to bind specific consensus
sequences, such as the GREs contained in the MMTV promoter(1) ,
no specific mineralocorticoid-responsive element has yet been
identified. P1 contains a sequence resembling a GRE in an inverted
orientation, which has been shown to confer hormone responsiveness to
exogenous promoters in an orientation-independent manner(47) .
It is worth noting that a significant and selective increase in MR In conclusion, the determination of the genomic
structure of the hMR will allow the study of its transcriptional
regulation and of the tissue-specific and developmental expression of
distinct hMR mRNA species. It will also facilitate the search for
mutations in the human mineralocorticoid receptor gene which may be
responsible for disorders of salt and water balance, such as
mineralocorticoid resistance or hypertension.
The nucleotide
sequence(s) reported in this paper has been submitted to the
GenBank[GenBank]and U30816[GenBank].
Volume 270,
Number 36,
Issue of September 08, pp. 21016-21020, 1995
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
Discussion
FOOTNOTES
ACKNOWLEDGEMENTS
REFERENCES
and 1
) that
encode different 5`-untranslated sequence. Expression of the two
different hMR variants is under the control of two different promoters
that contain no obvious TATA element, but multiple GC boxes. Our
results indicate that hMR expression is regulated by alternative
promoters perhaps in a tissue- or developmental-specific manner.
)(1) identified it
as a member of the nuclear receptor superfamily, which includes the
other steroid hormone receptors as well as the thyroid and retinoic
acid receptors and a large group of orphan
receptors(2, 3) . Nuclear receptors are highly
specialized ligand-dependent transcription factors which interact with
specific cis-acting elements to enhance or repress target gene
expression(4) . They share the same structure-function
organization, and their cDNAs are highly conserved particularly in
those regions associated with DNA and hormone binding. The
mineralocorticoid and glucocorticoid receptor are closely related, and
together with the progesterone and androgen receptors they form a
subfamily which is closely related both by sequence and functional
criteria(3, 5) .-hydroxysteroid dehydrogenase, which converts cortisol to the
less active compound cortisone, thus allowing aldosterone to bind to
mineralocorticoid receptor(6, 7) . The
mineralocorticoid receptor is expressed in so called
``classical'' aldosterone target tissues, which are sodium
transporting epithelia (kidney, colon, salivary, and sweat glands) and
in a variety of non-epithelial target tissues, such as the central
nervous system, mononuclear leukocytes, large blood vessels, and the
heart(8) . In the kidney, the mineralocorticoid receptor
regulates the sodium, potassium, and hydrogen ion balance in the distal
part of the nephron. In the central nervous system, the
mineralocorticoid receptor is expressed in many areas of the forebrain
with very high levels of expression reported in the rodent hippocampus.
In some, but not all regions in the brain, the mineralocorticoid
receptor responds to the diurnal fluctuations in cortisol levels and
thus provides, together with the glucocorticoid receptor, a system
capable of responding to normal and elevated cortisol concentrations,
respectively(9) .
Isolation and Characterization of Genomic
Clones
A human placental cosmid library (Stratagene, La Jolla,
CA), a human placental lambda phage library(13) , two human
leukocyte cosmid libraries, and a chromosome 4 enriched cosmid library
were screened using three different EcoRI restriction
fragments of the human mineralocorticoid receptor cDNA following
standard colony hybridization techniques(14) . Labeling was
performed by random priming with nonamers and
[-P]dCTP (Megaprime DNA labeling system,
Amersham). Positively hybridizing colonies were picked and passaged
until complete purification. DNA of positive clones was prepared
following standard techniques(14) . Cosmid and phage DNA was
digested with different restriction enzymes and characterized by
Southern blot analysis using specific
[
-
P]dATP-labeled oligonucleotides as
probes(15, 16) . Positive restriction fragments were
subcloned and sequenced by the dideoxy chain termination method (17) using Sequenase (U. S. Biochemical Corp.). The sequence of
the exon 1
/intron P1 boundary and confirmation of the cDNA
sequence was obtained by direct sequencing of the cosmid and by
subcloning into M13 for single-stranded sequencing using Taq polymerase (Promega Biotech) and formamide-containing
polyacrylamide gels.Inverse PCR
Inverse PCR was performed according to
Ochman et al.(18) . Briefly, human genomic DNA was
digested with different restriction enzymes (HaeIII, RsaI, MspI, and Sau3A). The purified digests were
circularized and submitted to 35 rounds of PCR amplification using
exon-specific primer pairs. Oligonucleotide primers (20-23-mers)
were designed, using the predicted exon-intron organization of the
hMR(19, 20) , to be located in the center of each exon
to be amplified. PCR primers were as follows (numbering corresponds to
the position of the 5`-nucleotide according to the published hMR cDNA
sequence(1) , S identifies primers in sense orientation and A
in the antisense orientation): S180 and A83; S2190 and A2187; S2810 and
A2803; S2969 and A2942. PCR products were fractionated on a 2% agarose
gel, subcloned into Bluescript-KS, and sequenced.Rapid Amplification of cDNA Ends (RACE)
Mapping of
the hMR transcription initiation site by RACE (21) was
performed using a commercial kit (5`-RACE, Life Technologies, Inc.)
following the instructions of the manufacturer. Total human kidney RNA
was extracted by standard techniques (22) and submitted to
reverse transcription using a reverse primer (23-mer) located at
position 480 according to the published mineralocorticoid receptor cDNA
sequence(1) . The 3`-tailed cDNA was submitted to 30 rounds of
PCR amplification using an oligo(dC) sense primer and a nested reverse
primer (at position 311). PCR included a denaturation step at 96 °C
for 30 s, an annealing step at 56 °C for 30 s, and an elongation
step at 72 °C for 1 min, after an initial denaturation at 94 °C
for 5 min and followed by 10 min elongation. 0.05% of the initial PCR
product was subsequently reamplified under the same conditions with a
sense oligo(dC) primer containing several cloning sites and a second
nested reverse primer at position 83. The PCR products were subcloned
into Bluescript-KS and screened with an exon 1-specific
oligonucleotide (position 7); positive clones were sequenced by the
dideoxy chain termination method.-specific
oligonucleotide (position 7) probe were sequenced. Exon 1-specific
oligonucleotide probes were synthesized and used for direct sequencing
of a cosmid containing exon 1.
Positions of Cosmid Clones, Phage Clones, and Inverse
PCR Products on the hMR Gene
Four cosmid clones and three phage
clones were characterized after the screening for clones containing hMR
gene sequences using the hMR cDNA as probe (Fig. 1). Cosmid
clones cos25 and cos31 were mapped to the 3`-end of the gene using
primer A3206 as a probe (primer position according to the published
cDNA(1) . 9b was characterized using oligonucleotide S1786
and A448 and mapped to the 5`-end of the mineralocorticoid receptor
gene. Primer S2054, which maps to the DNA-binding domain, was used to
characterize clone
14, and phage clone
131 was mapped to the
hormone-binding domain of the receptor using oligonucleotides S2381 and
A2683. Clones cos72 and cos953 were isolated using EcoRI
fragments of the original hMR cDNA(1) . Three different inverse
PCRs were performed to specifically amplify putative exons not covered
by the cosmid/phage clones as indicated (i1-i3). The sequence
of the exon for the published 5`-untranslated and its flanking sequence
were determined from both cosmid clone cos72 and also using inverse PCR (ip1). Following the nomenclature used for the rat
gene(10) , this is designated as the
5`-untranslated. The
cosmid cos72 also hybridized with both exon 2 and rat exon
1-specific probes. Exon 1 5`-untranslated was identified by
RACE which enabled the sequencing of the flanking region and
exon-intron junction from the cosmid. Using this strategy, we
determined the exon-intron boundaries and flanking sequences of the
mineralocorticoid receptor gene. As shown in Table 1, the
intron-exon boundaries have the canonical consensus sequence.
and 1) and the eight coding
exons(2, 3, 4, 5, 6, 7, 8, 9) .
The location of the translational start and stop codons is indicated. B, genomic organization of the hMR gene. Cosmid (cos72, cos31, cos25, and cos953)
and phage clones (9b,
14b, and
131) and inverse PCR products (i1, i2, i3, and ip1) are positioned on the gene and indicated
by arrows.
Exon-Intron Organization of the Gene
The hMR gene (Fig. 1A and Table 1) consists of a total of 10
exons and spans over 60-90 kb, as deduced from Southern
hybridization experiments (data not shown). Exons 1 and 1 are
composed only of 5`-untranslated sequence. The N-terminal part of the
receptor is encoded by exon 2, which contains 2 bp of 5`-untranslated
region and 1757 bp of coding sequence. Two small exons, exons 3 and 4,
encode each of the two zinc fingers of the DNA-binding domain of the
receptor. The hormone-binding domain of the mineralocorticoid receptor
is encoded by five exons, exons 5-9. Among the
glucocorticoid/mineralocorticoid/androgen/protesterone receptor
subfamily of nuclear receptor genes (20, 23, 24) the length of the exons is
identical for those encoding both the second zinc finger (exon 4 in the
hMR) and the ligand-binding domain (6-8 in the hMR).Transcription Initiation Site of hMR
Two different hMR 5`-mRNA ends were identified,
designated as hMR and 5`-Flanking
Region (P1) and hMR. The 5`-untranslated sequence
containing exon 1 was obtained both from the cosmid clone cos72
and by inverse PCR (Fig. 1). A 2.1-kb HindIII fragment
of cos72 shown to hybridize with a rat exon 1 probe yielded
sequence extending from intron A (900 bp) through the
5`-untranslated and into the flanking region (P1:950 bp). The inverse
PCR fragment obtained was
1.2 kb in size and similarly extends
from intron A to include
750 bp of flanking sequence. Fig. 2shows the hMR
5`-untranslated and flanking sequences
obtained from these clones. No consensus TATA box sequence is present
in the putative promoter sequence, and no CCAAT motif is found within
the first 100 bp upstream of the transcription initiation site,
although two are found at positions -172 and -225 (these
sequences could be found by chance every 1025 bp). The region is very
rich in GC boxes, and computer-assisted analysis revealed seven
consensus sequences for the binding of transcription factor Sp-1
(-33, -59, -152, -254, -328, -347,
and ;402)(25, 26) , three very closely clustered
activating protein 2 (AP-2)-binding sites(-32, -62,
-77)(27, 28) , as well as a binding motif for
transcription factor PEA-3(-165)(29) . At position
-217 the sequence 3`-AGAATAnnnTGTTAG-5` very closely resembles
the GRE consensus sequence
5`-AGAACAnnnTGTTCT-3`(30, 31) , although it is
inserted in inverse orientation. The 5`-untranslated encoded by exon
1 shows 90% identity with the rat sequence and the first 400 bp of
the flanking region of exon 1 show 73% identity with the rat
genomic sequence in this region(32) .
(P1). The transcription initiation site is indicated by an arrow. Consensus sequences for Sp1-binding sites are boxed, and those for transcription factors Ap-1 and PEA3 are underlined; consensus sequences for AP-2 are indicated by a line above the sequence. The exonic sequence is indicated in bold letters. Numbering is relative to the transcription
initiation site of hMR.
mRNA was determined by RACE-PCR. The most
5`-sequence obtained corresponds to nucleotide positions
-45/-46, according to the published cDNA
sequence(1) , which is therefore the putative transcription
initiation site (underlined in Fig. 2). By Southern
hybridization with an oligonucleotide at position -45, about 61%
of clones were positive for this sequence. Several shorter transcripts
could represent minor sites of transcription initiation or truncated
artifacts of reverse transcription and amplification.Cloning of hMR
We identified a novel 5`-sequence that spliced onto the
mineralocorticoid receptor mRNA at intron A-exon 2 boundary located 2
bp upstream of the mineralocorticoid receptor translation initiation
site (Fig. 3). This sequence shares 85% homology with the first
untranslated exon of the rat MR and Its 5`-Flanking Region
(P2) cDNA isolated from rat
hippocampus(33) . The longest transcripts obtained by
subsequent RACE using exon 1-specific reverse primers at position
124 and 103 of the cloned cDNA enabled us to determine a putative
transcription initiation site of hMR (underlined in Fig. 3). Sequencing of cosmid cos72 with
5`-untranslated-specific primers enabled the identification of both the
exon1-intron P1 junction and the region flanking the
5`-untranslated (P2). It is possible, given the very GC-rich nature of
the region which rendered sequencing difficult, that the RACE products
are prematurely terminated in the 5`-untranslated. Sequence homology
with the rat exon 1 cDNA is observed over 216 bp to the putative
transcription initiation site of hMR 1, after which the sequence
similarity decreases. Additional experiments are required to precise
whether alternative transcription start sites exist in the human and
the rat MR promoter. Computer-assisted analysis of P2 revealed two
binding sites for transcription factor Sp-1(-62, -150) and
one consensus sequence for binding of transcription factor
AP-2(-26).
and its
5`-flanking region (P2). An arrow indicates a putative
transcription initiation site of hMR, which is numbered as
+1. The exonic sequence is indicated in bold letters. The
3`-intron sequence is indicated by lowercase letters.
Sp1-binding sites are boxed, and a consensus sequence for AP-2
is underlined. N indicates ambiguous nucleotide
determination due to high GC content of the
region.
or
1 generates two different hMR transcripts, hMR and hMR,
with the same translation product. A third mRNA isoform was found in
rat hippocampus (MR)(10) , and although we could not
detect this mRNA in the human kidney, this and possibly other
mineralocorticoid receptor mRNA species might be present in low
abundance or restricted to particular tissues.
(5`-CCCTCCTCT-3`) resembles the initiator sequence
from the terminal deoxynucleotidyltransferase gene
5`-CCCTCA
TTCT-3`, which appears to be important in
TATA-less promoters, and which has been shown to interact in a
position-dependent manner with Sp-1 binding sites to direct high levels
of transcription(36, 37) . This sequence also shares
homology with the androgen receptor transcription initiation site II
(TISII) surrounding sequence
(CCCTC
C
GAGA), and with the
sequence surrounding the putative transcription initiation site of the
rat MR
(CTCCTGCGC).
is the predominant form expressed
in the kidney, whereas in the hippocampus MR and MR are
expressed in equal proportions(10) . In addition, alternative
transcription initiation can affect both the stability of the
transcripts and the efficiency of mRNA translation(42) .
Indeed, mineralocorticoid receptor expression seems to be regulated in
a tissue-specific manner by the level of its ligand, although
conflicting data are reported in the literature. Whereas there is good
evidence for hormonal regulation of mineralocorticoid receptor in the
hippocampus(10, 43, 44) , for the kidney both
regulation (45) and lack of regulation by corticosteroids have
been reported(44) . For the rat distal colonic
mineralocorticoid receptor, protein and mRNA levels are neither
up-regulated after adrenalectomy nor down-regulated in response to a
mineralocorticoid receptor agonist(46) .
mRNA levels has been reported in rat hippocampus after adrenalectomy,
which was reversed by exogenous corticosterone administration, whereas
MR mRNA levels did not change. Thus, in the rat, MR may be
the hormonally regulated mRNA variant, suggesting that the putative
hormone responsive sequence identified in P1 might be of functional
significance.
)
We thank Dr. J. Arriza for providing plasmid phMR3750,
Dr. S. Watson for the rat mineralocorticoid receptor genomic sequence,
Dr. K. H. Choo for human leukocyte cosmid libraries, and Dr. J. C.
Murray for the chromosome 4 enriched cosmid library. We also thank P.
Villedieu for technical assistance and Dr. P. Corvol and Dr. M.
Lombès for helpful discussion.
©1995 by The American Society for Biochemistry and Molecular Biology, Inc.
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