| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Departments of Internal Medicine & Pharmacology (N.A.H.,
K.L.P.) Division of Reproductive Endocrinology (W.E.R.)
Department of Obstetrics & Gynecology University of Texas
Southwestern Medical Center Dallas, Texas 75390-8857
School of Biochemistry & Genetics (N.A.H., D.I.W.) Department
of Medicine (D.I.W., S.G.B.) University of Newcastle Newcastle
upon Tyne, United Kingdom
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
|---|
-hydroxylase/17–20 lyase
(P450C17) is a critical branchpoint enzyme for
steroid hormone biosynthesis. During human gestation,
P450C17 is required for the production of
dehydroepiandrostenedione sulfate by the fetal adrenal cortex and
for testicular production of androgens that mediate male sexual
differentiation. In this study, we investigate the regulation of the
human CYP17 gene by two orphan nuclear receptors,
steroidogenic factor 1 (SF-1) and DAX1. In human embryos, SF-1 and DAX1
are expressed throughout the developing adrenal cortex from its
inception at 33 days post conception (dpc). In contrast,
P450C17 expression, which commences between 41
and 44 dpc, is limited to the fetal zone. The 5'-flanking region of the
human CYP17 gene contains three functional SF-1 elements
that collectively mediate a 
25-fold induction of promoter activity by
SF-1. In constructs containing all three functional SF-1 elements, DAX1
inhibited this activation by 55%. In the presence of only one or two
SF-1 elements, DAX1 inhibition was lost even though SF-1
transactivation persisted. These data suggest that efficient repression
of SF-1-mediated activation of the human CYP17 gene by DAX1
requires multiple SF-1 elements. Opposing effects of SF-1 and DAX1 may
fine tune the differential responses of various SF-1 target genes in
different endocrine tissues. |
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
|---|
-hydroxylase/17–20
lyase (P450C17) is a critical branchpoint enzyme
in steroid biosynthesis, converting progesterone to
17-hydroxyprogesterone in the glucocorticoid pathway and
pregnenolone to dehydroepiandrostenedione (DHEA) in the
sex steroid pathways. In the fetal testis, 17-hydroxylase activity
is essential for the production of testosterone, which stimulates male
sexual differentiation in utero. The combined actions of
P450C17 and sulfotransferase in the human fetal
adrenal cortex of both sexes produce enormous quantities of
DHEA sulfate (DHEAS, 
50 mg/day); DHEAS serves as
substrate for estrogen biosynthesis by the placenta and thereby helps
to maintain pregnancy (1). Although steroidogenesis by the human fetal
adrenal is regulated at least partly by pituitary ACTH (2), little is
known about the mechanisms that initiate P450C17
expression in the human fetal adrenal cortex or that regulate its
transcription from the human CYP17 gene
(hCYP17). The orphan nuclear receptor steroidogenic factor 1 (SF-1, officially designated NR5A1) is critical for development and function of the steroidogenic organs. Many cell transfection studies have highlighted important roles for SF-1 in the transcriptional activation of the genes that encode steroidogenic enzymes (3), while targeted disruption of the mouse gene encoding SF-1 defined essential roles in adrenal and gonadal development (4, 5, 6). SF-1 likely plays similar roles in humans, as evidenced by adrenal insufficiency and male-to-female sex reversal in a patient with a heterozygous mutation in the human gene that encodes SF-1 (7).
Another orphan nuclear receptor, DAX1 [dosage-sensitive sex reversal, adrenal hypoplasia congenita (AHC), critical region on the X chromosome gene 1], colocalizes with SF-1 during mouse development (8) and inhibits SF-1-mediated transactivation of target genes in both steroidogenic and nonsteroidogenic tissues. In addition to the cytochrome P450 steroid hydroxylases, promoters shown previously to be inhibited by DAX1 include: steroidogenic acute regulatory protein (StAR) (9, 10), Type II 3ß-hydroxysteroid dehydrogenase (Type II 3ßHSD) (10), and Müllerian inhibiting substance (MIS) (11)].
In this study, we investigate the expression profiles of SF-1, DAX1, and P450C17 during the development of the human adrenal gland. We further study the regulation of hCYP17 gene expression by SF-1 and DAX1. Our results provide new insight into the onset of P450C17 expression in the human embryonic adrenal cortex and suggest that hCYP17 is especially sensitive to DAX1-mediated repression via actions at multiple SF-1 response elements.
|
RESULTS |
|---|
|
TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
|---|
). Human P450C17
expression commences centrally in a few cells between 41 and 44 dpc
(CS17 and 18), 8–11 days after the adrenal primordium first forms
(Fig. 1B, 44 dpc). By 52 dpc/CS21, the human embryonic adrenal cortex
contains an inner cluster of large eosinophilic cells—the fetal
zone—that stain strongly for cytoplasmic P450C17
expression. This region is surrounded by the small, densely packed
basophilic cells of the definitive zone, which do not express
P450C17 (asterisk in Fig. 1, A and B,
52 dpc). By 18 weeks gestation, P450C17
expression is less clearly defined, with strongly expressing cells
within a transitional zone (15) flanked by more weakly staining cells
in the inner fetal zone and scattered expression in the outer
definitive zone (arrow, Fig. 1B, 18 weeks gestation).
|
, D and E); their levels in both
sexes exceed those in the urogenital ridge (12, 16). The detection of
SF-1 transcripts is greater than for DAX1 at all embryonic stages. In
contrast to the absence of P450C17 expression in
the definitive zone, both transcripts are distributed throughout the
entire adrenal cortex at 52 dpc/CS21 (Fig. 1, C–E, 52 dpc). Lower
levels of SF-1 and DAX1 expression persist throughout the fetal adrenal
cortex at 18 weeks gestation (Fig. 1, D and E).
SF-1 Activates Transcription of the Human CYP17 Gene
through Multiple cis-Elements
Although previous studies have implicated SF-1 in the expression
of hCYP17, the role of DAX1 has not been explored. Using
transient transfection studies in NCI-H295R human adrenocortical cells,
which preferentially secrete DHEAS (W. E. Rainey, unpublished
observation), we examined the regulation of the hCYP17 gene
by SF-1. Cotransfection of SF-1 with promoter constructs containing
either 2,845 bp (p-2845Luc) or 381 bp (p-381Luc) of hCYP17
5'-flanking region stimulated luciferase activity by 25-fold over
basal expression (Fig. 2). Progressive
deletion of the hCYP17 5'-flanking region incrementally
decreased SF-1 stimulation, suggesting that multiple promoter elements
mediate SF-1 induction (Fig. 2).
|
). Electrophoretic mobility shift
assays (EMSAs) showed that oligonucleotide probes corresponding to each
of these putative SF-1 elements formed two specific complexes with
NCI-H295R nuclear extracts. Complex 1 comigrated with the complex
formed by in vitro translated SF-1 and was either abolished
(–211/–204 bp) or supershifted (–150/–142 and –290/–276 bp) by
preincubation with anti-SF-1 antiserum (Fig. 3B), suggesting strongly
that it results from the binding of SF-1.
|
), and
DAX1 reportedly interferes with SF-1-dependent transcriptional
activation (9, 10, 11, 17, 18, 19). We therefore studied the effect of DAX1 on
SF-1-mediated stimulation of the hCYP17 promoter. DAX1
inhibited SF-1 activation of the p-381Luc construct in a
concentration-dependent manner (Fig. 4A);
when cotransfected in equal amounts, DAX1 inhibited the activity
achieved by SF-1 alone by 55%. This DAX1 inhibition was partly
overcome by cotransfection with increasing amounts of SF-1 (Fig. 4B),
suggesting a competition between the two proteins. Similar results were
obtained with the hCYP17 promoter constructs in multiple
cell types [e.g. mouse Y1 adrenocortical cells, monkey
kidney COS-1 cells, a human ovarian thecal tumor cell line (20), and
primary cultures of adult human adrenocortical cells] using either
cytomegalovirus- or Rous sarcoma virus-based expression vectors (data
not shown). In contrast to the DAX1 inhibition of SF-1-stimulated
luciferase activity, transfection with DAX1 alone weakly stimulated
(
3-fold) the expression of a number of plasmids, including
hCYP17 promoter constructs (Figs. 4 and 5), pGL3 basic
vector (Fig. 5, A, C, and D), or a
cytomegalovirus-based ß galactosidase vector (data not shown). This
nonspecific activation, which has been observed previously (17), may
reflect squelching of corepressors by DAX1.
|
|
), despite the fact that
this reporter still responds to SF-1. Similarly, DAX1 did not inhibit
SF-1-mediated activation of p-182Luc, even though this construct
retains the functional SF-1 site at–150/–142 bp (Fig. 3A). Taken
together, these data suggest either that the shorter constructs lack a
specific promoter region important for DAX1 inhibition or that DAX1
requires multiple SF-1 sites to inhibit SF-1-stimulated transcription
of the hCYP17 gene.
To differentiate between these models, we carried out
cotransfection experiments using combinations of the mutated SF-1
elements within the p-381Luc construct (Fig. 5, B and C). As shown in
Fig. 5B, constructs containing mutations of any of the three SF-1
binding sites were still significantly induced by SF-1 (range 12- to
17-fold), but DAX1 inhibition was either absent
(p-381Luc
–150/–142) or severely
decreased (p-381Luc-211/-204 and
p-381Luc-290/-276). Although SF-1 still
stimulated promoter activity by 5- to 8-fold, mutation of any two SF-1
sites within p-381Luc completely abolished DAX1 inhibition (Fig. 5C).
Coupled with the observation that SF-1 can override DAX-1 inhibition of
reporter gene expression, these findings suggest that DAX1 requires the
presence of multiple SF-1 sites to effectively inhibit SF-1
transactivation of the hCYP17 promoter.
To determine whether the apparent need for multiple sites reflects
a requirement for an absolute number of sites or for specific
sequences of the SF-1 binding elements, we placed multiple copies of
the –150/–142 binding site at the 5'-end of the wild-type p-182Luc
construct. The p-182Luc+2(–150/–142) and
p–182Luc+1(–150/–142) constructs contain,
respectively, a total of three or two copies of the –150/–142 SF-1
binding site. SF-1 induced luciferase activity of the
p–182Luc+2(–150/–142) construct by 44-fold and
DAX1 inhibited promoter activity to a degree similar to that observed
with the wild-type p-381Luc construct (which also contains three SF-1
sites in a different combination of orientation and spacing). This
repression was not altered when the spacing of the most 5'-element was
modified by 20 or 40 bp (data not shown). Although SF-1 cotransfection
induced promoter activity of
p-182Luc+1(–150/–142) by 20-fold, DAX1
inhibition was reduced to the levels seen with
p-381Luc-290/-276 and
p–381Luc-211/-204 (Fig. 5B). In the wild-type p-182Luc construct, which contains a single copy
of the –150/–142 element, SF-1 still induced luciferase activity by
10-fold, but was not inhibited by DAX1. These data suggest that
DAX1 inhibition of hCYP17 requires a minimal number of
functional SF-1 sites—irrespective of orientation or position—rather
than a particular sequence of the binding elements and their flanking
nucleotides.
The Effect of Copy Number of SF-1 Elements on DAX1 Repression of
Other Steroidogenic Promoters
To investigate whether DAX1 also represses other promoters most
efficiently through multiple SF-1 sites, we studied the human
CYP11B1 (hCYP11B1) and mouse Cyp21
(mCyp21) promoters. Previous analyses of the 5'-flanking
region of the mCyp21 gene identified three SF-1 binding
elements, the most proximal of which was located 65 bp upstream of the
transcription initiation site (21). By itself, this single SF-1 site
(mCyp21p-65Luc) responds poorly to SF-1 (Fig. 6A), and the 1.4-fold induction was not
inhibited by DAX1. Strikingly, when five copies of the –65 element are
placed upstream of the PRL core promoter (mCyp21p-65x5Luc),
SF-1 induced luciferase activity by 38-fold; in this setting, DAX1
inhibited SF-1-induced transactivation to a degree comparable to that
seen with the hCYP17 promoter constructs containing three
SF-1 elements. Transactivation of the hCYP11B1 gene by SF-1
occurs almost exclusively through a single SF-1 site at –243 bp (N.
Hanley and W. Rainey, unpublished observation). Although the
hCYP11B1p-1102Luc construct, which contains this site, was
induced 12-fold upon cotransfection with SF-1, DAX1 failed to inhibit
this transactivation (Fig. 6B).
|
). Although
the V385G mutant differentially repressed the two
SF-1-stimulated constructs (34% of wild-type DAX1 activity with
p-381Luc compared with 51% with
p-182Luc+2(–150/–142)), this difference was
statistically insignificant (Fig. 7). Like wild-type DAX1, none of the
AHC mutations repressed reporter activity with the p-182Luc construct
containing a single SF-1 element (data not shown).
|
|
DISCUSSION |
|---|
|
TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
|---|
To date, studies of CYP17 gene regulation have not
identified mechanisms that are conserved across species such as human
(22, 23, 24), bovine (25, 26), rodent (27, 28, 29), and pig (28, 30). Previous
analyses of hCYP17 gene expression in NCI-H295R cells
identified a region in the proximal 63 bp of the promoter that
contributes to basal transcription, with an additional minor element
located between –206 and –184 bp (24). Relative to other species, the
hCYP17 promoter responded only minimally to cAMP. Although
our finding that SF-1 regulates promoter activity is not
surprising—given its extensive role as a transcriptional activator of
steroidogenic enzymes (3)—our results define for the first time three
distinct promoter elements by which SF-1 regulates the
hCYP17 gene. The –150/–142 and –211/–204 elements have
been shown previously to bind SF-1 (31), implicating the sequences in
Table 1 as central to SF-1 action on
these elements. In contrast, the –290/–276 site has not been
characterized previously either by functional or DNA-binding studies.
All three sites differ somewhat in sequence from the corresponding
elements in CYP17 genes from other species (Table 1). In
particular, the nuclear hormone receptor half-sites at –62/–40 bp of
the bovine CYP17 promoter (25) are not conserved completely
in the human sequence. Taken together, these data define three SF-1
responsive elements within the proximal –381 bp of the
hCYP17 promoter that support a functional role for SF-1 in
the regulation of P450C17 expression within the
human fetal adrenal cortex.
|
).
Previous reports of DAX1-mediated repression of SF-1 transactivation
generally are consistent with this model. These data can be divided
into three categories according to the nature of the promoter linked to
the reporter gene: steroidogenic (9, 10, 32), nonsteroidogenic (9, 11, 19), and synthetic (17, 18) (Table 2). In
the steroidogenesis pathway, genes such as human StAR (33)
and CYP11A (31) that contain multiple SF-1-responsive
elements are strongly repressed by DAX1. In contrast, only a single
SF-1 site has been defined in the proximal 5'-flanking region of the
Type II 3ßHSD promoter, and DAX1 did not
significantly repress its promoter activity (10, 32). Similarly, DAX1
repression of promoter activity of nonsteroidogenic SF-1 target genes
is most marked in the setting of multiple SF-1 sites. Finally,
synthetic promoter constructs containing multiple SF-1-responsive
elements are repressed most strongly by DAX (17, 18).
|
) (18). Modifying
the number of available SF-1 sites, either by modulating chromatin
structure or by affecting the binding of other factors to SF-1 sites
(e.g. complex 2 in Fig. 3B), would alter both the magnitude
of SF-1 transactivation and the ability of DAX1 to inhibit
SF-1-stimulated gene transcription. Such a mechanism could fine tune
the differential responses of various SF-1 target genes, facilitating
regulation of the steroid biosynthetic pathway within steroidogenic
tissues.
|
|
MATERIALS AND METHODS |
|---|
|
TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
|---|
Polyclonal anti-human P450C17 antiserum was raised in rabbits immunized with a peptide containing amino acid residues 384–398. This antiserum produced a single band of the appropriate size on immunoblotting of human adrenal cell lysate (data not shown). Indirect immunohistochemistry was carried out on dewaxed trypsinized sections previously fixed in 4% paraformaldehyde. Slides were incubated with primary antiserum (1:1,000 dilution) overnight at 4 C. Biotinylated antirabbit secondary antibody (Sigma, St. Louis, MO) was incubated for 2 h at 4 C, before treatment at room temperature with streptavidin-horseradish peroxidase, and the color reaction was developed with diaminobenzidine. Negative controls included preabsorption of antibody with the antigen and omission of primary or secondary antibodies.
In situ hybridization was performed as described previously for SF-1 and DAX1 using [35S]-labeled probes on 5-µm transverse sections (12). Sections for morphological study were within 10 µm of the corresponding section used for in situ hybridization analysis. For optimal use of material, experiments were carried out on both right and left sides of sectioned embryos.
Cloning and Plasmid Constructs
Human SF-1 cDNA (34) was subcloned into the expression
vector, pcDNA3.1Zeo+ (Invitrogen, San Diego, CA). Human
DAX1 cDNA is available as an expressed sequence tag (GenBank accession
no. S74720) and was subcloned into pcDNA3.1Zeo+. AHC mutants were
generated by PCR using complimentary upper and lower primers, which
incorporated the single base pair mutations. The 5'-flanking sequence
of the human CYP17 gene is available (GenBank accession no.
L41825 and M63871). All promoter constructs were cloned into pGL3 Basic
(Promega Corp., Madison, WI) and numbered relative to the
transcriptional start site. Wild-type hCYP17 promoter
constructs were generated by PCR using specific forward primers
(–2,914 bp, 5'-TGGGACTCTGATTGGCATTAT; –381 bp,
5'-GAAGATCTACTTTAACAGTCCCTG; –228 bp, 5'-GAAGATCTCCTCAGAGGGTGAT)
and/or by the use of unique restriction endonuclease sites. Additional
details are available from the authors upon request. The
mCyp21 promoter constructs have been described previously
(21) and the hCYP11B1 p-1102Luc construct was a gift from
Dr. Perrin White.
Mutations of the SF-1 binding sites within p-381 were created by PCR with oligonucleotides shown below (wild-type sequence with mutated nucleotides above and below shown in bold).
To incorporate additional SF-1 binding sites into
p-182Luc, oligonucleotide linkers were synthesized and annealed to
recreate the wild-type –150/–142 element with overhangs compatible
with unique restriction sites in the 5'-multiple cloning sites of pGL3
Basic. One or two linkers were then cloned directly upstream of the
p-182Luc promoter sequence. All constructs were verified by sequencing.
The base pair numbering of our constructs does not strictly align with
the GenBank accession no. M63871, which lacks a SacI
restriction site described in the published reference (23). The
wild-type sequence and numbering of the human CYP17 promoter
used in this study was verified by direct sequencing of PCR products
amplified from human genomic DNA. Sequences in Table 1 were aligned by
Clustal.
Cell Culture, Transfections, and Luciferase Assays
NCI-H295R cells (American Type Culture Collection,
Manassas, VA; CRL-2128) were cultured as described previously in 5%
CO2 at 37 C (35). Twenty-four hours before
transfection, cells were plated on 12-well plates at a density of
150,000 cells per well. Cells were transfected with Fugene 6 using
the manufacturer’s protocol (Roche Clinical Laboratories, Indianapolis, IN) in a serum-free
DMEM/F12 medium (LifeTechnologies, Gaithersburg, MD).
Total DNA transfected per well (up to 3 µg) was kept constant by
adjusting the amount of empty pcDNA3.1Zeo+ vector. Luciferase assays
were performed 24 h after transfection according to the
manufacturer’s instructions (Promega Corp., Madison,
WI).
EMSA
Nuclear extract was prepared from NCI-H295R cells as
described previously (36). Human SF-1 was synthesized by
coupled in vitro transcription/translation from the
pcDNA3.1Zeo+ vector by T7 polymerase using the TNT reticulocyte lysate
system (Promega Corp.). Anti-SF-1 antibody was developed
and used as described previously (37). Oligonucleotides corresponding
to the wild-type SF-1 response elements were annealed and labeled with
[32P]dCTP by Klenow polymerase.
Nuclear extract (2 µg) and each radiolabeled probe (40,000 dpm) were incubated at room temperature for 20 min in 20 µl of reaction mixture (20 mM HEPES; pH 8.0, 80 mM KCl, 1 mM EDTA, 10% glycerol, 1 mM dithiothreitol, 0.5 mg/ml BSA, and 0.025 mg/ml poly dI-dC as nonspecific competitor). Where appropriate, nuclear extract and antibody were preincubated on ice for 20 min before addition of probe and reaction mixture. The resulting DNA/protein complexes were resolved by electrophoresis on 4% nondenaturing polyacrylamide gels in high ionic strength Tris-glycine buffer (38). The gel was dried and visualized after autoradiography at –70 C overnight.
 |
 |
 |
|
ACKNOWLEDGMENTS |
|---|
|
FOOTNOTES |
|---|
N.A.H. is a Wellcome Trust Clinical Training Fellow. D.I.W. is supported by the Knott Trust. This work was funded by NIH Grants DK-54480 (K.L.P.) and DK-43140 (W.E.R.).
Received for publication February 18, 2000. Revision received September 5, 2000. Accepted for publication October 9, 2000.
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
|---|
-hydroxylase/17, 20-lyase, and 3ß-hydroxysteroid dehydrogenase
isomerase steroidogenic enzymes in human and rhesus monkey fetal
adrenal glands: reappraisal of functional zonation. J Clin
Endocrinol Metab 77:1184–1189[Abstract]
-hydroxylase/17,
20-lyase) in cultured human fetal adrenal cells. J Clin Endocrinol
Metab 65:170–175-hydroxylase/C17–20-lyase gene (Cyp17):
transcriptional regulation of the gene by cyclic adenosine
3',5'-monophosphate in MA-10 Leydig cells. Mol Endocrinol 6:927–934-hydroxylase/C17–20 lyase (CYP17) in
porcine Leydig cells: identification of a DNA sequence that mediates
cAMP response. Biochim Biophys Acta 1307:73–82[Medline]
- hydroxylase/C17–20 lyase gene (Cyp17) by androgens.
Mol Endocrinol 11:87–96
5-4 isomerase promoter by the transcription factor
steroidogenic factor-1/adrenal 4-binding protein and phorbol ester.
J Biol Chem 272:7960–7967This article has been cited by other articles:
 |
|
 |
|
  Y. Nakamura, Y. Xing, H. Sasano, and W. E. Rainey The Mediator Complex Subunit 1 Enhances Transcription of Genes Needed for Adrenal Androgen Production Endocrinology, September 1, 2009; 150(9): 4145 - 4153. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Yazawa, Y. Inanoka, T. Mizutani, M. Kuribayashi, A. Umezawa, and K. Miyamoto Liver Receptor Homolog-1 Regulates the Transcription of Steroidogenic Enzymes and Induces the Differentiation of Mesenchymal Stem Cells into Steroidogenic Cells Endocrinology, August 1, 2009; 150(8): 3885 - 3893. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Xu, W.-H. Yang, I. Gerin, C.-D. Hu, G. D. Hammer, and R. J. Koenig Dax-1 and Steroid Receptor RNA Activator (SRA) Function as Transcriptional Coactivators for Steroidogenic Factor 1 in Steroidogenesis Mol. Cell. Biol., April 1, 2009; 29(7): 1719 - 1734. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Lourenco, R. Brauner, L. Lin, A. De Perdigo, G. Weryha, M. Muresan, R. Boudjenah, G. Guerra-Junior, A. T. Maciel-Guerra, J. C. Achermann, et al. Mutations in NR5A1 Associated with Ovarian Insufficiency N. Engl. J. Med., March 19, 2009; 360(12): 1200 - 1210. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Attar, H. Tokunaga, G. Imir, M. B. Yilmaz, D. Redwine, M. Putman, B. Gurates, R. Attar, N. Yaegashi, D. B. Hales, et al. Prostaglandin E2 Via Steroidogenic Factor-1 Coordinately Regulates Transcription of Steroidogenic Genes Necessary for Estrogen Synthesis in Endometriosis J. Clin. Endocrinol. Metab., February 1, 2009; 94(2): 623 - 631. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Shi, M. D. Schonemann, and S. H. Mellon Regulation of P450c17 Expression in the Early Embryo Depends on GATA Factors Endocrinology, February 1, 2009; 150(2): 946 - 956. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. R. Manna, M. T. Dyson, Y. Jo, and D. M. Stocco Role of Dosage-Sensitive Sex Reversal, Adrenal Hypoplasia Congenita, Critical Region on the X Chromosome, Gene 1 in Protein Kinase A- and Protein Kinase C-Mediated Regulation of the Steroidogenic Acute Regulatory Protein Expression in Mouse Leydig Tumor Cells: Mechanism of Action Endocrinology, January 1, 2009; 150(1): 187 - 199. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. A. Hoivik, L. Aumo, R. Aesoy, H. Lillefosse, A. E. Lewis, R. M. Perrett, N. R. Stallings, N. A. Hanley, and M. Bakke Deoxyribonucleic Acid Methylation Controls Cell Type-Specific Expression of Steroidogenic Factor 1 Endocrinology, November 1, 2008; 149(11): 5599 - 5609. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Piper Hanley, F. Oakley, S. Sugden, D. I. Wilson, D. A. Mann, and N. A. Hanley Ectopic SOX9 Mediates Extracellular Matrix Deposition Characteristic of Organ Fibrosis J. Biol. Chem., May 16, 2008; 283(20): 14063 - 14071. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. E. Beshay, J. C. Havelock, R. Sirianni, P. Ye, T. Suzuki, W. E. Rainey, and B. R. Carr The Mechanism for Protein Kinase C Inhibition of Androgen Production and 17{alpha}-Hydroxylase Expression in a Theca Cell Tumor Model J. Clin. Endocrinol. Metab., December 1, 2007; 92(12): 4802 - 4809. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. L Reuter, K. Goji, N. C Bingham, M. Matsuo, and K. L Parker A novel mutation in the accessory DNA-binding domain of human steroidogenic factor 1 causes XY gonadal dysgenesis without adrenal insufficiency Eur. J. Endocrinol., August 1, 2007; 157(2): 233 - 238. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Mueller, A. Atanasov, I. Cima, N. Corazza, K. Schoonjans, and T. Brunner Differential Regulation of Glucocorticoid Synthesis in Murine Intestinal Epithelial Versus Adrenocortical Cell Lines Endocrinology, March 1, 2007; 148(3): 1445 - 1453. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. H. Mellon, S. R. Bair, C. Depoix, J.-L. Vigne, N. B. Hecht, and P. B. Brake Translin Coactivates Steroidogenic Factor-1-Stimulated Transcription Mol. Endocrinol., January 1, 2007; 21(1): 89 - 105. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Ragazzon, A.-M. Lefrancois-Martinez, P. Val, I. Sahut-Barnola, C. Tournaire, C. Chambon, J.-L. Gachancard-Bouya, R.-J. Begue, G. Veyssiere, and A. Martinez Adrenocorticotropin-Dependent Changes in SF-1/DAX-1 Ratio Influence Steroidogenic Genes Expression in a Novel Model of Glucocorticoid-Producing Adrenocortical Cell Lines Derived from Targeted Tumorigenesis Endocrinology, April 1, 2006; 147(4): 1805 - 1818. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Tsuchiya, M. Nakajima, S. Takagi, M. Katoh, W. Zheng, C. R Jefcoate, and T. Yokoi Binding of Steroidogenic Factor-1 to the Regulatory Region Might Not Be Critical for Transcriptional Regulation of the Human CYP1B1 Gene. J. Biochem., March 1, 2006; 139(3): 527 - 534. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. A. Myers, K. Hyatt, M. Mlynarczyk, I. M. Bird, and C. A. Ducsay Long-term hypoxia represses the expression of key genes regulating cortisol biosynthesis in the near-term ovine fetus Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2005; 289(6): R1707 - R1714. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.-C. Battista, M. Otis, M. Cote, A. Laforest, M. Peter, E. Lalli, and N. Gallo-Payet Extracellular Matrix and Hormones Modulate DAX-1 Localization in the Human Fetal Adrenal Gland J. Clin. Endocrinol. Metab., September 1, 2005; 90(9): 5426 - 5431. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. H. Bassett, B. Mayhew, K. Rehman, P. C. White, F. Mantero, G. Arnaldi, P. M. Stewart, I. Bujalska, and W. E. Rainey Expression Profiles for Steroidogenic Enzymes in Adrenocortical Disease J. Clin. Endocrinol. Metab., September 1, 2005; 90(9): 5446 - 5455. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Seely, K. S. Amigh, T. Suzuki, B. Mayhew, H. Sasano, V. Giguere, J. Laganiere, B. R. Carr, and W. E. Rainey Transcriptional Regulation of Dehydroepiandrosterone Sulfotransferase (SULT2A1) by Estrogen-Related Receptor {alpha} Endocrinology, August 1, 2005; 146(8): 3605 - 3613. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. N Kelly, T J. McKenna, and L. S Young Coregulatory protein-orphan nuclear receptor interactions in the human adrenal cortex J. Endocrinol., July 1, 2005; 186(1): 33 - 42. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Y. Park, J. J. Meeks, G. Raverot, L. E. Pfaff, J. Weiss, G. D. Hammer, and J. L. Jameson Nuclear receptors Sf1 and Dax1 function cooperatively to mediate somatic cell differentiation during testis development Development, May 15, 2005; 132(10): 2415 - 2423. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Zwermann, F. Beuschlein, E. Lalli, A. Klink, P. Sassone-Corsi, and M. Reincke Clinical and molecular evidence for DAX-1 inhibition of steroidogenic factor-1-dependent ACTH receptor gene expression Eur. J. Endocrinol., May 1, 2005; 152(5): 769 - 776. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. D. Hammer, K. L. Parker, and B. P. Schimmer Minireview: Transcriptional Regulation of Adrenocortical Development Endocrinology, March 1, 2005; 146(3): 1018 - 1024. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Jo and D. M. Stocco Regulation of Steroidogenesis and Steroidogenic Acute Regulatory Protein in R2C Cells by DAX-1 (Dosage-Sensitive Sex Reversal, Adrenal Hypoplasia Congenita, Critical Region on the X Chromosome, Gene-1) Endocrinology, December 1, 2004; 145(12): 5629 - 5637. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. H. Bassett, T. Suzuki, H. Sasano, C. J. M. de Vries, P. T. Jimenez, B. R. Carr, and W. E. Rainey The Orphan Nuclear Receptor NGFIB Regulates Transcription of 3{beta}-Hydroxysteroid Dehydrogenase: IMPLICATIONS FOR THE CONTROL OF ADRENAL FUNCTIONAL ZONATION J. Biol. Chem., September 3, 2004; 279(36): 37622 - 37630. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. W. Kim, N. Peng, W. E. Rainey, B. R. Carr, and G. R. Attia Liver Receptor Homolog-1 Regulates the Expression of Steroidogenic Acute Regulatory Protein in Human Granulosa Cells J. Clin. Endocrinol. Metab., June 1, 2004; 89(6): 3042 - 3047. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Hossain, C. Li, and G. F. Saunders Generation of Two Distinct Functional Isoforms of Dosage-Sensitive Sex Reversal-Adrenal Hypoplasia Congenita-Critical Region on the X Chromosome Gene 1 (DAX-1) by Alternative Splicing Mol. Endocrinol., June 1, 2004; 18(6): 1428 - 1437. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. V. Correa, S. Domenice, N. C. Bingham, A. E. C. Billerbeck, W. E. Rainey, K. L. Parker, and B. B. Mendonca A Microdeletion in the Ligand Binding Domain of Human Steroidogenic Factor 1 Causes XY Sex Reversal without Adrenal Insufficiency J. Clin. Endocrinol. Metab., April 1, 2004; 89(4): 1767 - 1772. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. K. Wickenheisser, V. L. Nelson-DeGrave, P. G. Quinn, and J. M. McAllister Increased Cytochrome P450 17{alpha}-Hydroxylase Promoter Function in Theca Cells Isolated from Patients with Polycystic Ovary Syndrome Involves Nuclear Factor-1 Mol. Endocrinol., March 1, 2004; 18(3): 588 - 605. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Peng, J. W. Kim, W. E. Rainey, B. R. Carr, and G. R. Attia The Role of the Orphan Nuclear Receptor, Liver Receptor Homologue-1, in the Regulation of Human Corpus Luteum 3{beta}-Hydroxysteroid Dehydrogenase Type II J. Clin. Endocrinol. Metab., December 1, 2003; 88(12): 6020 - 6028. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Borud, G. Mellgren, J. Lund, and M. Bakke Cloning and Characterization of a Novel Zinc Finger Protein that Modulates the Transcriptional Activity of Nuclear Receptors Mol. Endocrinol., November 1, 2003; 17(11): 2303 - 2319. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-W. Liu, W. Gao, H.-L. Teh, J.-H. Tan, and W.-K. Chan Prox1 Is a Novel Coregulator of Ff1b and Is Involved in the Embryonic Development of the Zebra Fish Interrenal Primordium Mol. Cell. Biol., October 15, 2003; 23(20): 7243 - 7255. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. O. Muench, J. V. Ratcliffe, M. Nakanishi, H. Ishimoto, and R. B. Jaffe Isolation of Definitive Zone and Chromaffin Cells Based upon Expression of CD56 (Neural Cell Adhesion Molecule) in the Human Fetal Adrenal Gland J. Clin. Endocrinol. Metab., August 1, 2003; 88(8): 3921 - 3930. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Lalli and P. Sassone-Corsi DAX-1, an Unusual Orphan Receptor at the Crossroads of Steroidogenic Function and Sexual Differentiation Mol. Endocrinol., August 1, 2003; 17(8): 1445 - 1453. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. M. Gummow, J. N. Winnay, and G. D. Hammer Convergence of Wnt Signaling and Steroidogenic Factor-1 (SF-1) on Transcription of the Rat Inhibin {alpha} Gene J. Biol. Chem., July 11, 2003; 278(29): 26572 - 26579. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Klonisch, K. Steger, A. Kehlen, W. R. Allen, C. Froehlich, J. Kauffold, M. Bergmann, and S. Hombach-Klonisch INSL3 Ligand-Receptor System in the Equine Testis Biol Reprod, June 1, 2003; 68(6): 1975 - 1981. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Chai, P. Brereton, T. Suzuki, H. Sasano, V. Obeyesekere, G. Escher, R. Saffery, P. Fuller, C. Enriquez, and Z. Krozowski 17{beta}-Hydroxysteroid Dehydrogenase Type XI Localizes to Human Steroidogenic Cells Endocrinology, May 1, 2003; 144(5): 2084 - 2091. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Osman, C. Murigande, A. Nadakal, and A. M. Capponi Repression of DAX-1 and Induction of SF-1 Expression. TWO MECHANISMS CONTRIBUTING TO THE ACTIVATION OF ALDOSTERONE BIOSYNTHESIS IN ADRENAL GLOMERULOSA CELLS J. Biol. Chem., October 18, 2002; 277(43): 41259 - 41267. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Gizard, B. Lavallee, F. DeWitte, E. Teissier, B. Staels, and D. W. Hum The Transcriptional Regulating Protein of 132 kDa (TReP-132) Enhances P450scc Gene Transcription through Interaction with Steroidogenic Factor-1 in Human Adrenal Cells J. Biol. Chem., October 11, 2002; 277(42): 39144 - 39155. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Gurates, S. Sebastian, S. Yang, J. Zhou, M. Tamura, Z. Fang, T. Suzuki, H. Sasano, and S. E. Bulun WT1 and DAX-1 Inhibit Aromatase P450 Expression in Human Endometrial and Endometriotic Stromal Cells J. Clin. Endocrinol. Metab., September 1, 2002; 87(9): 4369 - 4377. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. G. Lehmann, E. Lalli, and P. Sassone-Corsi From the Cover: X-linked adrenal hypoplasia congenita is caused by abnormal nuclear localization of the DAX-1 protein PNAS, June 11, 2002; 99(12): 8225 - 8230. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. S. Babu, D. L. Bavers, F. Beuschlein, S. Shah, B. Jeffs, J. L. Jameson, and G. D. Hammer Interaction Between Dax-1 and Steroidogenic Factor-1 in Vivo: Increased Adrenal Responsiveness to ACTH in the Absence of Dax-1 Endocrinology, February 1, 2002; 143(2): 665 - 673. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Lopez, W. Shea-Eaton, M. D. Sanchez, and M. P. McLean DAX-1 Represses the High-Density Lipoprotein Receptor Through Interaction with Positive Regulators Sterol Regulatory Element-Binding Protein-1a and Steroidogenic Factor-1 Endocrinology, December 1, 2001; 142(12): 5097 - 5106. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. J. Lin, J. W. M. Martens, and W. L. Miller NF-1C, Sp1, and Sp3 Are Essential for Transcription of the Human Gene for P450c17 (Steroid 17{alpha}-hydroxylase/17,20 lyase) in Human Adrenal NCI-H295A Cells Mol. Endocrinol., August 1, 2001; 15(8): 1277 - 1293. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Sugawara, S. Abe, N. Sakuragi, Y. Fujimoto, E. Nomura, K. Fujieda, M. Saito, and S. Fujimoto RIP 140 Modulates Transcription of the Steroidogenic Acute Regulatory Protein Gene through Interactions with Both SF-1 and DAX-1 Endocrinology, August 1, 2001; 142(8): 3570 - 3577. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
