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Ontogeny and Reproduction Research Unit, CHUL Research Center and Center for Research in Biology of Reproduction, Department of Obstetrics and Gynecology, Laval University, Ste-Foy, Québec, Canada G1V 4G2
Address all correspondence and requests for reprints to: Dr. Robert S. Viger, Ontogeny and Reproduction Research Unit, T1–49, CHUL Research Center, 2705 Laurier Boulevard, Ste-Foy, Québec, Canada G1V 4G2. E-mail: robert.viger{at}crchul.ulaval.ca
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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and Müllerian inhibiting substance) and a
transcription factor (SF-1) known to be essential for gonadal
development and function. Thus, our results identify GATA-4 as an
important regulator of gonadal gene transcription where its specificity
of action is mediated through synergistic interactions with other
transcription factors such as SF-1. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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GATA regulatory elements were originally identified in studies of erythroid-specific gene expression (2, 8). A novel transcription factor that specifically bound to GATA cis-elements was cloned from erythroid cells and named GATA-1 (9). GATA-1 was shown to contain a DNA-binding domain that consisted of two similar zinc fingers with the distinctive form C-X2-C-(X17)-C-X2-C (2, 9). Since the initial cloning of the prototypic GATA-1 factor, five additional vertebrate factors (GATA-2 to GATA-6), with similar DNA-binding domains, have been identified (1, 2). The six vertebrate GATA factors can be separated into two subgroups based on sequence homology and tissue distribution: the hemopoietic group (GATA-1/2/3) and the cardiac group (GATA-4/5/6). Within a single species, the highest identity among GATA factors is observed within their zinc finger DNA-binding domain. This conservation is probably the reason why the different GATA family members exhibit similar DNA-binding properties (10, 11). The C-terminal finger is required for site-specific recognition and DNA binding to the core WGATAR motif, whereas the N-terminal finger contributes to the specificity and stability of the DNA binding (12, 13, 14). Although GATA factors share similar DNA-binding properties, they exhibit distinct spatial and developmental expression patterns and play essential, nonredundant functions (1, 2, 15, 16, 17, 18, 19, 20, 21, 22). The functional specificity of the different GATA factors appears to be achieved in part via protein-protein interactions with other cell-restricted factors. The latter include the FOG-1 and FOG-2 (Friend of GATA) proteins that were cloned as GATA-specific cofactors (23, 24, 25, 26).
GATA-like DNA-binding proteins are found in the gonads of several
species, including worms, fruit flies, snakes, birds, rodents, and
humans (4, 5, 6, 7, 27, 28, 29, 30). In Drosophila
melanogaster, an ovary-specific GATA factor named dGATAb has been
shown to activate transcription of the yolk protein genes, Yp1 and Yp2,
in ovarian follicles (29). A similar GATA-binding protein
has also been reported in the silkworm, Bombyx mori, which
regulates follicle-specific expression of the chorion genes
(27). Another GATA-like protein, termed the Bkm-binding
protein, is also present in the snake ovary and mouse testis
(30). Bkm-binding protein was identified by its ability to
bind to Bkm, a satellite fraction of the W chromosome in snakes and
birds enriched in GATA repeats (30). Of the six vertebrate
GATA factors, three are expressed in the mammalian gonads: GATA-1
(6, 7, 31), GATA-4 (4, 5, 6, 32), and GATA-6
(4, 5, 32). In the testis, GATA-1 and GATA-4 both localize
to Sertoli cells, the major somatic cells of the seminiferous
epithelium of the testis, but at different stages of development
(6, 7). GATA-1 is the predominant GATA factor of postnatal
Sertoli cells, where its expression may be negatively regulated by one
or more paracrine factors produced by germ cells (7). In
contrast, we have recently shown that GATA-4 marks Sertoli cells from
the onset of gonadal development in the mouse (6). Thus,
GATA factors are probably key regulators of Sertoli cell-specific gene
expression and function during ontogeny. Indeed, GATA-dependent Sertoli
cell promoters have been postulated (5, 6, 33, 34, 35). These
include the inhibin promoter (5, 33) and the
Müllerian inhibiting substance (MIS) promoter, which we
identified as the first known downstream target for GATA-4 in fetal
Sertoli cells (6, 34). GATA-4 has also been proposed to
regulate expression of the gene encoding the steroidogenic acute
regulatory protein (StAR) (36, 37). GATA factors are also
expressed in the mouse ovary (4, 6, 32); their target
genes, however, have yet to be identified.
Although GATA factors are expressed in multiple cell lineages of both the testis and ovary, the identification of target genes has been rather limited. However, the presence of numerous consensus GATA binding motifs in several gonadal promoters invariably suggests that GATA factors regulate a broad spectrum of genes in these tissues. In the present study we have characterized the GATA-dependent activation of five different gonadal promoters. Moreover, we provide evidence that GATA cofactors, such as SF-1, are involved in the GATA-dependent transcription of some, but not all, gonadal target genes.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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promoter sequences were amplified by PCR from mouse genomic DNA using
the following sets of oligonucleotide primers: PII aromatase (forward,
5'-CGGGATCCTCTGGAATGAACTTCAGA-3'; reverse,
5'-GGGGTACCGTTTGGCTGTGGCTCCTGTCA-3'), SF-1 (forward,
5'-ATGGATCCACACCCTTAGCCCAGCAGTCT-3'; reverse,
5'-TGGGTACCGGGCTCTCAGAAACTTCTTC-3'), StAR (forward,
5'-ATGGATCCATCTGGCCCAGTACCACCAGGGAT-3'; reverse,
5'-GAGGTACCTGAGTCCTGCAGCTGTGGC-3'), and inhibin (forward,
5'-ATGGATCCAGCCC-CCTCCCACAGCCT-3'; reverse,
5'-CGAAGCTTCACGCTGCCCTGTGCCCTTTC-3'). The amplified promoter
sequences were cloned into either the
BamHI/HindIII or BamHI/KpnI
sites of a modified pxP1-luciferase reporter plasmid (34).
The -182-bp and -182mut SF-1 constructs were obtained by PCR using
the -588-bp SF-1 promoter as template and forward primers (-182 bp,
5'-GCGGATCCATAAAGATAGGGATATTTTTTTTTCTTTTAGAAGAG-3'; -182mut, 5'-
GCGGATCCATAAAGGTAGGGATATTTTTTTTTCTTTTAGAAGAG-3') used with the
reverse primer described above for the -588-bp SF-1 construct. The
remaining SF-1 promoter construct (-210 bp) was obtained by enzymatic
digestion of a naturally occurring StyI restriction site in
the -588-bp SF-1 promoter. The -71-bp and -71mut StAR promoter
deletion constructs were generated by PCR using the -902-bp StAR
promoter as template, the reverse StAR primer described above, and
forward primers 5'-ACGGATCCTTTTTTATCTCAAGTGATGA-3' (-71 bp) and
5'-ACGGATCCTTTTTTACCTCAAGTGATGATGCACAG-3' (-71mut), respectively. The
aromatase promoter construct deleted of its GATA site (-93 bp) was
obtained by PCR on the -218-bp aromatase promoter using forward primer
5'-ACGGATCCTTGTTTTGACTTGTAACC-3' and the aromatase reverse primer given
above. All SF-1, aromatase, and StAR promoter deletion constructs were
cloned into the BamHI/KpnI sites of the same pxP1
luciferase reporter plasmid described above. The -99-bp inhibin
promoter deleted of its GATA sites was obtained by enzymatic digestion
of a naturally occurring NcoI restriction site in the
-679-bp inhibin promoter. The synthetic 2xGATA luciferase
reporters were generated by cloning two copies of a double stranded
SF-1 GATA element (sense oligonucleotide,
5'-GATCCCATAAAGATAGGGATATTA-3'; antisense oligonucleotide,
5'-GATCTAATATCCCTATCTTTATGG-3') upstream of the minimal MIS or POMC
promoters. An expression plasmid for GATA-6 was obtained by cloning a
PCR fragment, corresponding to the GATA-6 open reading frame, into the
XbaI/KpnI sites of a Rous sarcoma virus-driven
expression vector. The PCR fragment was amplified using first
strand complementary DNA (cDNA) prepared from neonate testis RNA as
template for the PCR reaction (forward primer,
5'-AGTCTAGAACTGAGCCCCTTCGCGGCCG-3'; reverse primer, 5'-
TCGGTACCGCTGCCATCTGGACTGCTGG-3'). The full-length GATA-4 cDNA was
cloned by PCR (forward primer,
5'-CGAAGCTTATGGCGAGACACCCCAATCTCGATATG-3'; reverse primer,
5'-ATGGATCCTTAACCTGCTGGTGTCTTAGATTTATT-3') using the neonate testis
cDNA as template and inserted into the
HindIII/BamHI sites of pcDNA3
(Invitrogen, Carlsbad, CA). A GATA-4 protein (
N-term)
deleted of its N-terminal domain up to the second zinc finger
(1–254) was obtained by PCR (forward primer,
5'-GATCTAGAAAGCCTCAGCGCCGGCTGTCT-3'; reverse primer,
5'-ATGGATCCTTACGCGGTGATTATGTCCCC-3') using the full-length GATA-4 cDNA
as template and cloned into the XbaI/BamHI sites
of a cytomegalovirus-driven expression vector. Expression vectors for
Sox9, Lhx9, and GATA-1 were also generated by PCR using cDNAs prepared
from testis (Sox9 and GATA-1) or embryonic day 9 mouse head (Lhx9)
using the following pairs of oligonucleotide primers: Sox9 (forward,
5'-TGAAGCTTCGTATGAATCTCCTGGACCCCTT; reverse,
5'-TGTCTAGACCTCAAGGTCGAGTGAGCTGTG-3'), Lhx9 (forward,
5'-CTGGTACCATGCT-CTTCCACGGAATCTCC-3'; reverse,
5'-CGCTCGAGTTAGAAAAGGTTCGTTAAGGT-3'), and GATA-1 (forward,
5'-CTAAGCTTATGGATTTTCCTGGTCTAGGGG-3'; reverse,
5'-CTGGATCCGTACCTTCAAGAACTGAGTGG-3'). The PCR products were cloned into
the HindIII/XbaI (Sox9),
KpnI/XhoI (Lhx9), or
HindIII/BamHI (GATA-1) sites of the pcDNA3
expression vector (Invitrogen). The validity of all our
luciferase promoter constructs and expression plasmids was verified by
DNA sequencing. The USF-1 and USF-2 expression plasmids were generously
provided by Michèle Sawadogo (38). Expression
plasmids for the C/EBP isoforms were provided by Steven McKnight
(39). The SF-1 expression plasmid was a gift from Keith
Parker (40).
Cell culture and transfections
African green monkey kidney CV-1 and mouse fibroblast L
cells were grown in DMEM supplemented with 10% newborn calf serum.
Pituitary T3–1 (41), MSC-1 Sertoli, and adrenal Y-1
cells were maintained in DMEM containing 10% FBS. The TM3 Leydig cell
line was cultured in a 1:1 mixture of Ham’s F-12 and DMEM containing
5% horse serum and 2.5% FBS. All transfections were performed in
24-well plates using the calcium phosphate precipitation method
(42). The day before transfection, CV-1, L, TM3, T3–1,
Y-1, and MSC-1 cells were plated at densities of 2.2 x
104, 5 x 104, 4
x 104, 1.5 x 105,
8 x 104, and 5 x
104 cells/well, respectively. Cells were
transfected 24 h after the initial plating. Culture medium was
changed 12–16 h after transfection, and the cells were finally
harvested the following morning. Cells were lysed by adding 50 µl
lysis buffer [100 mM Tris-HCl (pH 7.9), 0.5% Igepal
(Sigma-Aldrich Corp., Oakville, Canada), and 5
mM dithiothreitol] directly to the culture wells. An
aliquot of the lysate was then assayed for luciferase activity using an
E.G.&G Berthold LB 9507 luminometer and luciferine (BD
PharMingen, San Diego, CA) as substrate. In all
experiments, the total amount of DNA was kept constant at 1.5 µg/well
using Sp64 (Promega Corp., Madison, WI) as carrier DNA;
several DNA preparations of the plasmids were used to ensure
reproducibility of the results. The data reported represent the average
of at least three experiments, each performed in duplicate.
DNA binding and Western blot assays
Recombinant GATA-4 protein was obtained by transfecting L cell
fibroblasts (which are devoid of GATA-binding activity) with an
expression vector encoding the full-length GATA-4 protein. Nuclear
extracts were prepared 48 h after transfection by the procedure
outlined by Schreiber et al. (43). DNA binding
assays were performed using a 32P-labeled double
stranded oligonucleotide corresponding to the conserved GATA element in
the proximal SF-1 promoter at position -175 bp (sense oligo,
5'-CCCATAAAGATAGGGATATT-3'; antisense oligo,
5'-AATTATCCCTATCTTTATGGG-3'). Binding reactions and electrophoresis
conditions were previously described (6). A double
stranded mutant (M1) oligonucleotide (sense oligo,
5'-CCCATAAAGGTAGGGATATT-3'; antisense oligo,
5'-AATATCCCTACCTTTATGGG-3') was used to confirm the specificity of
GATA-4 binding to the SF-1 GATA element. The sequences of the MIS
wild-type and mutated oligonucleotides that were also used as
competitors in the gel shift assay have been reported previously
(6). In the Western blot analysis, 20-µg aliquots of
nuclear extract containing either the full-length or N-terminal-deleted
GATA-4 proteins (GATA-4 F.L. and N-term) were separated by
SDS-PAGE and then transferred to Hybond polyvinylidene difluoride
membranes (Amersham Pharmacia Biotech,
Baie-D’Urfé, Canada). Immunodetection of the GATA proteins was
achieved using a GATA-4-specific antibody (Santa Cruz Biotechnology, Inc., Santa Cruz, CA) and a commercially
available Vectastain-ABC-Amp Western blot detection kit
(Vector Laboratories, Inc., Burlingame, CA).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. Consistent with most GATA-dependent
promoters described to date, the conserved GATA motifs found in gonadal
promoters are located in close proximity to the transcriptional start
site (Fig. 1A). Although we and others found that these gonadal GATA
elements are capable of specifically interacting with exogenously or
endogenously expressed GATA factors (Fig. 5) and (6, 33, 36), a direct comparison of their ability to respond to GATA
factors has not yet been assessed. The potential of GATA-4 to activate
gonadal promoters is shown in Fig. 2. The
GATA-4 transcription factor is a logical choice to evaluate the GATA
responsiveness of the selected promoters, as it is the sole GATA family
member that is expressed in all cell types (Sertoli, granulosa, thecal,
and Leydig) where the promoters are normally active. Interestingly, the
gonadal promoters were differentially activated by GATA-4 in
heterologous (non-GATA-expressing) CV-1 cells (Fig. 2A) despite the
fact that the conserved GATA elements found in each respective promoter
are not differentially bound by GATA proteins. The MIS and inhibin
promoters were moderately activated by GATA-4 (3.5- and 7-fold),
whereas the PII aromatase (Cyp19) and StAR promoters were strongly
activated (11.5- and 22-fold) with an equivalent dose of GATA-4.
Interestingly, the SF-1 promoter was very poorly activated by GATA-4.
Similar activations were also observed with other GATA factors (GATA-1
and GATA-6) that are known to be expressed in the gonads (data not
shown). The observed GATA-4 activations were specific, because the
corresponding promoters deleted or mutated of their respective GATA
elements were not activated by GATA-4 (Fig. 2B). Thus, it appears that
promoter context plays an important role in how GATA-containing gonadal
promoters respond to exogenously expressed GATA factors.
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promoters all contain consensus SF-1 regulatory elements
(44, 45, 46, 47, 48). As we previously reported that GATA-4 can
cooperate with SF-1 to synergistically activate MIS transcription
(34), we tested whether GATA-4/SF-1 synergism also
contributes to the transcription of these other gonadal genes. As shown
in Fig. 3, in addition to MIS, marked
GATA-4/SF-1 synergism was observed on the aromatase and inhibin
promoters, but not on the SF-1 and StAR promoters. Thus,
transcriptional synergism constitutes another aspect of the
differential activation of gonadal genes by GATA-4.
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). We
then tested whether this GATA element could specifically interact with
recombinant GATA-4 protein. Gel shift experiments showed that the SF-1
GATA element bound GATA-4 with high affinity (Fig. 5
). This binding was specific, because it
was competed by both the unlabeled SF-1 probe (Fig. 5, lanes 4–7) and
an oligonucleotide corresponding to the previously defined GATA element
from the MIS promoter (Fig. 5, lane 9), but not by oligonucleotides
containing a mutated GATA motif (Fig. 5, lanes 8 and 10).
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). Knowing that all GATA family members
share similar DNA-binding properties (10, 11), we then
tested whether the SF-1 promoter could be activated by other GATA
factors known to be expressed in the gonads. As shown in Fig. 6B, GATA-1 and GATA-6, much like GATA-4, were unable to augment SF-1
promoter activity in CV-1 cells. To determine whether the lack of
GATA-dependent trans-activation in CV-1 cells was not simply
due to the absence of some critical factor, similar GATA-4
trans-activation experiments were performed in several other
cell lines (Fig. 7). They included L cell
fibroblasts (another heterologous cell model) and T3–1, TM3, Y-1,
and MSC-1 cells, which are known to endogenously express SF-1 and GATA
factors (4, 44, 52, 53, 54 ; and our unpublished
observations). In L, TM3, and Y-1 cells, GATA-4 remained a poor
activator of SF-1 transcription (Fig. 7). However, in the T3–1 and
MSC-1 cell lines, the proximal SF-1 promoter was significantly
activated by GATA-4 (Fig. 7). To confirm that the SF-1 GATA element was
indeed functional, we generated two synthetic promoter constructs where
the SF-1 GATA element was taken out of its natural promoter context and
placed upstream of two heterologous promoters. When tested in
trans-activation experiments, these synthetic constructs
were markedly activated by GATA-4 (12- to 30-fold), indicating that the
SF-1 GATA element is functional when taken out of its natural promoter
context (Fig. 8A). The GATA-dependent
activations were specifically mediated by the SF-1 GATA element and not
the minimal promoters, as we have previously shown the latter to be
unresponsive to GATA factors (34).
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) is an
indication that GATA-4 transcriptional activity on the SF-1 promoter is
also modulated by cell-specific cofactors and/or a posttranslational
modification. This interaction/modification may lead to a
conformational change in GATA-4 that is necessary to activate the SF-1
promoter in its natural context. Consistent with this hypothesis, a
truncated GATA-4 protein, which was deleted of its entire N-terminal
region (1–254 amino acids), was able to significantly activate the
SF-1 promoter in heterologous CV-1 cells (Fig. 8B). The difference in
trans-activation potential between the full-length and
truncated GATA-4 proteins was not due to differences in expression
level, because both recombinant proteins were found to be similarly
expressed (Fig. 8C). As a first step to address the potential
implication of cooperative actions of GATA in SF-1 promoter activation,
we performed cotransfection experiments involving GATA-4 and other
transcription factors known to be important for gonadal gene expression
and possibly SF-1 gene transcription. As shown in Fig. 9A, neither the HMG-box factor Sox9 nor
the LIM homeobox protein Lhx9, which are both coexpressed with SF-1 at
the onset of gonadal development (55, 56, 57), was able to
activate the SF-1 promoter on their own or in combination with GATA-4.
As a conserved E box for the binding of the bZIP-HLH factors USF-1 and
USF-2 and a CCAAT-containing motif for the potential binding of C/EBP
proteins are present in the proximal SF-1 promoter, we tested whether
these factors could transcriptionally cooperate with GATA-4 to activate
the SF-1 promoter (Fig. 9B). Although the USF proteins could
significantly activate the SF-1 promoter on their own, the addition of
GATA-4 did not lead to further activation (Fig. 9B, left
panel). Interestingly, the C/EBP isoforms were also able to
individually activate the SF-1 promoter. Again, transcriptional
cooperation was not observed when the C/EBP isoforms were used in
combination with GATA-4. However, as the C/EBP isoforms are expressed
in Sertoli cells (58), they may be important contributors
to SF-1 transcription in the testis.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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GATA-4: a key regulator of gonadal gene transcription
The promoters of several genes (MIS, aromatase, SF-1, StAR, and
inhibin ), known to be important for proper gonadal development and
steroidogenic function, contain species-conserved GATA regulatory
elements in their proximal promoter regions (Fig. 1). Moreover, we have
shown that these promoters are all activated by GATA-4 (Fig. 2), the
GATA factor common to granulosa, thecal, Sertoli, and Leydig cells. The
requirement for a single factor in the control of multiple target genes
appears to be a common regulatory mechanism in many tissues, including
the endocrine organs. Indeed, within the pituitary, the homeoprotein
Pitx1 was defined as a pan-pituitary regulator of gene expression
(59). Similar roles have been ascribed to the homeobox
protein STF-1/Pdx1 in the pancreas (60, 61) and the orphan
nuclear receptor SF-1 in the hypothalamo-pituitary-gonadal axis
(62, 63). Thus, the ability of GATA-4 to activate multiple
gonadal promoters shown here supports an analogous role for GATA-4 in
gonadal gene expression.
The involvement of pan-regulatory factors in tissue-specific
transcription, however, most often requires precise combinatorial
interactions with other cell-restricted factors. For example, in the
pituitary, the Pitx1 homeobox protein has been reported to interact
with different factors present only in a subset of pituitary cell
types, thereby creating a cell-specific code for lineage-specific gene
expression (64). Similar combinatorial interactions have
also been described for the orphan nuclear receptor SF-1 in the control
of SF-1 target genes in the gonads (34, 65, 66). In
heterologous cells, both Pitx1 and SF-1 differentially activate target
promoters despite no real differences in Pitx1 and SF-1 binding
affinities to their respective promoter elements (59, 63, 64). Interestingly, this is what was observed for GATA-4 on the
different gonadal promoters. Thus, it is likely that GATA-4 contributes
to tissue-specific expression in the gonads through cooperative
interactions with other transcription factors. Indeed, we have shown
that GATA-4 cooperates with SF-1 to enhance MIS transcription
(34), and we now extend this to include the aromatase and
inhibin promoters. Similarly, binding sites for both GATA-4 and
C/EBP
were shown to be required for StAR promoter activity
(36, 37).
The SF-1 promoter is a potential downstream target for
GATA-4
The orphan nuclear receptor SF-1 is a critical regulator of gene
expression at all levels of the reproductive axis; it is indispensable
for adrenal and gonadal development and is later recruited as an
essential factor required for cell-specific gene expression in the
pituitary, hypothalamus, adrenals, and gonads (62, 63, 67). Although SF-1 was identified nearly a decade ago
(40), surprisingly little is known about the
transcriptional mechanisms that control its expression. Recent analyses
of the SF-1 promoter have all identified an essential E box motif that
binds members of the USF family of bZIP-HLH factors (46, 68, 69, 70, 71). Mutation or deletion of this conserved element leads to
a marked decrease in SF-1 promoter activity in multiple cell types,
including fibroblasts, which do not express SF-1 (46, 68, 69, 70, 71). Taken together, these data suggest that the E box
element alone cannot account for the specificity of SF-1 expression
in vivo. Therefore, additional regulatory elements must
exist.
Interestingly, GATA factors are found in most, if not all, SF-1 target tissues. Indeed, GATA factors are present in pituitary gonadotropes, Sertoli and Leydig cells of the testis, ovarian granulosa and thecal cells, and cells of the fetal and postnatal adrenal cortex (4, 5, 6, 7, 32, 51, 52). This observation raises the intriguing possibility that GATA factors might be involved in the initiation and/or up-regulation of SF-1 expression in certain tissues, such as the gonads, where both factors are expressed from an early developmental stage (6, 57). Indeed, we have shown that the mouse, rat, and human SF-1 promoters all contain a consensus GATA-binding element. Moreover, different groups have shown that deletion of the region containing the conserved GATA element leads to a drop in SF-1 promoter activity in different gonadal cell lines (69, 70). Although GATA-4 specifically bound this element, GATA-4 was a poor activator of the SF-1 promoter in heterologous cells. Interestingly, these data are reminiscent of the well characterized SF-1 element that is present in the proximal MIS promoter (34, 44). Although this element is essential for MIS promoter activity in vivo (72, 73), it is nonetheless weakly activated by SF-1 alone in in vitro transfection assays (34, 44). With respect to the MIS promoter, SF-1 transcriptional activity was shown to be mediated through synergistic interactions with other transcription factors (34, 65, 66). A similar mechanism may also be required to modulate GATA activity in context of the SF-1 promoter. Indeed, GATA-4-mediated trans-activation of the natural SF-1 promoter was strictly dependent on cell type, and in heterologous cells, the N-terminal region of the GATA-4 protein had to be deleted for activation to occur. Taken together, our data suggest that the GATA-dependent regulation of SF-1 promoter requires the participation of a cofactor, the disruption of an interaction with a repressor, or a specific posttranslational modification of the GATA-4 protein, such as phosphorylation or acetylation. Alternatively, regulatory elements for the binding of GATA cooperative factors might be located outside of the promoter region used in this study. An in vivo analysis of the 5'-regulatory elements of the SF-1 gene would be required to examine this possibility.
Besides the conserved GATA motif in the SF-1 promoter, we recently identified an SF-1-like element in the proximal rat GATA-4 gene promoter (Legault, E., J. J. Tremblay, and R. S. Viger, unpublished observations). Thus, in addition to regulating downstream target genes in the gonads, cross-talk between GATA-4 and SF-1 may be an important mechanism for ensuring the proper spatiotemporal expression of these crucial factors during development.
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Acknowledgments |
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T3–1 cell line), and Michael Griswold (MSC-1 cell line) are
thanked for generously providing plasmids and cell lines used in this
study. |
Footnotes |
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2 Recipient of a postdoctoral fellowship from the Natural Sciences
and Engineering Research Council of Canada.
3 Chercheur-Boursier of the Fonds de la Recherche en Santé du
Québec.
Received August 22, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-subunit
gene in MA-10 Leydig tumor cells. Mol Endocrinol 12:378–390-promoter by steroidogenic
factor-1 and cyclic adenosine 3',5'-monophosphate. Mol Endocrinol 14:66–81-subunit gene in the
placenta and pituitary gland. Mol Cell Biol 14:5592–5602-subunit gene in pituitary gonadotropes. Mol Endocrinol 8:878–885This article has been cited by other articles:
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Y. Y. Hui and H. A. LaVoie GATA4 Reduction Enhances 3',5'-Cyclic Adenosine 5'-Monophosphate-Stimulated Steroidogenic Acute Regulatory Protein Messenger Ribonucleic Acid and Progesterone Production in Luteinized Porcine Granulosa Cells Endocrinology, November 1, 2008; 149(11): 5557 - 5567. [Abstract] [Full Text] [PDF]
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L. J Martin and J. J Tremblay Glucocorticoids antagonize cAMP-induced Star transcription in Leydig cells through the orphan nuclear receptor NR4A1 J. Mol. Endocrinol., September 1, 2008; 41(3): 165 - 175. [Abstract] [Full Text] [PDF]
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L. J. Martin, N. Boucher, C. Brousseau, and J. J. Tremblay The Orphan Nuclear Receptor NUR77 Regulates Hormone-Induced StAR Transcription in Leydig Cells through Cooperation with Ca2+/Calmodulin-Dependent Protein Kinase I Mol. Endocrinol., September 1, 2008; 22(9): 2021 - 2037. [Abstract] [Full Text] [PDF]
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H. Nishida, S. Miyagawa, M. Vieux-Rochas, M. Morini, Y. Ogino, K. Suzuki, N. Nakagata, H.-S. Choi, G. Levi, and G. Yamada Positive Regulation of Steroidogenic Acute Regulatory Protein Gene Expression through the Interaction between Dlx and GATA-4 for Testicular Steroidogenesis Endocrinology, May 1, 2008; 149(5): 2090 - 2097. [Abstract] [Full Text] [PDF]
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R. S. Viger, S. M. Guittot, M. Anttonen, D. B. Wilson, and M. Heikinheimo Role of the GATA Family of Transcription Factors in Endocrine Development, Function, and Disease Mol. Endocrinol., April 1, 2008; 22(4): 781 - 798. [Abstract] [Full Text] [PDF]
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 E. W Kabithe and N. J Place Photoperiod-dependent modulation of anti-Mullerian hormone in female Siberian hamsters, Phodopus sungorus Reproduction, March 1, 2008; 135(3): 335 - 342. [Abstract] [Full Text] [PDF]
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C. M. Wayne, H.-Y. Fan, X. Cheng, and J. S. Richards Follicle-Stimulating Hormone Induces Multiple Signaling Cascades: Evidence that Activation of Rous Sarcoma Oncogene, RAS, and the Epidermal Growth Factor Receptor Are Critical for Granulosa Cell Differentiation Mol. Endocrinol., August 1, 2007; 21(8): 1940 - 1957. [Abstract] [Full Text] [PDF]
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N. Sher, N. Yivgi-Ohana, and J. Orly Transcriptional Regulation of the Cholesterol Side Chain Cleavage Cytochrome P450 Gene (CYP11A1) Revisited: Binding of GATA, Cyclic Adenosine 3',5'-Monophosphate Response Element-Binding Protein and Activating Protein (AP)-1 Proteins to a Distal Novel Cluster of cis-Regulatory Elements Potentiates AP-2 and Steroidogenic Factor-1-Dependent Gene Expression in the Rodent Placenta and Ovary Mol. Endocrinol., April 1, 2007; 21(4): 948 - 962. [Abstract] [Full Text] [PDF]
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J. Kwintkiewicz, Z. Cai, and C. Stocco Follicle-Stimulating Hormone-Induced Activation of Gata4 Contributes in the Up-Regulation of Cyp19 Expression in Rat Granulosa Cells Mol. Endocrinol., April 1, 2007; 21(4): 933 - 947. [Abstract] [Full Text] [PDF]
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 S. Mazaud Guittot, A. Tetu, E. Legault, N. Pilon, D. W. Silversides, and R. S. Viger The Proximal Gata4 Promoter Directs Reporter Gene Expression to Sertoli Cells During Mouse Gonadal Development Biol Reprod, January 1, 2007; 76(1): 85 - 95. [Abstract] [Full Text] [PDF]
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B. D. Looyenga and G. D. Hammer Origin and Identity of Adrenocortical Tumors in Inhibin Knockout Mice: Implications for Cellular Plasticity in the Adrenal Cortex Mol. Endocrinol., November 1, 2006; 20(11): 2848 - 2863. [Abstract] [Full Text] [PDF]
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M Anttonen, H Parviainen, A Kyronlahti, M Bielinska, D B Wilson, O Ritvos, and M Heikinheimo GATA-4 is a granulosa cell factor employed in inhibin-{alpha} activation by the TGF-{beta} pathway. J. Mol. Endocrinol., June 1, 2006; 36(3): 557 - 568. [Abstract] [Full Text] [PDF]
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J. Weck and K. E. Mayo Switching of NR5A Proteins Associated with the Inhibin {alpha}-Subunit Gene Promoter after Activation of the Gene in Granulosa Cells Mol. Endocrinol., May 1, 2006; 20(5): 1090 - 1103. [Abstract] [Full Text] [PDF]
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 S. Perlman, T. Bouquin, B. van den Hazel, T.H. Jensen, H.T. Schambye, S. Knudsen, and J.S. Okkels Transcriptome analysis of FSH and FSH variant stimulation in granulosa cells from IVM patients reveals novel regulated genes Mol. Hum. Reprod., March 1, 2006; 12(3): 135 - 144. [Abstract] [Full Text] [PDF]
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 M. Bielinska, S. Kiiveri, H. Parviainen, S. Mannisto, M. Heikinheimo, and D. B. Wilson Gonadectomy-induced Adrenocortical Neoplasia in the Domestic Ferret (Mustela putorius furo) and Laboratory Mouse. Vet. Pathol., February 1, 2006; 43(2): 97 - 117. [Abstract] [Full Text] [PDF]
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 G. S. Huggins, J. Y.Y. Wong, S. E. Hankinson, and I. De Vivo GATA5 Activation of the Progesterone Receptor Gene Promoter in Breast Cancer Cells Is Influenced by the +331G/A Polymorphism Cancer Res., February 1, 2006; 66(3): 1384 - 1390. [Abstract] [Full Text] [PDF]
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N. M. Robert, L. J. Martin, and J. J. Tremblay The Orphan Nuclear Receptor NR4A1 Regulates Insulin-Like 3 Gene Transcription in Leydig Cells Biol Reprod, February 1, 2006; 74(2): 322 - 330. [Abstract] [Full Text] [PDF]
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M. F. Bouchard, H. Taniguchi, and R. S. Viger Protein Kinase A-Dependent Synergism between GATA Factors and the Nuclear Receptor, Liver Receptor Homolog-1, Regulates Human Aromatase (CYP19) PII Promoter Activity in Breast Cancer Cells Endocrinology, November 1, 2005; 146(11): 4905 - 4916. [Abstract] [Full Text] [PDF]
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L. J. Martin, H. Taniguchi, N. M. Robert, J. Simard, J. J. Tremblay, and R. S. Viger GATA Factors and the Nuclear Receptors, Steroidogenic Factor 1/Liver Receptor Homolog 1, Are Key Mutual Partners in the Regulation of the Human 3{beta}-Hydroxysteroid Dehydrogenase Type 2 Promoter Mol. Endocrinol., September 1, 2005; 19(9): 2358 - 2370. [Abstract] [Full Text] [PDF]
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N. Huang, A. Dardis, and W. L. Miller Regulation of Cytochrome b5 Gene Transcription by Sp3, GATA-6, and Steroidogenic Factor 1 in Human Adrenal NCI-H295A Cells Mol. Endocrinol., August 1, 2005; 19(8): 2020 - 2034. [Abstract] [Full Text] [PDF]
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J. F. Couse, M. M. Yates, B. J. Deroo, and K. S. Korach Estrogen Receptor-{beta} Is Critical to Granulosa Cell Differentiation and the Ovulatory Response to Gonadotropins Endocrinology, August 1, 2005; 146(8): 3247 - 3262. [Abstract] [Full Text] [PDF]
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 J. Simard, M.-L. Ricketts, S. Gingras, P. Soucy, F. A. Feltus, and M. H. Melner Molecular Biology of the 3{beta}-Hydroxysteroid Dehydrogenase/{Delta}5-{Delta}4 Isomerase Gene Family Endocr. Rev., June 1, 2005; 26(4): 525 - 582. [Abstract] [Full Text] [PDF]
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B. Ritz-Laser, A. Mamin, T. Brun, I. Avril, V. M. Schwitzgebel, and J. Philippe The Zinc Finger-Containing Transcription Factor Gata-4 Is Expressed in the Developing Endocrine Pancreas and Activates Glucagon Gene Expression Mol. Endocrinol., March 1, 2005; 19(3): 759 - 770. [Abstract] [Full Text] [PDF]
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B. F. Clem, E. A. Hudson, and B. J. Clark Cyclic Adenosine 3',5'-Monophosphate (cAMP) Enhances cAMP-Responsive Element Binding (CREB) Protein Phosphorylation and Phospho-CREB Interaction with the Mouse Steroidogenic Acute Regulatory Protein Gene Promoter Endocrinology, March 1, 2005; 146(3): 1348 - 1356. [Abstract] [Full Text] [PDF]
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L. J. Martin and J. J. Tremblay The Human 3{beta}-Hydroxysteroid Dehydrogenase/{Delta}5-{Delta}4 Isomerase Type 2 Promoter Is a Novel Target for the Immediate Early Orphan Nuclear Receptor Nur77 in Steroidogenic Cells Endocrinology, February 1, 2005; 146(2): 861 - 869. [Abstract] [Full Text] [PDF]
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K. J. Saner, T. Suzuki, H. Sasano, J. Pizzey, C. Ho, J. F. Strauss III, B. R. Carr, and W. E. Rainey Steroid Sulfotransferase 2A1 Gene Transcription Is Regulated by Steroidogenic Factor 1 and GATA-6 in the Human Adrenal Mol. Endocrinol., January 1, 2005; 19(1): 184 - 197. [Abstract] [Full Text] [PDF]
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Y. Wu, S. Ghosh, Y. Nishi, T. Yanase, H. Nawata, and Y. Hu The Orphan Nuclear Receptors NURR1 and NGFI-B Modulate Aromatase Gene Expression in Ovarian Granulosa Cells: A Possible Mechanism for Repression of Aromatase Expression upon Luteinizing Hormone Surge Endocrinology, January 1, 2005; 146(1): 237 - 246. [Abstract] [Full Text] [PDF]
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 G. Vanpoucke, S. Goossens, B. De Craene, B. Gilbert, F. van Roy, and G. Berx GATA-4 and MEF2C transcription factors control the tissue-specific expression of the {alpha}T-catenin gene CTNNA3 Nucleic Acids Res., August 9, 2004; 32(14): 4155 - 4165. [Abstract] [Full Text] [PDF]
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 R. S. Viger, H. Taniguchi, N. M. Robert, and J. J. Tremblay The 25th Volume: Role of the GATA Family of Transcription Factors in Andrology J Androl, July 1, 2004; 25(4): 441 - 452. [Full Text] [PDF]
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C. E. Fluck and W. L. Miller GATA-4 and GATA-6 Modulate Tissue-Specific Transcription of the Human Gene for P450c17 by Direct Interaction with Sp1 Mol. Endocrinol., May 1, 2004; 18(5): 1144 - 1157. [Abstract] [Full Text] [PDF]
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H. Hiroi, L. K. Christenson, L. Chang, M. D. Sammel, S. L. Berger, and J. F. Strauss III Temporal and Spatial Changes in Transcription Factor Binding and Histone Modifications at the Steroidogenic Acute Regulatory Protein (StAR) Locus Associated with StAR Transcription Mol. Endocrinol., April 1, 2004; 18(4): 791 - 806. [Abstract] [Full Text] [PDF]
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 H. A. LaVoie The Role of GATA in Mammalian Reproduction Experimental Biology and Medicine, December 1, 2003; 228(11): 1282 - 1290. [Abstract] [Full Text] [PDF]
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 J. J. Tremblay and R. S. Viger A Mutated Form of Steroidogenic Factor 1 (SF-1 G35E) That Causes Sex Reversal in Humans Fails to Synergize with Transcription Factor GATA-4 J. Biol. Chem., October 24, 2003; 278(43): 42637 - 42642. [Abstract] [Full Text] [PDF]
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P. Jimenez, K. Saner, B. Mayhew, and W. E. Rainey GATA-6 Is Expressed in the Human Adrenal and Regulates Transcription of Genes Required for Adrenal Androgen Biosynthesis Endocrinology, October 1, 2003; 144(10): 4285 - 4288. [Abstract] [Full Text] [PDF]
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A. Balla, N. Danilovich, Y. Yang, and M. R. Sairam Dynamics of Ovarian Development in the FORKO Immature Mouse: Structural and Functional Implications for Ovarian Reserve Biol Reprod, October 1, 2003; 69(4): 1281 - 1293. [Abstract] [Full Text] [PDF]
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F. Lindeboom, N. Gillemans, A. Karis, M. Jaegle, D. Meijer, F. Grosveld, and S. Philipsen A tissue-specific knockout reveals that Gata1 is not essential for Sertoli cell function in the mouse Nucleic Acids Res., September 15, 2003; 31(18): 5405 - 5412. [Abstract] [Full Text] [PDF]
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M. Bielinska, H. Parviainen, S. B. Porter-Tinge, S. Kiiveri, E. Genova, N. Rahman, I. T. Huhtaniemi, L. J. Muglia, M. Heikinheimo, and D. B. Wilson Mouse Strain Susceptibility to Gonadectomy-Induced Adrenocortical Tumor Formation Correlates with the Expression of GATA-4 and Luteinizing Hormone Receptor Endocrinology, September 1, 2003; 144(9): 4123 - 4133. [Abstract] [Full Text] [PDF]
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V. R. Harley, M. J. Clarkson, and A. Argentaro The Molecular Action and Regulation of the Testis-Determining Factors, SRY (Sex-Determining Region on the Y Chromosome) and SOX9 [SRY-Related High-Mobility Group (HMG) Box 9] Endocr. Rev., August 1, 2003; 24(4): 466 - 487. [Abstract] [Full Text] [PDF]
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J. J. Tremblay and R. S. Viger Transcription Factor GATA-4 Is Activated by Phosphorylation of Serine 261 via the cAMP/Protein Kinase A Signaling Pathway in Gonadal Cells J. Biol. Chem., June 6, 2003; 278(24): 22128 - 22135. [Abstract] [Full Text] [PDF]
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 I. Ketola, J. Toppari, T. Vaskivuo, R. Herva, J. S. Tapanainen, and M. Heikinheimo Transcription Factor GATA-6, Cell Proliferation, Apoptosis, and Apoptosis-Related Proteins Bcl-2 and Bax in Human Fetal Testis J. Clin. Endocrinol. Metab., April 1, 2003; 88(4): 1858 - 1865. [Abstract] [Full Text] [PDF]
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M. Anttonen, I. Ketola, H. Parviainen, A.-K. Pusa, and M. Heikinheimo FOG-2 and GATA-4 Are Coexpressed in the Mouse Ovary and Can Modulate Mullerian-Inhibiting Substance Expression Biol Reprod, April 1, 2003; 68(4): 1333 - 1340. [Abstract] [Full Text] [PDF]
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C. Gillio-Meina, Y. Y. Hui, and H. A. LaVoie GATA-4 and GATA-6 Transcription Factors: Expression, Immunohistochemical Localization, and Possible Function in the Porcine Ovary Biol Reprod, February 1, 2003; 68(2): 412 - 422. [Abstract] [Full Text] [PDF]
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J. J. Tremblay, F. Hamel, and R. S. Viger Protein Kinase A-Dependent Cooperation between GATA and CCAAT/Enhancer-Binding Protein Transcription Factors Regulates Steroidogenic Acute Regulatory Protein Promoter Activity Endocrinology, October 1, 2002; 143(10): 3935 - 3945. [Abstract] [Full Text] [PDF]
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N. M. Robert, J. J. Tremblay, and R. S. Viger Friend of GATA (FOG)-1 and FOG-2 Differentially Repress the GATA-Dependent Activity of Multiple Gonadal Promoters Endocrinology, October 1, 2002; 143(10): 3963 - 3973. [Abstract] [Full Text] [PDF]
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S. Kiiveri, J. Liu, M. Westerholm-Ormio, N. Narita, D. B. Wilson, R. Voutilainen, and M. Heikinheimo Differential Expression of GATA-4 and GATA-6 in Fetal and Adult Mouse and Human Adrenal Tissue Endocrinology, August 1, 2002; 143(8): 3136 - 3143. [Abstract] [Full Text] [PDF]
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C. K. Cheng, C. M. Yeung, B. K. C. Chow, and P. C. K. Leung Characterization of a New Upstream GnRH Receptor Promoter in Human Ovarian Granulosa-Luteal Cells Mol. Endocrinol., July 1, 2002; 16(7): 1552 - 1564. [Abstract] [Full Text] [PDF]
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Z. Zhang, A. Z. Wu, Z.-M. Feng, D. Mruk, C. Y. Cheng, and C.-L. C. Chen Gonadotropins, via cAMP, Negatively Regulate GATA-1 Gene Expression in Testicular Cells Endocrinology, March 1, 2002; 143(3): 829 - 836. [Abstract] [Full Text] [PDF]
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P.T.K. Saunders, S.M. Maguire, S. Macpherson, M.C. Fenelon, S. Sakakibara, and H. Okano RNA Binding Protein Musashi1 Is Expressed in Sertoli Cells in the Rat Testis from Fetal Life to Adulthood Biol Reprod, February 1, 2002; 66(2): 500 - 507. [Abstract] [Full Text] [PDF]
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P. R. Manna, M. T. Dyson, D. W. Eubank, B. J. Clark, E. Lalli, P. Sassone-Corsi, A. J. Zeleznik, and D. M. Stocco Regulation of Steroidogenesis and the Steroidogenic Acute Regulatory Protein by a Member of the cAMP Response-Element Binding Protein Family Mol. Endocrinol., January 1, 2002; 16(1): 184 - 199. [Abstract] [Full Text] [PDF]
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J. Teixeira, S. Maheswaran, and P. K. Donahoe Mullerian Inhibiting Substance: An Instructive Developmental Hormone with Diagnostic and Possible Therapeutic Applications Endocr. Rev., October 1, 2001; 22(5): 657 - 674. [Abstract] [Full Text] [PDF]
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J. J. Tremblay, N. M. Robert, and R. S. Viger Modulation of Endogenous GATA-4 Activity Reveals Its Dual Contribution to Mullerian Inhibiting Substance Gene Transcription in Sertoli Cells Mol. Endocrinol., September 1, 2001; 15(9): 1636 - 1650. [Abstract] [Full Text] [PDF]
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D. T. MacLaughlin, J. Teixeira, and P. K. Donahoe Perspective: Reproductive Tract Development--New Discoveries and Future Directions Endocrinology, June 1, 2001; 142(6): 2167 - 2172. [Full Text] [PDF]
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J. S. Richards Perspective: The Ovarian Follicle--A Perspective in 2001 Endocrinology, June 1, 2001; 142(6): 2184 - 2193. [Full Text] [PDF]
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D. B. Hales Editorial: Gonadal-Specific Transcription Factors--GATA (Go) 4 It! Endocrinology, March 1, 2001; 142(3): 974 - 976. [Full Text] [PDF]
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, Control (empty) expression vector; 
, promoter
trans-activations in the presence of 50 ng GATA-4.
Similar activations were also observed for other members of the GATA
family of factors. Data are reported as fold activation relative to
control (±SEM).
), SF-1 (
), or both GATA-4 and
SF-1 (
(right panel) on the activity of the -182-bp SF-1
promoter.