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From the * Department of Reproduction, Perinatal,
and Child Health, Le Centre Hospitalier Universitaire de Québec (CHUQ)
Research Centre, and the Centre for Research
in Biology of Reproduction, Department of Obstetrics and Gynecology, Faculty
of Medicine, Université Laval, Quebec City, Quebec, Canada.
| Correspondence to: Dr Jacques J. Tremblay, Reproduction, Perinatal, and Child Health, CHUQ Research Centre, CHUL Room T1-49, 2705 Laurier Blvd, Quebec City, QC Canada G1V 4G2 (e-mail: Jacques-J.Tremblay{at}crchul.ulaval.ca). |
| Received for publication July 20, 2008; accepted for publication September 30, 2008. |
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Abstract |
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Key words: NR4A1, NGFI-B, forskolin, luteinizing hormone, steroidogenesis, Ca2+/calmodulin kinase I
Nur77 is expressed in several tissues, including the testis, ovary, muscle, thymus, adrenal gland, pituitary, and central nervous system (Giguere, 1999; Eells et al, 2000; Maxwell and Muscat, 2005). NUR77 has been shown to play key roles in regulating expression of several genes involved in inflammation, steroidogenesis, and male sex differentiation along the hypothalamo-pituitary-adrenal and hypothalamo-pituitary-gonadal axes. These genes include the rat Pomc (Philips et al, 1997), Cyp17a1 (Zhang and Mellon, 1997), and Akr1c18 (Stocco et al, 2000); the mouse Star (Martin and Tremblay, 2008; Martin et al, 2008) and Cyp21a1 (Wilson et al, 1993b); and the human CRH (Murphy et al, 2001), HSD3B2 (Bassett et al, 2004a; Martin and Tremblay, 2005), CYP11B2 (Bassett et al, 2004b), and INSL3 (Tremblay and Robert, 2005; Robert et al, 2006).
In testicular Leydig cells, steroid hormone biosynthesis is controlled mainly by the pituitary gonadotropin LH, which acts by binding to its G protein–coupled LH receptor (LH-R). Although it is well accepted that the effects triggered by the activated LH-R are mostly mediated by the adenylate cyclase/cyclic adenosine monophosphate (cAMP)/protein kinase A pathway, other signaling pathways also are involved. These include the protein kinase C, phospholipase C, mitogen-activated protein kinase cascade, and Ca2+/calmodulin (CaM) pathways (reviewed in Ascoli et al, 2002). In agreement with a role for the CaM pathway, we reported recently the expression of Ca2+/calmodulin kinase I (CaMKI) specifically in Leydig cells of the testis (Martin et al, 2008). Although Nur77 is rapidly and strongly induced in response to LH/forskolin/cAMP in Leydig cells (Park et al, 2001, 2003; Song et al, 2001; Li et al, 2004; Martin and Tremblay, 2005; Martin et al, 2008), where it regulates expression of several genes, surprisingly very little is known regarding the mechanisms regulating expression of Nur77 itself in these cells. There is only one recent report that revealed the implication of AP-1 and CREB members in Nur77 promoter activity in Leydig cells (Inaoka et al, 2008).
In the present study we have performed a detailed characterization of the mechanisms involved in Nur77 upregulation at the protein, mRNA, and promoter levels in response to cAMP signaling in MA-10 Leydig cells. At the protein level, cAMP-induced NUR77 protein involves transcription and de novo protein synthesis, whereas at the transcriptional level, increased Nur77 mRNA following hormonal stimulation relies solely on transcription factors already present in the cell. At the promoter level we found that different regulatory elements are involved in basal and cAMP-induced Nur77 transcription. Finally, we report that a Ca2+/calmodulin kinase (CaMK)-dependent pathway is essential for maximal cAMP-mediated induction of Nur77 and that CaMKI activates the Nur77 promoter. Collectively, our results demonstrate the involvement of various mechanisms, including the implication of CaMKI, in the regulation of Nur77 expression in response to hormonal stimulation, and therefore constitute key new data regarding this important regulator of Leydig cell gene expression and function.
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Materials and Methods |
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Plasmids
The rat –1013-bp Nur77 (NGFI-B) promoter sequence
was amplified by polymerase chain reaction (PCR) from rat genomic DNA using
the following primers: forward (includes a BamHI site shown in
italics), 5'-CGGGATCCG CTA CTA CCT AGC TTA GTG ACC-3',
and reverse (contains a KpnI site shown in italics), 5'-CTG
GTA CCG CGT GCG CTC TGC AAT CCT TC-3'. The amplified promoter
sequence was cloned into a BamHI/KpnI site of a modified
pXP1-luciferase reporter plasmid (Tremblay
and Viger, 1999). Deletions of the Nur77 promoter to
–747, –331, –276, –233, –121, and –65 bp
were obtained by PCR using the –1013-bp Nur77 promoter as
template, along with a common reverse primer containing a KpnI
(italicized) cloning site (5'-CTG GTA CCG CGT GCG CTC TGC AAT
CCT TC-3') and the following forward primers containing a BamHI
(italicized) cloning site: –747 bp, 5'-CGG GAT CCG TAG
TCA GCA GTG AAA CTG-3'; –331 bp, 5'-CGG GAT CCG TCT
GGA AGC TGC TAT ATT TAG CC-3'; –276 bp, 5'-CGG GAT
CCG ATC AAA CAA TCC GCG CTC-3'; -233 bp, 5'-CGG GAT
CCG TCA CGC GCG CAG ACA TTC CAG-3'; –121 bp, 5'-CGG
GAT CCT TGT ATG GCC AAA GCT C-3'; and –65 bp,
5'-CGG GAT CCA TGC GTC ACG GAG CGC TTA AGA G-3'. All
promoter fragments were cloned into a modified pXP1 luciferase reporter
plasmid. Constructs harboring different regions called NIR (Nur77 important
region) of the rat Nur77 promoter were obtained by PCR using the
–1013-bp Nur77 promoter as a template, along with various
combinations of primers. For NIR-A, NIR-AB, and NIR-ABC, a common forward
primer was used (the same as described above for the –331-bp deletion
construct) along with the following reverse primers containing BglII
sites for NIR-A and NIR-AB and a KpnI site for NIR-ABC: NIR-A at
–234 bp, 5'-CGA GAT CTC ACG CGG GGT TCC ATT GAC GCA
GGG-3'; NIR-AB at –122 bp, 5'-CGA GAT CTG CGC GGG
GGG CGG CGC GGT TCC-3'; NIR-ABC at +45 bp, 5'-CTG GTA CCG
CGT GCG CTC TGC AAT CCT TC-3'. For NIR-B and NIR-BC, a common forward
primer was used (same as described above for the –233-bp deletion
construct) along with the following reverse primers: NIR-B at –122 bp,
containing a BglII site, 5'-CGA GAT CTG CGC GGG GGG
CGG CGC GGT TCC-3'; NIR-BC at +45 bp, containing a KpnI site,
5'-CTG GTA CCG CGT GCG CTC TGC AAT CCT TC-3'. For NIR-C,
the forward primer was the same as the one used to generate the –121-bp
deletion construct described above whereas the reverse primer was the one used
to generate the NIR-ABC construct (at +45 bp as described above). The NIR-AC
construct was obtained by combining NIR-A and NIR-C. Fragments NIR-A, NIR-AB,
and NIR-B were inserted in a luciferase reporter plasmid containing the
–65-bp to +45-bp minimal rat Nur77 promoter, whereas NIR-ABC,
NIR-BC, NIR-AC, and NIR-C fragments were inserted directly into the empty
luciferase reporter plasmid. All plasmids were verified by sequencing (Centre
de Génomique de Québec, Centre Hospitalier de
l'Université Laval Research Centre, Quebec City, Canada). The
expression vectors for CREB and CBP (Mayr
and Montminy, 2001) were provided by Dr Marc Montminy (The Salk
Institute for Biological Studies, La Jolla, California). The c-JUN, c-FOS, and
JUND expression vectors (Teyssier et al,
2001) were obtained from Dr Dany Chalbos (Endocrinologie
Moléculaire et Cellulaire des Cancers, Institut National de la
Santé et de la Recherche Médicale, Montpellier, France). The
CaMKI wild-type and constitutively active expression vectors
(Wayman et al, 2004) were
obtained from Dr Thomas Soderling (Oregon Health Sciences University,
Portland, Oregon).
Protein Purification and Western Blots
Protein isolation and Western blots were performed as described previously
(Martin and Tremblay, 2008;
Martin et al, 2008).
RNA Isolation and Real-Time PCR
Preparation of total RNA from MA-10 Leydig cells and real-time PCR were
performed as described by Martin et al
(2008).
Cell Culture and Transfections
Mouse MA-10 Leydig cells (Ascoli,
1981), which were provided by Dr Mario Ascoli (University of Iowa,
Iowa City, Iowa), were grown and transfected as described previously
(Martin et al, 2008). In
experiments with cAMP stimulation, cells were treated with 0.5 mM
(Bu)2cAMP for different time intervals before harvesting. In
experiments with protein kinase inhibitors, MA-10 cells were treated with 100
nM bisindolylmaleimide I, 10 µM H-89, 20 µM KN-93, 1 µM ML-7, 100 nM
staurosporine, or 10 µM PD98059 for 30 minutes before addition of 0.5 mM
(Bu)2cAMP for 4 hours prior to harvesting. Data reported represent
the average of at least 3 experiments, each performed in duplicate.
Statistical Analysis
Statistical analyses were done using 1-way analysis of variance followed by
comparison of selected pairs of columns using the Bonferroni post test to
identify significant differences (Figures
2 and
6). For Figures
3,
4, and
7, comparisons were done using
a 1-sample t test to determine whether column means were
statistically different from the hypothetical value of 1.0. For all
statistical analyses, P < .05 was considered significant.
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Results |
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-amanitin oleate, a specific inhibitor of RNA polymerase II (data not
shown). In the presence of CHX, however, the (Bu)2cAMP-mediated
increase in Nur77 mRNA levels was not inhibited
(Figure 2, lanes 36 through
42). Rather, it was enhanced when compared with cAMP alone
(Figure 2, compare lanes 13 and
41). All these experiments also were performed using 10 µM FSK, an
activator of adenylate cyclase, instead of (Bu)2cAMP, and similar
results were obtained, with the only exception that the levels of
Nur77 mRNA were decreased to 15% to 35% of the maximal levels after 6
hours of stimulation (data not shown). This is consistent with the fact that
(Bu)2cAMP is more resistant to degradation than naturally generated
cAMP within the cell in response to FSK. Together, these results indicate that
Nur77 transcriptional activation in response to cAMP in MA-10 Leydig
cells does not require de novo protein synthesis and relies mainly on
activation (eg, posttranslational modifications) of transcription factors
already present in the cell.
Distinct Elements of the Nur77 Promoter Are Required for Basal Activity and Hormone Responsiveness
Because Nur77 expression is regulated mainly at the
transcriptional level, we sought to map the regulatory regions of the
Nur77 promoter in MA-10 Leydig cells. A –1013-bp rat
Nur77 promoter fragment was isolated, and a series of 5'
progressive deletions were generated and transiently transfected in MA-10
Leydig cells. As shown in Figure
3A, deletion to –331 bp did not affect Nur77 basal
promoter activity. Further deletion to –276 bp resulted in a 21%
decrease in basal activity, whereas removal of the region between –233
and –122 bp led to an important loss (80%) in Nur77 promoter
activity. The remaining basal activity was lost with a deletion to –65
bp. These results indicate that 3 regions, –331/–234 bp,
–233/–122 bp, and –121/–66 bp, contribute to the basal
activity of the rat Nur77 promoter. We named these regions NIR-A,
NIR-B, and NIR-C. To assess whether NIR-A, NIR-B, and NIR-C work autonomously
or are interdependent, we generated a series of constructs containing the 3
NIR elements in various combinations. As shown in
Figure 3B, absence of NIR-B
(–233 to –122 bp) consistently led to a dramatic loss in
Nur77 basal promoter activity, ranging between 64% and 83%. In fact,
NIR-B alone was found to be sufficient to confer 70% of Nur77 basal
promoter activity (Figure 3B),
indicating that this 112-bp region contains the majority of the regulatory
elements involved in basal activity.
Next, the same reporter constructs (5' deletions and NIR elements) were used to locate the cAMP-responsive region(s) of the Nur77 promoter. As shown in Figure 4A, treatment of MA-10 cells with 0.5 mM (Bu)2cAMP resulted in a 4.6-fold stimulation of the –1013-bp Nur77 reporter. This stimulation was still observed and even slightly increased with a –331-bp Nur77 promoter construct (Figure 4A). Deletion to –233 bp, however, resulted in a decrease in cAMP responsiveness (Figure 4A). Additional 5' deletions revealed that the region between –121 and –65 bp was also required for cAMP-dependent activation (Figure 4A). These results indicate that 2 regions of the Nur77 promoter, NIR-A (–331 to –234 bp) and NIR-C (–121 to –66 bp) are involved in cAMP-dependent activation. As shown in Figure 4B, we found that the presence of either NIR-A or NIR-C was sufficient to confer cAMP responsiveness (7.3-fold and 4.1-fold, respectively) to the Nur77 promoter. Interestingly, the combination of both elements (NIR-AC) resulted in a 17-fold activation of the Nur77 promoter in response to cAMP (Figure 4B), which indicates that the NIR-A and NIR-C elements cooperate to confer maximal cAMP responsiveness to the Nur77 promoter. The NIR-B element and basal promoter fragment (–65 bp) were only weakly activated (about 2-fold) by cAMP (Figure 4B). Furthermore, cAMP-mediated activation of the NIR-AC reporter occurred in a time-dependent manner, with a 5-fold increase after 1 hour of cAMP treatment to an 18-fold increase after 6 hours (Figure 4C). These kinetics in NIR-AC promoter activity closely parallel the increase in endogenous Nur77 mRNA levels in response to cAMP (Figure 2), thus suggesting that the NIR-A and NIR-C elements would be sufficient to reconstitute the in vivo responsiveness of the Nur77 promoter. Furthermore, the 3 NIR regions are well conserved across a wide range of species (Figure 5).
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The proximal region of the Nur77 promoter was shown to contain 4 elements, TGCGTCA (2 in each NIR-A and NIR-C region), that have recently been implicated in cAMP responsiveness in MA-10 Leydig cells (Inaoka et al, 2008). The 4 elements closely resemble binding sites for CREB (TGACGTCA) and AP-1 (TGA[G/C]TCA; Watson and Milbrandt, 1989; Yoon and Lau, 1994). We therefore tested whether CREB and AP-1 family members could activate the Nur77 promoter. As shown in Figure 4D, we found that CREB, in the presence of PKA and its coactivator CBP, as well as c-JUN both activated the Nur77 promoter in MA-10 Leydig cells.
cAMP-Mediated Increase in Nur77 Expression Involves CaMKI Activity
Because Nur77 transcription in response to cAMP in MA-10 cells
does not require de novo protein synthesis
(Figure 2), and rather relies
on the posttranslational modifications of transcription factors already
present in the cells, we next examined which signaling/kinase pathway(s) was
involved in cAMP-mediated increase in Nur77 expression using various
kinase inhibitors. As shown in Figure
6A, of the inhibitors tested, only KN-93 (20 µM), an inhibitor
of Ca2+/CaMKs, resulted in a significant 50% decrease in the cAMP
responsiveness of the Nur77 promoter (similar results on 2 different
reporter constructs), whereas it had no effect in the absence of cAMP. As
revealed by Western blot, the cAMP-mediated induction of the NUR77 protein was
also inhibited in a dose-dependent manner by KN-93. A slight inhibition was
first detected with 0.8 µM, reached about 50% with 4 µM, and was
complete with 20 µM KN-93 (Figure
6B), in agreement with previous data regarding
KN-93–mediated Nurr1 and Nur77 inhibition in adrenal
steroidogenic cells (Bassett et al,
2004b). These data are also consistent with our recent
demonstration that KN-93 prevents the increase in NUR77 protein levels in
Leydig cells in response to the adenylate cyclase activator FSK
(Martin et al, 2008).
Leydig cells were found recently to express CaMKI, a member of the CaMK family (Martin et al, 2008). To test the possibility that the Nur77 promoter might be regulated directly by CaMKI, different Nur77 reporter constructs were transfected in MA-10 Leydig cells along with a CaMKI expression vector. As shown in Figure 7A, CaMKI activated the –1013-bp and –331-bp Nur77 reporter constructs. CaMKI-dependent activations were consistently higher when a calcium-independent constitutively active form of CaMKI (CaMKI CA), generated by removing an autoinhibitory domain (Wayman et al, 2004), was used compared with the wild-type form (CaMKI WT; Figure 7A). As for the cAMP responsiveness (Figure 4B), CaMKI responsiveness was higher when the NIR-A or NIR-C regions were present (individually or combined), whereas the NIR-B element was only weakly responsive, as was the minimal –65-bp Nur77 promoter (Figure 7B). These results indicate that the CaMKI pathway contributes to cAMP-induced Nur77 expression.
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Discussion |
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cis-Regulatory Elements in the Nur77 Promoter
In the present study we have isolated and characterized a 1-kb fragment of
the rat Nur77 promoter, a fragment reported previously to
recapitulate the kinetics of endogenous Nur77 expression in PC12
cells (Yoon and Lau, 1993).
Our analyses of this promoter fragment in MA-10 Leydig cells revealed that it
contains 3 separate regions, which we named NIR-A, NIR-B, and NIR-C, each of
which plays distinct roles in basal and hormone responsiveness of the
promoter. Importantly, these 3 regions have been evolutionarily conserved
across several species, including various mammals and marsupials, which
strongly suggests important regulatory functions.
The regulatory elements critical for basal activity of the rat Nur77 promoter are located mainly within the NIR-B region (–233 to –122 bp). Inaoka et al (2008) recently reported similar results using 5' deletion constructs of the mouse Nur77 promoter in MA-10 Leydig cells (–253 to –125 bp). This 112-bp region was sufficient to restore nearly 80% of the activity of the –1013-bp reporter when fused to the minimally active –65-bp promoter (2% of –1013 bp activity), whereas the NIR-A and NIR-C regions could only confer 15% of activity. The sequence of the NIR-B region is GC rich and contains several potential binding sites for transcription factors belonging to the Sp1/Krüppel family known to be implicated in basal promoter activity of numerous genes. In PC12 and 3T3 cells, these GC-rich boxes were indeed shown to contribute to Nur77 promoter activity (Williams and Lau, 1993; Yoon and Lau, 1993; Yoon and Lau, 1994).
Although several signaling pathways can stimulate Nur77 expression in different tissues, FSK/cAMP was found to be the main pathway inducing its expression in Leydig cells (Song et al, 2001; Martin et al, 2008). Consistent with this, we (in this study) and others (Song et al, 2001; Inaoka et al, 2008) have shown that Nur77 promoter activity is induced by FSK/cAMP in Leydig cells. In addition, we have found that the NIR-A (–331 to –234 bp) and NIR-C (–121 to –66 bp) regions were responsible for the cAMP responsiveness of the Nur77 promoter. The NIR-B region, mostly implicated in basal promoter activity, was only weakly stimulated by cAMP, as was the minimal –65-bp promoter. Each of the NIR-A and NIR-C regions individually was sufficient to confer cAMP responsiveness to the minimal promoter or to the NIR-B region, whereas the combination of both A and C regions led to a more robust cAMP responsiveness. Furthermore, the NIR-AC reporter was upregulated within 1 hour of cAMP stimulation, which closely parallels induction of the endogenous Nur77 mRNA in Leydig cells. This rapid and strong response is consistent with the fact that the upregulation of Nur77 transcription in response to cAMP does not require de novo protein synthesis and relies instead on transcription factors already present in the cell.
NIR-A and NIR-C regions contain binding sites for transcription factors that are known to be available rapidly following hormonal stimulation. These include CREB and AP-1 family members, which can both activate the Nur77 promoter in MA-10 Leydig cells (as shown in this study and in Inaoka et al, 2008) and are both targets of various kinases (Karin, 1996; Whitmarsh and Davis, 1996; Mayr and Montminy, 2001; Inaoka et al, 2008). Given that CREB and AP-1 are expressed ubiquitously, it is very likely that other transcription factors are involved in the cAMP regulation of Nur77 expression in Leydig cells. In agreement with this, we have recently mapped a C/EBPβ responsive element in the NIR-C region (El-Asmar et al, 2008). Because C/EBPβ is upregulated in response to LH/cAMP in Leydig cells (Nalbant et al, 1998), it could participate in the hormonal regulation of Nur77 expression in these cells. Other interesting candidates include members of the NFAT and MEF2 families of transcription factors that have been reported to cooperate in a CaMK-dependent manner through elements in the NIR-A region of the Nur77 promoter in T cells (Youn et al, 2000). No data, however, are currently available regarding expression of MEF2 and NFAT family members in testicular Leydig cells and whether they also contribute to Nur77 transcription in these cells.
Involvement of CaMKI in cAMP-dependent Nur77 Promoter Activation
We reported recently that induction of NUR77 protein in response to
FSK/cAMP was mediated through a CaMK-dependent pathway in Leydig cells and
that it did not involve ERK1/2 as in the ovary (no effect of the ERK inhibitor
PD98059; Martin et al, 2008).
Here, we found that KN-93, an inhibitor of CaMKs I, II, and IV, also inhibited
the cAMP-mediated stimulation of the Nur77 promoter and of the NUR77
protein. Within the testis, we demonstrated recently that CaMKI is the only
CaMK family member expressed in Leydig cells
(Martin et al, 2008).
Consistent with a role for CaMKI in Nur77 expression, we found that
CaMKI directly activated the Nur77 promoter in MA-10 Leydig cells and
that the NIR-A and NIR-C regions were predominantly targeted by CaMKI. To
date, however, the exact target(s) of CaMKI in the regulation of
Nur77 expression in Leydig cells remain to be elucidated fully. There
are several nonexclusive possibilities that could explain CaMKI action. For
example, CaMKI could directly phosphorylate transcription factors involved in
Nur77 transcription. Consistent with this, CREB, a transcription
factor whose activity is regulated by CaMK-dependent phosphorylation in other
systems (Dash et al, 1991;
Sheng et al, 1991), can bind
to (Inaoka et al, 2008) and
activate (this study) the Nur77 promoter. Other potential targets
include AP-1 and C/EBPβ. Another possibility involves transcriptional
cooperation between different regulators that would be modulated by a
CaMKI-dependent pathway. For instance, CREB and AP-1 family members have been
shown to heterodimerize (Hai and Curran,
1991), and both can activate the Nur77 promoter.
Additional work is therefore required to fully elucidate the mechanism of
action of CaMKI in cAMP-mediated Nur77 expression.
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Acknowledgments |
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Footnotes |
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These authors contributed equally to this work. 
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