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Divisions of Reproductive and Pediatric Endocrinology (M.H.B., P.C.W., W.E.R.), University of Texas Southwestern Medical Center, Dallas, Texas 75390-9032; and Department of Pathology (T.S., H.S.), Tohoku University School of Medicine, Sendai, Miyagi-ken 980-8575, Japan
Address all correspondence and requests for reprints to: William E. Rainey, Ph.D, Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9032. E-mail: william.rainey{at}utsouthwestern.edu.
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ABSTRACT |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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The trans-acting factors that regulate hCYP11B2 expression remain poorly defined. The orphan nuclear receptor, steroidogenic factor-1 (SF-1), is a major regulator of other steroid hydroxylase genes including hCYP11B1 (7, 8), but it fails to stimulate and indeed represses expression of hCYP11B2 (9). Other transcription factors that are expressed in the adrenal cortex include the NGFIB family of orphan nuclear receptors (termed the NR4A subgroup for nuclear receptor subgroup 4) (10). This family includes NGFIB (nerve growth factor-induced clone B, also termed NR4A1), NURR1 (Nur-related factor 1, NR4A2) and neuron-derived orphan receptor 1 (NR4A3) (11). All three nuclear receptors are rapidly induced early response genes that enhance transcription by binding to a consensus sequence (AAAGGTCA) called a NGFIB response element (NBRE) (12, 13). Among steroidogenic genes, the human and mouse CYP21 gene promoters contain canonical NBREs and a role for NGFIB in CYP21 transcription has been proposed (14, 15).
In the current study, we examined the role of two NGFIB family members, NGFIB and NURR1, in the regulation of hCYP11B2. Our results show that NGFIB and NURR1 activate the hCYP11B2 promoter. Both transcription factors are up-regulated by Ang II, the primary regulator of hCYP11B2 expression in vivo. Both are expressed in the zona glomerulosa, the site of hCYP11B2 expression. Finally, whereas NGFIB and NURR1 are potent activators of hCYP11B2 expression, they do not stimulate transcription of hCYP11B1. Thus, NGFIB and/or NURR1 may contribute to the localized expression of hCYP11B2 within the zona glomerulosa as well as agonist-regulated expression.
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RESULTS |
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). The hCYP11B2 promoter was activated by NGFIB and NURR1 in a concentration-dependent manner with activity increasing to 3.2- and 3.9-fold above basal levels, respectively, when cells were cotransfected with 1 µg/ml of expression plasmid. As expected from our prior study (9), SF-1 failed to activate the hCYP11B2 promoter at any of the concentrations tested. In fact, 1 µg/ml of SF-1 reduced hCYP11B2 reporter expression to 72% of basal levels.
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SF-1 Inhibits NGFIB- and NURR1-Stimulated Activation of hCYP11B2
Because SF-1 is a known repressor of hCYP11B2, we next demonstrated that SF-1 inhibited NGFIB and NURR1 activation of the hCYP11B2 promoter in a concentration-dependent manner (Fig. 2A). When cotransfected in equal amounts (1 µg/ml), SF-1 reduced the activity achieved by NGFIB or NURR1 alone to that observed with the basal hCYP11B2 reporter construct. As expected, cotransfection of H295R cells with SF-1 reduced both basal and Ang II-stimulated hCYP11B2 reporter activity (Fig. 2B).
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). Low levels of NGFIB transcripts were present in untreated samples at 6 and 24 h, but NURR1 transcripts were not detectable in untreated samples. Both NGFIB and NURR1 expression levels were high after 6 h of incubation with Ang II, but they returned to control levels by 24 h of treatment. Western analysis using cell lysates from similarly treated H295R cells confirmed that immunoreactive NGFIB and NURR1 proteins increased in parallel with transcript levels (Fig. 3B). These data demonstrate that NGFIB and NURR1 are Ang II target genes.
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). Both NGFIB and NURR1 stimulated the reporter activity of pB2-1521 and pB2-864 approximately 4-fold over basal levels. Further deletion to -747 bp decreased NGFIB and NURR1 stimulation to twice basal levels suggesting that DNA between -864 and -747 contained an NBRE. Further deletion to -135 bp, which eliminated an SF-1 binding site (Ad4), did not significantly affect NGFIB or NURR1 stimulation of hCYP11B2 promoter activity. However, deletion to -106 bp abolished NGFIB and NURR1 stimulation of hCYP11B2 reporter activity indicating that nucleotides between -135 and -106 contained an additional NBRE.
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). To determine the relative importance of the NBRE-1 (-766/-759) and Ad5 (-129/-114) cis-elements, both were mutated in the context of the full-length (pB2-1521) hCYP11B2 gene promoter. As shown in Fig. 5B, mutation of the NBRE-1 cis-element reduced both NGFIB- and NURR1-stimulated hCYP11B2 activity by 52% and 55%, respectively, compared with basal level. Mutation of the Ad5 site further reduced both NGFIB- and NURR1-stimulated hCYP11B2 reporter activities. Simultaneous mutations of both cis-elements reduced NGFIB- and NURR1-stimulated reporter activity to that observed with the pGL3Basic empty vector.
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). When H295R nuclear extract was incubated with the NBRE-1 probe (panel 1), protein/DNA complex C1 comigrated with the complex formed by in vitro-translated NGFIB or NURR1, whereas C2 migrated with the complex formed by SF-1. With the Ad5 probe, (panel 2), complex C3 did not comigrate with any of the in vitro-translated proteins whereas C4 migrated with the complex formed by SF-1. No binding of the Ad5 probe to proteins in the H295R nuclear extract corresponding to NGFIB or NURR1 was observed. Formation of C1–C4 was specifically inhibited by a 100-fold excess of unlabeled homologous oligonucleotide, indicating that all four complexes represented specific binding.
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Localization of NGFIB and NURR1 in Human Adrenal Gland
A previous study localized NURR1 to the mouse zona glomerulosa (20). To determine whether NGFIB or NURR1 might contribute to the zone-specific expression of hCYP11B2, we examined the expression of these transcription factors in human adrenal sections using immunohistochemistry (Fig. 7). NGFIB immunoreactivity was detected in nuclei of both glomerulosa and fasciculata cells. NURR1 immunoreactivity was highest in nuclei of glomerulosa cells with modest expression observed in the fasciculata. Neither NGFIB nor NURR1 immunoreactivity was detected in cells of the adrenal capsule or in inner medullary cells. No staining was observed in the absence of NGFIB or NURR1 antibody. These data support a potential role for NURR1 and/or NGFIB in glomerulosa-specific expression of hCYP11B2.
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) and partially inhibited NGFIB and NURR1 expression (Fig. 8, B and C). KN93 also partially inhibited the effect of Ang II on hCYP11B2 and NURR1 mRNA levels but had no effect on transcription of NGFIB. These data support the hypothesis that NURR1 may play a more important role than NGFIB in Ang II-regulated hCYP11B2 expression.
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). The fold induction by Ang II was similar in the wild-type hCYP11B2 (4.4-fold) and the mutated NBRE-1 (5.3-fold) and Ad5 (4-fold) constructs, whereas the Ad1/CRE mutant was induced by Ang II only 2.2-fold over basal. Ang II stimulated the hCYP11B2 triple mutant construct only 1.8-fold over basal, which was similar to that observed with the pGL3Basic empty vector (2-fold).
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DISCUSSION |
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) of the mechanisms that control hCYP11B2 expression and thus, aldosterone biosynthesis.
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Whereas protein kinase C-dependent pathways activated by diacylglycerol apparently do not play a major role in the regulation of hCYP11B2 (26), increases in intracellular calcium activate CaM, which in turn activates several CaM-dependent protein kinases (CaMKs). Calcium appears to act through CaMKI and possibly CaMKIV to regulate hCYP11B2 transcription (21). CaM and CaMKs also appear to regulate the acute steps of aldosterone production (27).
Important cis-Elements in hCYP11B2
The cis-elements and trans-acting factors that regulate the differential expression of hCYP11B2 in the adrenal zona glomerulosa have been an area of ongoing study in this laboratory. We have identified three important cis-elements in the hCYP11B2 promoter: a CRE at -71/-64, a cis-element termed Ad5 at -129/-114 (19), and, herein, a third cis-element termed NBRE-1 (-766/-759). The CRE is common to both hCYP11B1 and hCYP11B2 and is regulated by both protein kinase A- and CaMK-dependent mechanisms.
Neither the NBRE-1 nor Ad5 cis-elements found in the 5'-flanking region of hCYP11B2 are present in hCYP11B1, making these elements likely candidates in the specific regulation of hCYP11B2. Herein, we found that mutation of either the NBRE-1 or Ad5 element dramatically decreased the basal levels of reporter construct expression and blunted maximal agonist stimulation. The NBRE-1 site is a nuclear receptor half-site that we demonstrate has the ability to bind NGFIB family members. The Ad5 cis-element represents a direct repeat of two nuclear receptor half-sites in tandum (DR-0), which we show can bind members of the NGFIB family as well as SF-1 and COUP-TF (chicken ovalbumin upstream promoter-transcription factor) (19).
The Ad1/CRE is highly conserved between species and is important for bovine, rodent (mouse, rat, hamster) and human CYP11B2 gene activity (16, 17, 28, 29, 30, 19). Whereas sequence analysis of 2 kb of the mouse and hamster promoters failed to locate the -766/-759 NBRE-1 cis-element seen in hCYP11B2, variant and consensus NBREs were found more distal, at about -1500 bp, in the mouse and hamster promoters, respectively. However, the most intriguing of the cis-elements, the Ad5 site, does not appear to be conserved among CYP11B2 of different species (22). Thus, these data support the hypothesis that there are species variations in the key cis-elements regulating CYP11B2 gene transcription.
Trans-Acting Factors Regulating CYP11B2
Previous work has shown that the hCYP11B2 CRE binds activating transcription factors, ATF-1 and ATF-2, and CRE binding protein (CREB) (31). Phosphorylation of ATF-1 and/or CREB by CaMKI and CaMKIV increases the ability of these factors to enhance gene transcription (32, 33). In a recent report, it was shown that mutation of the CRE was able to block CaMKI induction of hCYP11B2 reporter activity (21). Thus, it is likely that activated CaMKI phosphorylates ATF-1 and/or CREB leading to enhanced transcription of hCYP11B2.
We showed in the present study that treatment of H295R adrenal cells with Ang II and K+ rapidly and dramatically increased the levels of NGFIB and NURR1 mRNA and protein. Inhibition of the CaMKs with KN93 reduced agonist-stimulated NGFIB (only K+ stimulation), NURR1 and hCYP11B2 transcription. Activity of CaMKs are known to increase NGFIB expression in other cell model systems (34). We therefore propose that the effects of K+ and Ang II on hCYP11B2 transcription occur through two pathways: increased expression of NURR1/NGFIB and phosphorylation of ATF-1/CREB (Fig. 10).
NGFIB is abundantly expressed in brain, thymus, muscle, and some peripheral tissues (35, 36), whereas NURR1 is expressed predominantly in the central nervous system, where it is responsible for the differentiation and maintenance of dopaminergic neurons (37, 38). NGFIB and NURR1 have been detected in human adrenal, and NURR1 has been localized to the murine adrenal zona glomerulosa by in situ hybridization (20). Herein, we found that NURR1 was expressed in the human adrenal glomerulosa and to a lesser degree in the fasciculata, whereas NGFIB was expressed in both fasciculata and glomerulosa zones.
Both NGFIB and NURR1 markedly increased transcription of hCYP11B2, but neither factor had any effect on transcription of hCYP11B1. This presumably reflects transcriptional regulation through the NBRE-1 and Ad5 sites, which are unique to hCYP11B2. The ability of NGFIB and NURR1 to regulate transcription of hCYP11B2 extends the role of these nuclear receptors in the hypothalamic-pituitary-adrenal axis. Both NGFIB and NURR1 are known mediators of CRH function in the hypothalamus (39). In the adrenal, a role for NGFIB in the regulation of 21-hydroxylase (CYP21) transcription has been proposed (14, 15). The site of expression of each factor within the adrenal may influence the relative role of NGFIB or NURR1 on target gene selection. The overlap in expression and similarity in effects on gene transcription may explain why previous studies using targeted disruption of single NGFIB family members have not demonstrated an adrenal phenotype (37, 40). Nevertheless, these transcription factors are not functionally equivalent. Subtle changes in the consensus NBRE can differentially affect the trans-activation ability of each family member (41). Moreover their activities, and consequently their functional roles in vivo, can be modulated by posttranslational modifications and differing heterodimerization abilities (35, 42, 43, 44, 45). Our data suggest that NURR1 may play the more specific role in hCYP11B2 regulation.
In summary, Ang II and K+ regulation of adrenal aldosterone production appears to converge on calcium signaling pathways (Fig. 10). Both agonists increase [Ca2+]i, the activation of CaM, CaM kinases, and the expression of NGFIB family members. NURR1 and/or NGFIB along with CRE-binding transcription factors subsequently increase the transcription of hCYP11B2 thus controlling the long-term capacity of the adrenal gland to produce aldosterone.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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). All bases were numbered relative to the hCYP11B2 transcriptional start site.
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Cell Culture and Transfection Assay
Cell culture and transfection assays were carried out as previously described except that Transfast (Promega, Madison, WI) was used as the transfection reagent according to the manufacturer’s protocol (9).
RNA Extraction and Northern Blot Analysis
Total RNA was extracted from cells using the Ultraspec RNA isolation system (Biotecx Laboratories Inc., Houston, TX) and aliquots (10 µg) were resolved by electrophoresis on a 1% agarose/formaldehyde gel. RNA was transferred to a nylon membrane (Hybond-N+, Amersham Pharmacia Biotech Inc., Piscataway, NJ) by blotting overnight at 10 V and cross-linked under UV light. Prehybridization was carried out overnight at 42 C in formamide prehybridization/hybridization solution supplemented with 50 mM NaH2PO4, 0.5 mg/ml salmon sperm DNA and 5% dextran sulfate. The membrane was hybridized with a NGFIB or NURR1 cDNA probe (Rediprime II; Amersham) in formamide prehybridization/hybridization solution supplemented with 20 mM NaH2PO4, 0.25 mg/ml salmon sperm DNA and 10% dextran sulfate at 42 C overnight. The membrane was washed in 0.1x SSC (sodium chloride/sodium citrate)/0.1% SDS (sodium dodecyl sulfate) twice each at room temperature and at 42 C and then exposed to x-ray film. The membrane was subsequently rehybridized with 32P-radiolabeled 18S probe to confirm equal loading of RNA samples.
Western Blot Analysis
Nuclear extracts were prepared from H295R cells untreated or treated with Ang II as described (8). PAGE was carried out using precast 4–12% bis-Tris NuPage gels (Novex, San Diego, CA). After electrophoresis, proteins were electrophoretically transferred onto polyvinylidene difluoride membranes for 1 h at 25 V. After transfer, the membranes were incubated with NGFIB (1:500) or NURR1 (1:1000) antibodies overnight at 4 C. The NGFIB antibody (catalog no. 1600045) was obtained from Geneka Biotechnology (Montreal, Quebec, Canada) and the NURR1 antibody (sc-991) was obtained from Santa Cruz Biotechnology, Inc. (Santa Cruz, CA). In addition to the manufacturer’s characterization, we tested both antibodies for specificity using in vitro-translated NGFIB or NURR1. Membranes were incubated with horseradish peroxidase-conjugated secondary antibodies. Immunoreactive bands were visualized using enhanced chemiluminescence Western blotting detection reagents from Amersham Biosciences (Piscataway, NJ).
EMSA
H295R nuclear extracts were prepared and EMSA was carried out, as described, with certain modifications (8). For NBRE-1, 0.1 mg/ml poly(dG-dC) (deoxyguanosine-deoxycytidine) was added to the binding buffer as nonspecific competitor. For the Ad5 probe, binding was carried out in 25 mM Tris, 100 mM KCl, 0.125% Nonidet P-40, 15% glycerol, 2.5 mM dithiothreitol, and 0.05 mg/ml poly(dI-dC) deoxyinosine-deoxycytidine). After binding, the resulting DNA/protein complexes were separated from free probe by electrophoresis through a 4% native polyacrylamide gel in either 1x Tris-glycine (NBRE-1) or 0.50x Tris-borate-EDTA (Ad5) running buffer. The gel was dried and visualized after autoradiography at -70 C for 24 h. Rat NGFIB, mouse NURR1, and human SF-1 were prepared using an in vitro transcription/translation system (Promega). The hCYP11B2-specific NBRE-1 (-766/-759) and Ad5 (-129/-114) wild-type oligonucleotide sequences used for EMSA are listed in Table 1.
Immunolocalization of NGFIB and NURR1 in Human Adrenal Cortex
Nonpathologic human adrenals were retrieved from autopsy files of Tohoku University Hospital (Sendai, Japan). Tissues were fixed in 10% formalin and embedded in paraffin. Histological examinations revealed no significant pathologic abnormalities including nodules or neoplasms. Review of the charts revealed that these patients had not received any forms of adrenocortical steroids before their demise.
Rabbit polyclonal antibodies for NURR1 (sc-991, Santa Cruz Biotechnology) and NGFIB (NAK1/Nur77;1600045, Geneka Biotechnology) were used for immunohistochemical analysis employing the streptavidin-biotin amplification method and a Histofine Kit (Nichirei, Tokyo, Japan). Briefly, deparaffinized sections were pretreated by heating the slides in an autoclave at 120 C for 5 min in citric acid buffer [3 mM citric acid and 9 mM trisodium citrate dehydrate (pH 6.0)]. The slides were then treated with 1% normal goat serum for 20 min at room temperature and incubated with anti-NURR1 (dilution; 1/250) or anti-NGFIB (dilution: 1/200) for 18 h at 4 C. The slides were subsequently reacted with Envision (DAKO, Copenhagen, Denmark), then visualized with 3.3'-diaminobenzidine solution [1 mM diaminobenzidine, 50 mM Tris-HCl buffer (pH 7.6), and 0.006% H2O2] For negative controls, the sections were incubated with normal rabbit IgG instead of the primary antibodies and no specific immunoreactivity was detected in these sections.
RNA Extraction and Real-Time RT-PCR
Total RNA was extracted from tissue, using the method of Chirgwin (46), followed by deoxyribonuclease I treatment. Two micrograms of total RNA were reverse transcribed using the High Capacity cDNA Archive Kit (Applied Biosystems, Foster City, CA). Primers and probes for real-time RT-PCR were designed using the Primer Express computer program (Applied Biosystems) (Table 2). For NGFIB or NURR1 quantitation, a double-stranded DNA dye, SYBR Green I (Molecular Probes Inc., Eugene, OR) was used along with 15 µl 2x SYBR Green Universal PCR Master Mix (Applied Biosystems) and 0.1 µM of each primer. hCYP11B2 and 18S quantitation were performed using a TaqMan Ribosomal RNA Reagent kit (Applied Biosystems) and 10 µl of primer/probe mix. For CYP11B2, the final concentrations of primer and probe used were 0.1 µM each. For 18S, the final concentrations of primer and probe were 0.05 µM and 0.1 µM, respectively. All real-time RT-PCRs were carried out, in two steps, using the ABI Prism 7000 Sequence Detection System (Applied Biosystems) and the dissociation protocol. Step 1: 50 C for 2 min followed by 95 C for 10 min, one cycle. Step 2: 95 C for 15 sec, followed by 60 C for 60 sec, 40 cycles. Standard curve cDNA plasmids for NGFIB, NURR1, and CYP11B2 were used to quantitate transcript levels. As an internal standard, each individual sample was normalized to its 18S ribosomal RNA content. mRNA levels were expressed as attomoles per microgram 18S rRNA.
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FOOTNOTES |
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Abbreviations: Ad, Adrenal; Ang, angiotensin; ATF, activating transcription factor; CaM, calmodulin; CaMK, CaM-dependent protein kinase; CRE, cAMP response element; CREB, CRE binding protein; CYP, cytochrome P450; hCYP11B2, human CYP11B2; NGFIB, nerve growth factor-induced clone B; NBRE, NGFIB response element; NR, nuclear receptor; NURR1, Nur-related factor 1; SF-1, steroidogenic factor-1.
Received for publication January 8, 2003. Accepted for publication November 20, 2003.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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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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F. Q. Pirih, A. Tang, I. C. Ozkurt, J. M. Nervina, and S. Tetradis Nuclear Orphan Receptor Nurr1 Directly Transactivates the Osteocalcin Gene in Osteoblasts J. Biol. Chem., December 17, 2004; 279(51): 53167 - 53174. [Abstract] [Full Text] [PDF]
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D. G. Romero, M. Plonczynski, G. R. Vergara, E. P. Gomez-Sanchez, and C. E. Gomez-Sanchez Angiotensin II early regulated genes in H295R human adrenocortical cells Physiol Genomics, September 16, 2004; 19(1): 106 - 116. [Abstract] [Full Text] [PDF]
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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]
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L. Lu, T. Suzuki, Y. Yoshikawa, O. Murakami, Y. Miki, T. Moriya, M. H. Bassett, W. E. Rainey, Y. Hayashi, and H. Sasano Nur-Related Factor 1 and Nerve Growth Factor-Induced Clone B in Human Adrenal Cortex and Its Disorders J. Clin. Endocrinol. Metab., August 1, 2004; 89(8): 4113 - 4118. [Abstract] [Full Text] [PDF]
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K.-H. Song, Y.-Y. Park, K. C. Park, C. Y. Hong, J. H. Park, M. Shong, K. Lee, and H.-S. Choi The Atypical Orphan Nuclear Receptor DAX-1 Interacts with Orphan Nuclear Receptor Nur77 and Represses Its Transactivation Mol. Endocrinol., August 1, 2004; 18(8): 1929 - 1940. [Abstract] [Full Text] [PDF]
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