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Protein: Estrogen-Dependent Proteolysis Is Not Essential for Receptor Transactivation Function in the Pituitary
Department of Physiology, University of Wisconsin, Madison, Wisconsin 53706
Address all correspondence and requests for reprints to: Elaine T. Alarid, Ph.D., Department of Physiology, University of Wisconsin Madison, 120 Service Memorial Institute, 1300 University Avenue, Madison, Wisconsin 53706. E-mail: alarid{at}physiology.wisc.edu.
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Abstract |
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(ER) protein in lactotrope cells of the pituitary. The stabilization of ER protein by thyroid hormone represents a selective blockade against estradiol-stimulated degradation, because thyroid hormone (but not glucocorticoid) can protect estrogen-activated ER. Moreover, thyroid hormone treatment does not interfere with signal-induced proteolysis of a separate proteasome target, I
B or ER proteolysis induced by ICI182780. Using thyroid hormone as a tool to inhibit ER proteolysis, we examined the effect of loss of this regulatory function on estrogen-induced transcriptional responses. Consistent with earlier reports, estrogen activation of an idealized estrogen response element reporter gene was inhibited. However, thyroid hormone did not prevent induction of prolactin gene expression or the ability of ER to stimulate proliferation. These results demonstrate that estrogen-induced proteolysis of ER is not a general requirement for receptor transcriptional activation function, and they demonstrate that proteolytic regulation is a means by which other endocrine factors can indirectly modulate ER activity. |
Introduction |
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(ER) levels are dynamically regulated in direct opposition to circulating estrogen, setting up an autoregulatory loop in which receptor concentrations are limited when cells are stimulated with ligand. The feedback regulation of ER by estrogen is complex and implements regulatory mechanisms that function at transcriptional, posttranscriptional, and posttranslational levels (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14). This complexity not only implies an underlying importance to the regulation of receptor concentration but also provides cells with an increased number of potential mechanisms available for higher-order regulation of estrogen action in a complex cellular environment.
The most acute component of estrogen-induced down-regulation of ER is the regulated destruction of receptor protein by the 26S proteasome (1, 5, 7). Proteasome-mediated proteolysis is involved in the regulated turnover of several members of the nuclear receptor superfamily, including receptors for thyroid hormone, androgen, glucocorticoid, progesterone, retinoic acid, 9-cis retinoic acid, and vitamin D (15, 16, 17, 18, 19, 20, 21, 22, 23). The prevalent model describing the function of proteolysis suggests that receptor turnover is essential for efficient receptor transactivation. Pharmacological studies with peptide inhibitors of proteasome and mutagenesis analysis of the coactivator interaction domain of ER have demonstrated that blockade of proteolysis decreases the magnitude of ER-mediated activation of an estrogen response element (ERE) reporter gene (24). However, this evidence is limited to examination of reporter gene activity in heterologous systems, and the model has not been directly tested in physiologically relevant cell contexts.
We observed previously that diverse ligands, including the short-acting estrogen, estriol, and the cell-type specific agonist, 17-estradiol, exhibit variable regulation of proteasome-dependent degradation of ER in lactotrope cells of the anterior pituitary (25). These results suggested the possibility that receptor proteolysis might be further regulated by events downstream of ligand binding and possibly by other endocrine factors. Early in vivo studies suggested that thyroid hormone might be just such a modulator. Chronic estrogen treatment of rats results in hyperplastic expansion of the lactotrope population of the anterior pituitary (26, 27, 28). The ability of estrogen to induce pituitary hyperplasia, however, requires that the animal have an intact thyroid gland (29, 30, 31). It has also been demonstrated that thyroid hormone treatment increases estrogen binding in the pituitary and hypothalamus of euthyroid and thyroidectomized animals (32, 33, 34, 35, 36). A similar increase in estrogen binding can be achieved by the inhibition of proteolysis with proteasome inhibitors (1).
In this report, we demonstrate that thyroid hormone can inhibit estrogen-induced proteolysis of ER in lactotrope cells. Prevention of ER down-regulation by thyroid hormone resulted in differential effects on ER-mediated gene activation but did not inhibit estrogen-stimulated proliferation. These results demonstrate that estrogen-induced proteolysis of ER is not required for receptor transactivation function, and they identify a novel physiological regulator of the ER proteolytic pathway in the pituitary.
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Materials and Methods |
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Experiments with TNF were carried out in phenol-red containing DMEM with 10% fetal bovine serum. As above, equivalent amounts of cells were treated with 10 ng/ml TNF (Calbiochem, La Jolla, CA) for 0, 10, and 20 min. Upon harvest, whole cell lysates were obtained and analyzed by Western blot analysis.
Western blot analysis
Western blot analysis was performed, as previously described (1), on whole-cell lysates that were obtained either by direct dissolution of cell pellet in 2x sample buffer (125 mM Tris-base, 20% glycerol, 4% sodium dodecyl sulfate, 10% ß-mercaptoethanol) or by extraction with Totex buffer (20 mM HEPES, pH 7.9, 350 mM NaCl, 20% glycerol, 1% NP-40, 1 mM MgCl2, 0.5 mM EDTA, 0.1 mM EGTA, and 0.5 mM dithiothreitol) followed by Bradford assay (37). Immunoblotting was performed using antirat ER no. 715 (38) or anti-IB (Santa Cruz Biotechnology, Inc., Santa Cruz, CA). Blots were reprobed with antiactin (Santa Cruz Biotechnology, Inc.) or anti--tubulin (Calbiochem) to verify equivalent loading of samples. Saturating concentrations of antibody were used to allow for quantitative measurement of receptor levels. Bands were visualized by ECL (Amersham Pharmacia Biotech, Arlington Heights, IL) and quantified by laser densitometry. For each gel, EtOH-treated control samples were used to generate an internal standard curve for linear regression analysis, against which relative ER levels were determined. The correlation coefficient for the standard curves ranged from 0.99–1.0, verifying that the measurements of relative receptor levels determined by laser densitometry were within a linear range for the ECL reaction. Statistical differences between groups were determined by one-way ANOVA followed by a paired Student’s t test based on a 95% confidence interval.
Northern blot analysis
Total RNA was isolated by phenol:chloroform extraction and EtOH precipitation (39). Twenty micrograms of RNA were electrophoresed on a 1% agarose gel containing formaldehyde (40). The gels were transferred to nylon membrane and probed with a radiolabeled fragment of cDNA for ER (41), prolactin (Prl) (42), or glyceraldehyde 6-phosphate dehydrogenase (GAPDH) (43) using conditions previously described (1). Messenger RNA levels were quantified by phosphoimager analysis using Imagequant software (Molecular Dynamics, Inc., Sunnyvale, CA). ER levels were corrected for loading by normalization against GAPDH levels.
Transient transfections
PR1 cells were deprived of steroid and thyroid hormones, for 2 d before transfection, by maintenance in phenol-red free medium containing 10% resin/dextran-coated charcoal-stripped serum. Cells were transfected using Superfect reagent (QIAGEN, Valencia, CA) according to manufacturer’s instructions. To assess ER transcriptional activity, two reporter genes were used: an ERE-tk-luc, which is comprised of a multimerized vitellogenin estrogen response element and a thymidine kinase promoter-driving luciferase (44); and a -2.5 Prl-luc comprised of 2.5 kb of the upstream regulatory region of the Prl gene fused to luciferase (45). Thyroid hormone receptor (TR) transcriptional activity was assessed using a reporter construct composed of a palindromic thyroid hormone response element (TRE) upstream of a minimal MTV promoter-driving luciferase expression (46). Glucocorticoid responsiveness was measured using a 4x multimerized glucocorticoid response element (GRE) fused to a tk-Luc reporter gene construct, which was provided by Dr. Chinghai Kao. To control for transfection efficiency, cells were cotransfected with a CMV-ßgal construct. The CMV-ßgal construct used in these experiments did not exhibit any regulation by E2 or T3. Hormone treatment began immediately after removal of transfection reagent. Assays for luciferase (Promega Corp., Madison, WI) and ß-galactosidase (Tropix, Bedford, MA) activity were performed according to manufacturers’ instructions. Statistically significant differences were determined using a paired Student’s t test.
For experiments using proteasome inhibitor, cells were cotransfected, as above, with -2.5 Prl luc and CMV-ßgal. The day after transfection, cells were pretreated for 30 min with either dimethylsulfoxide (DMSO) (solvent) or 100 µM ALLnL (Calbiochem). We previously demonstrated that this dose of ALLnL was sufficient to inhibit estrogen-induced proteolysis in PR1 cells (1). Hormone treatment proceeded for 24 h using 10 nM E2.
Proliferation assay
PR1 cells were placed in resin/dextran-coated charcoal-stripped serum for 3 d to deprive them of steroid and thyroid hormones. On the third day, 1 x 106 cells were replated and treated with the indicated hormone. E2 and T3 were administered at a dose of 0.1 nM. ICI was given at a dose of 100 nM as described (see Ref. 52). Cells were harvested after 24, 48, 72, 96, and 120 h; and total genomic DNA was isolated using the Puregene DNA purification kit (Gentra Systems, Inc., Minneapolis, MN) according to the manufacturer’s protocol. Statistical analysis, using a one-way ANOVA and a paired Student’s t test, was performed on data representing the last day (d 5) of the experiment.
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Results |
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levels and activity in lactotrope cells of the anterior pituitary, we tested whether estrogen-induced down-regulation of ER protein was altered in the presence of thyroid hormone (T3). To address this question, we used the PR1 lactotrope cell line as a model system. PR1 cells are derived from an estrogen-induced pituitary tumor (47) and express ER, but not ERß, based on RT-PCR analysis performed in our laboratory (data not shown). Thus, they represent an in vitro correlate to the early in vivo studies documenting thyroid hormone: estrogen interactions in the pituitary. In addition, ER protein levels are regulated by induction of proteasome-mediated proteolysis in this system (1). To test the effects of thyroid hormone on estrogen-induced ER protein degradation, PR1 cells were treated acutely for 2 h with E2 and T3. During this time frame, changes in steady-state levels of ER protein reflect direct regulation of receptor protein by the 26S proteasome (1). Western blot analysis of ER protein levels in EtOH-treated vs. E2-treated samples shows that ligand-stimulation induces an approximate 50% reduction in total ER protein (Fig 1
). Treatment with T3 alone did not alter ER levels, relative to control samples. However, coadministration of T3 resulted in an inhibition of E2-induced receptor protein down-regulation.
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protein levels, Western blots included a standard curve that was generated by dilution of the EtOH-treated control in each experiment. An example is shown in Fig. 1A
. Relative ER levels were then determined by linear regression analysis. The addition of T3, at varying doses ranging from 0.01–1000 nM, resulted in a dose-dependent increase in ER levels relative to E2-treated samples (Fig 1B). Doses of T3 greater than 1 nM were sufficient to maintain ER at control levels (Fig. 1B). Based on a sigmoidal dose-response curve, the EC50 for T3 inhibition of receptor down-regulation was determined to be 1.9 nM, which is consistent with T3 activation of TR.
To test whether T3 opposed the actions of estrogen by induction of ER gene expression, total RNA was isolated from cells treated with E2 and T3 under identical conditions, as described above. Northern analysis was performed to assess ER mRNA levels using radiolabeled probes for ER and GAPDH. Examination of the relative receptor expression levels shown in Fig. 2 reveals that ER gene expression is unaffected by treatment with either T3 or E2. These results are consistent with our previous findings and demonstrate that the acute regulation of ER protein occurring during a short exposure to hormones is mediated through direct regulation of receptor protein, not receptor mRNA. Further, they demonstrate that T3 does not induce increased synthesis of ER.
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B protein degradation (49). To test whether treatment with T3 disrupts proteasome activity, PR1 cells were treated with TNF in the presence and absence of T3, and IB protein levels were monitored over time. Results shown in Fig. 3, A and B, demonstrate that T3 treatment did not alter TNF-stimulated degradation of IB protein. Similar results were obtained when cells were treated with the pure antiestrogen, ICI, which also stimulates the destruction of ER by proteasomes (Fig. 3, C and D; and Refs. 22 ,25 , and 50). Pretreatment of cells with T3 for up to 2 h before addition of either TNF or ICI did not prevent inducible degradation of IB and ICI-bound ER, respectively (data not shown). These results suggest that the ability of T3 to protect ER protein is not attributable to a generalized inhibition of proteasome activity but is due to a selective disruption of the pathway by which estrogen, but not ICI, targets ER protein for degradation.
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activity by titrating shared components of the transcriptional machinery (52). To test whether activation of other nuclear receptors can function similarly to T3 and repress ER proteolysis, PR1 cells were treated with E2 in combination with either T3 or cortisol. Whereas thyroid hormone was effective at blocking proteolysis of ER, identical treatment with cortisol failed to alter estrogen’s ability to induce degradation of receptor protein (Fig. 4A). Repeated quantitative measurement of relative ER levels in six independent experiments showed that only thyroid hormone significantly increased ER steady-state levels in the presence of estrogen, as shown in Fig. 1. Cortisol treatment had no effect on estrogen-induced down-regulation of ER protein (E2 = 45 ± 6.8%, and E2 + F = 43 ± 7.1%, relative to control ER levels). Despite the differences in effects of T3 and cortisol on ER protein levels, both hormones were able to induce transcriptional activation of a reporter gene construct (Fig. 4B), indicating that both TR and glucocorticoid receptor are active in PR1 cells. These results demonstrate that the ability to inhibit estrogen-induced ER proteolysis is specific for T3.
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function without a general inhibition of proteolysis. Moreover, we were afforded the opportunity to examine the impact on both receptor activation of reporter gene activity and endogenous target genes. For comparison with previous studies in HeLa cells (22, 24), an idealized estrogen-response element driven reporter construct (ERE-tk-Luc) was transiently introduced into PR1 cells. In parallel, a separate group of PR1 cells was transfected with a TRE-driven reporter (TRE-pal-Luc) to examine TR transcriptional activity. Cells were treated with E2 and T3, alone and in combination. Figure 5A shows that T3 inhibits estrogen induction of an ERE reporter gene in PR1 cells. Reciprocally, E2 inhibits thyroid-hormone-induced TRE-pal-Luc reporter gene activity (Fig. 5B). These results are in agreement with the model that inhibition of proteolysis results in decreased ER transcriptional activity.
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and TR is consistent with the coupling of ER proteolysis and transactivation but can also be explained by competition for a common DNA binding element (52, 53, 54, 55, 56, 57, 58, 59, 60, 61). Therefore, we examined the effects of thyroid hormone on the activation of an endogenous target of ER in lactotrope cells, Prl. A Prl reporter gene, consisting of 2.5 kb of the upstream regulatory region of the Prl gene fused to luciferase, was cotransfected into PR1 cells along with a CMV-ßgal reporter gene. As predicted, estrogen treatment stimulated a robust induction of reporter gene activity. T3 alone also induced Prl reporter gene activity. However, in contrast to effects seen on an idealized ERE, the addition of thyroid hormone did not inhibit the activity of ER but rather increased it (Fig. 6A). To independently confirm this finding, Northern analysis was done on total RNA isolated from PR1 cells treated with E2 and T3. Results shown in Fig. 6B illustrate that T3 does not inhibit estrogen induction of endogenous Prl expression. Treatment with estrogen or thyroid hormone alone induced a 2.7 ± 0.3- and 2.2 ± 0.6-fold increase in Prl gene expression, respectively, whereas the combined treatment resulted in a 4.0 ± .9-fold induction. Western analysis of ER levels in Fig. 6C confirms that T3 inhibits ER down-regulation under these conditions.
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). Chun et al. (62) previously demonstrated that estrogen directly stimulates the growth of PR1 cells. As expected, estrogen stimulated an increase in DNA content, which was apparent 48 h after initiation of hormone stimulation. Samples treated with EtOH, thyroid hormone, and ICI remained static over the entire period of the experiment. Statistical analyses of DNA content on d 5 of treatment (Fig. 7B) show that PR1 cells exhibit a proliferative response to estrogen in the presence and absence of T3. Furthermore, this increased proliferation is mediated through ER, as demonstrated by the inhibition by ICI, an antagonist of ER but not TR function. These results are similar to the findings with induction of Prl gene expression and indicate that prevention of ER proteolysis and blockade of receptor down-regulation does not have a generalized inhibitory effect on ER-mediated transcription.
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proteolysis. Thus, to directly test whether proteolysis is essential in estrogen induction of gene expression in the pituitary, Prl reporter gene activity was measured in PR1 cells in which proteasome function was inhibited by pretreatment with ALLnL. ALLnL has previously been demonstrated to prevent estrogen-induced proteolysis of ER in PR1 cells (1). After transfection with -2.5 Prl-luc reporter gene, cells were pretreated with ALLnL for 30 min before stimulation with EtOH or E2 for 24 h. Controls consisted of pretreating cells with DMSO, which is a solvent for ALLnL. Pretreatment of cells with proteasome inhibitor did not disrupt estrogen induction of Prl reporter gene activity (Fig. 8A), despite stabilizing ER protein (Fig. 8B). Thus, inhibition of proteolysis with a pharmacological inhibitor functioned similarly to T3 and did not disrupt ER transactivation capacity.
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Discussion |
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by proteasomes. With this endogenous regulator, it was possible to ascertain the functional role(s) of proteolysis in the control of ER transcriptional activity in the pituitary without globally inhibiting the activity of proteasomes. Moreover, it allowed the investigation into complex responses to estrogen, including the regulation of an endogenous target gene expression and growth. Thyroid hormone disrupts proteolysis but can modulate ER induction of gene expression both positively and negatively in a promoter-specific manner. Whereas ER induction of an ERE was diminished by T3, induction of Prl and growth was not inhibited. Thus, ER retains the capacity to activate transcriptional processes on certain genes, such as Prl, while escaping destruction by proteasomes. The inference of these findings is that receptor proteolysis is not a general requirement for activation of transcription. Further, these data suggest the possibility that modulation of the proteolytic pathway may contribute to promoter-specific regulation of ER function. Elucidation of the mechanism by which thyroid hormone protects ER from degradation will likely yield important insight not only into the signaling pathway that targets ER to proteasomes but also into a potential underlying mechanism responsible for promoter selectivity.
Neither T3 nor pharmacological inhibition of estrogen-induced proteolysis resulted in a reduction in ER activation of Prl gene expression. This is in contrast to other reports that show an inverse relationship between receptor proteolysis and transcriptional efficiency (24, 63). This discrepancy cannot be attributed to compensatory activation of ERß because PR1 cells in our laboratory express only the ER isoform (data not shown). However, one possible explanation that could account for this phenomenon in pituitary is that preventing ER degradation effectively increases the number of functional receptors available to participate in transcriptional processes. We previously demonstrated that inhibiting receptor proteolysis with proteasome inhibitors increases the estrogen-binding capacity in PR1 cells (1). Thus, receptors that evade proteolysis retain certain ER functions, including ligand binding. Similar results have been reported with glucocorticoid receptor in embryonic hippocampal neurons, which show that activated receptors that are not targeted to proteasomes retain transactivation capacity (64). Studies of ER in stable CHO (65) and tet-inducible MCF-7 breast cancer cells (Fowler, A. M., N. M. Solodin, M. T. Preisler-Mashek, P. Zhang, A. V. Lee, and E. T. Alarid, submitted) demonstrate that the magnitude of ER transcriptional activity is directly related to the concentration of receptor. Thus, any regulatory mechanism that has the potential to elevate the concentration of functional receptor could potentially augment the transcriptional output of ER.
The two most efficient ligands at signaling ER degradation are E2 and ICI (14, 22, 25). Their shared activity in stimulating proteolysis despite opposing activities on receptor transcriptional function could be explained either by the uncoupling of the proteolytic and transactivation pathways or by multiple ER degradation pathways. The finding that thyroid hormone preferentially disrupts estrogen-induced degradation over ICI-induced proteolysis provides evidence in support of the latter hypothesis that estrogen and ICI signal receptor degradation by distinct routes. Our previous studies demonstrate that both are initiated by ligand binding; however, the branch point between these two pathways has not been delineated. Studies by Wijayaratne et al. (22) would argue that activation of transcription distinguishes agonist- vs. antagonist-signaled proteolysis. A conclusive separation, however, awaits the dissection of the events required in estrogen and ICI degradation pathways. Nevertheless, it is intriguing that ER may be targeted to proteasomes by more than one mechanism, increasing the number of potential ways through which proteolysis can contribute to the control of ER function.
We present evidence that the regulation of proteolysis may serve as an alternative means of controlling ER activity. Indeed, a number of conditions and regulatory molecules, such as hypoxia (66), aryl hydrocarbon receptor (67, 68), and calmodulin (69), have been demonstrated to alter ER protein stability. The complexity of the ubiquitin proteasome pathway provides multiple entry points where other regulatory pathways can interface with ER protein regulation and potentially modulate ER function indirectly. Based on the known transcriptional interactions between TR and ER, future investigations will be aimed at identifying the events in ER proteolysis that are disrupted by thyroid hormone, with the intent to better understand the control of ER activity in complex endocrine environments.
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Acknowledgments |
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antibodies and for insightful discussion throughout the undertaking of this project. We thank Dr. Fern Murdoch and Amy Fowler for critical review of the manuscript. We also thank Drs. Dave Furlow, Rich Maurer, and Chinghai Kao for TRE-pal-luc, -2.5 Prl-luc, and pGRE4-luc reporter constructs, respectively. |
Footnotes |
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Abbreviations: DMSO, Dimethylsulfoxide; E2, 17ß-estradiol; ER, estrogen receptor-; ERE, estrogen response element; EtOH, ethanol; F, cortisol; GAPDH, glyceraldehyde 6-phosphate dehydrogenase; GRE, glucocorticoid response element; ICI, ICI182780; Prl, prolactin; TR, thyroid hormone receptor; TRE, thyroid hormone response element.
Received December 2, 2002.
Accepted for publication April 16, 2003.
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References |
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and steroid receptor coactivator-1. Mol Endocrinol 14:518–534 and 
through the ubiquitin-proteasome pathway. J Biol Chem 275:33280–33288 is a ubiquitinated protein whose stability is affected differentially by agonists, antagonists and selective estrogen receptor modulators. J Biol Chem 276:35684–35692 (RAR) and oncogenic RAR fusion proteins. Proc Natl Acad Sci USA 96:14807–14812 and coactivator turnover and for efficient estrogen receptor- transactivation. Mol Cell 5:939–948[CrossRef][Medline]
, cholecystokinin, and preproenkephalin messenger ribonucleic acid in the limbic-hypothalamic circuit. Endocrinology 139:1221–1228T3-1 pituitary gonadotrope cells. Endocrinology 136:1361–1366[Abstract]
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in ZR-75 breast cancer cells. Mol Endocrinol 16:2231–2242 and the aryl hydrocarbon receptor in breast cancer cells involves unidirectional activation of proteasomes. FEBS Lett 478:109–112[CrossRef][Medline]
through activation of proteasomes. Mol Cell Biol 23:1843–1855This article has been cited by other articles:
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. The level of ER
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