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Endocrinology Vol. 139, No. 1 213-218
Copyright © 1998 by The Endocrine Society

ARTICLES

Sex Hormone-Binding Globulin Mediates Prostate Androgen Receptor Action via a Novel Signaling Pathway

Victor D. H. Ding, David E. Moller, William P. Feeney, Varsha Didolkar, Atif M. Nakhla, Linda Rhodes, William Rosner and Roy G. Smith

Department of Biochemistry and Physiology, Department of Laboratory Animal Resources, Merck Research Laboratories, Rahway, New Jersey 07065; and Department of Medicine, St. Luke’s/Roosevelt Hospital Center, College of Physicians and Surgeons, Columbia University New York, New York 10019

Address all correspondence and requests for reprints to: Dr. V. Ding, Department of Molecular Endocrinology, Merck Research Laboratories (RY80W-243), P.O. Box 2000, Rahway, New Jersey 07065. E-mail: victor-ding{at}merck.com


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Estradiol (E2) and 5{alpha}-androstan-3{alpha},17ß-diol (3{alpha}-diol) have been implicated in prostate hyperplasia in man and dogs, but neither of these steroids bind to androgen receptors (ARs). Recently, we reported that E2 and 3{alpha}-diol stimulated generation of intracellular cAMP via binding to a complex of sex hormone-binding globulin (SHBG) and its receptor (RSHBG) on prostate cells. We speculated that this pathway, involving steroids normally found in the prostate, was involved in the indirect activation of ARs. Using the dog as a model to test this hypothesis in normal prostate, we investigated whether E2, 3{alpha}-diol, and SHBG stimulated the production of the androgen-responsive protein, arginine esterase (AE), the canine equivalent of human prostate-specific antigen. In cultured dog prostate tissue preincubated with SHBG, E2 and 3{alpha}-diol stimulated AE activity. These effects were blocked by hydroxyflutamide, an AR antagonist, and by 2-methoxyestradiol, a competitive inhibitor of E2 and 3{alpha}-diol binding to SHBG. In the absence of exogenous steroids and SHBG, AE also was significantly increased by treatment with forskolin or 8-Bromoadenosine-cAMP. These observations support the hypothesis that in normal prostate, E2 and 3{alpha}-diol can amplify or substitute for androgens, with regard to activation of the AR via the RSHBG by a signal transduction pathway involving cAMP. Because both E2 and 3{alpha}-diol are involved in the pathogenesis of benign prostatic hyperplasia in dogs and implicated in benign prostatic hyperplasia in man, antagonism of the prostatic SHBG pathway may offer a novel and attractive therapeutic target.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
SEX hormone-binding globulin (SHBG) is a plasma glycoprotein that binds sex steroids with high affinity, thereby regulating their plasma concentrations (1). Also, by binding to a specific receptor (RSHBG) on prostate cell membranes, SHBG participates directly in cellular signaling pathways (2, 3, 4). Two steroids, 17ß-estradiol (E2) and 5{alpha}-androstan-3{alpha},17ß-diol (3{alpha}-diol), bind to the SHBG-RSHBG complex and stimulate cAMP production (3, 4, 5). Because cAMP transduces downstream signals implicated in modulation of cell growth (6, 7, 8, 9) and regulation of specific gene transcription and expression (10, 11, 12, 13, 14, 15, 16), activation of this pathway by E2 and 3{alpha}-diol may prove to play a critical role in prostate function.

The androgen receptor (AR) is a tissue-specific transcription factor that is directly activated by binding to testosterone and 5{alpha}-dihydrotestosterone (DHT). However, its indirect activation by FSH, by polypeptide growth factors, and through a cAMP pathway has been reported (17, 18, 19, 20, 21). Androgens cause an increase in the production of specific proteins in the prostate. For example, in humans, synthesis of prostate-specific antigen (PSA) is stimulated by DHT (22). In dogs, DHT increases prostate arginine esterase (AE) synthesis (23, 24, 25, 26, 27, 28).

The steroids, DHT, E2 and 3{alpha}-diol, implicated in prostate growth, all bind to SHBG with high affinity; but only E2 and 3{alpha}-diol activate SHBG-RSHBG in prostate tissue, causing rapid accumulation of intracellular cAMP (3, 4, 29). Traditionally, 3{alpha}-diol has been thought to be a biologically inert metabolite of DHT; however, this metabolite was recently shown to exhibit hormonal activity (3, 30). Further, for more than a decade, it has been known that administration of 3{alpha}-diol induces benign prostatic hyperplasia (BPH) in dogs (31, 32, 33, 34, 35). E2 also has been implicated in contributing to the pathogenesis of BPH. In castrated dogs, E2 prevents prostate regression; moreover, BPH can be induced experimentally by estrogens in intact dogs and monkeys (32, 33, 34, 35, 36). In humans, accumulation of E2 in the prostate is associated with advancing age (37). E2 also has been implicated in contributing to the growth and progression of human prostate cancer (38). In this regard, E2 binding to SHBG has been shown to stimulate cAMP accumulation in a human prostate cancer (LNCaP) cell line (5).

Prostate growth is known to be mediated by DHT activation of AR and consequent increase in the production of PSA (22). To address the mechanism by which E2 or 3{alpha}-diol stimulation, via the SHBG-RSHBG pathway, might contribute to prostate growth in the dog, we asked whether the increase in cAMP was linked functionally to an androgen-responsive pathway in primary cultures of dog prostate. We selected the canine equivalent of PSA, AE as a marker of activation of the AR. As anticipated, AE was stimulated by DHT, but most importantly, in the presence (but not in the absence) of SHBG, both E2 and 3{alpha}-diol mimicked the effect of DHT. While this work on normal prostate was in progress, similar observations were made using human BPH tissue, suggesting that this pathway has physiological relevance in the growth of both normal and hyperplastic tissue (39).


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Chemicals and reagents
Tissue culture medium RPMI-1640, FBS, and sodium pyruvate were purchased from GIBCO-BRL (Gaithersburg, MD). All steroid compounds were obtained from Steraloids Inc. (Wilton, NH). Highly purified canine SHBG was prepared as previously described (3). All reagents and apparatus for electrophoresis and Western blot analysis were purchased from Novex (San Diego, CA). The enhanced chemiluminescence system for Western blot detection was obtained from Amersham Life Science (Arlington Heights, IL). 8-Br-cAMP, benzoyl arginine ethyl ester, forskolin, and isobutyl-methylxanthine were obtained from Sigma Chemical Company (St. Louis, MO). Hydroxyflutamide was obtained from the Merck Chemical Data collection. The anti-AE antiserum was a gift of Dr. J. Y. Dubé, Laboratory of Hormonal Bioregulation, Laval University Hospital Research Center, Sainte-Foy, Québec, Canada. AE protein standard was a gift of Dr. Alan Partin, Johns Hopkins University, Baltimore, MD. All other reagents were of analytical grade.

Prostatic tissue explants
Unless otherwise specified, prostate tissue was obtained from pure-bred male beagle dogs, 2–3 yr of age (3). Dogs were euthanized 7 days after surgical castration. All procedures for the humane handling, care, and treatment of research animals were done according to humane animal use procedures approved by the Merck Institutional Animal Care and Use Committee. The prostatic tissue was removed and brought to the laboratory under sterile conditions. It was divided into approximately 5-mm3 cubes and placed in 100-mm culture dishes (Corning Glass Works, Corning, NY) in RPMI-1640 medium with 5% FBS containing 1 mM sodium pyruvate, 100 U/ml penicillin, 100 mg/ml streptomycin sulfate, and 0.25 mg/ml amphotericin B for 2 days at 37 C in an atmosphere of 95% air and 5% CO2. Tissue was then minced into 1–2 mm3 portions and transferred to 24-well plates in serum-free medium (0.5 ml/well) for approximately 18 h before beginning each experiment.

Tissue processing and AE activity determination
Prostatic minces were incubated in the presence or absence of steroid hormones for 2 days. To avoid having any SHBG in the culture medium, serum-free medium was used, as previously reported (3, 4). Fresh medium and hormones were replaced at 24 h. To saturate the SHBG receptor, prostatic minces were incubated with 50 nM purified dog SHBG (3) for 3 h. Subsequently, appropriate concentrations of steroids were added after washing to remove excess SHBG. Other treatments with hydroxyflutamide (100 nM), 2-methoxyestradiol (2MeOE2), were added 15 min before addition of steroids. All the steroids and the antagonists used in this study were initially dissolved in 100% ethanol. Tissue minces were harvested and homogenized using a polytron (Tekmar Co., Cincinnati, OH) for 30 sec in 0.5 ml cold PBS (10 mM, pH 7.2) containing 0.2% Triton X-100. The homogenates were centrifuged at 25,000 x g for 45 min at 4 C to remove particulate matter, and the supernatants were stored at -80 C. The protein concentration of the supernatant was determined using the Bio-Rad Protein microassay procedure. AE activity was determined as described previously (40, 41, 42, 43), with modifications. The substrate concentration was 1 mM, and the reaction was carried out at room temperature (~24 C) in 1 ml 0.01 M Tris/HCl buffer at pH 8.0. Total protein amounts (5–20 µg) were used to determine the enzyme activity by following the increase in optical density at 253 nm upon the hydrolysis of benzoyl arginine ethyl ester (42). AE activity present in tissue homogenates was found to be stable after sample storage at -80 C and a single freeze/thaw cycle did not affect the enzyme activity.

Western blotting analysis
Samples were resolved by electrophoresis through 4–20% SDS-polyacrylamide gradient gels, followed by electroblotting onto 100% methanol-treated PVDF membrane (0.45 µm, Immobilon P from Millipore, Bedford, MA). The membranes were blocked with 5% nonfat milk in PBS for 1 h. Immunostaining was performed by incubating with rabbit anti-AE polyclonal antibodies at 1:2,000 dilution in washing buffer (0.25% gelatin, 5 mM EDTA, 0.15 M NaCl, 0.05% Tween 20, 50 mM Tris/HCl, pH 7.4) for 1 h. The membranes were washed for 30 min, then incubated with horseradish peroxidase-conjugated donkey antirabbit IgG (Amersham) at 1:3,000 dilution for 40 min. The Western blots were developed using enhanced chemiluminescence procedures similar to those described by Amersham. All steps were carried out at room temperature.

Measurement of cAMP level
Levels of cAMP were measured using commercial enzyme-linked immunosorbent assay kits (Oxford Biomedical Research, Inc., Oxford, MI), as described previously (3). All samples contained isobutyl-methylxanthine (100 µM).

Statistical analysis
The significance of differences between treatment and control groups was assessed using Student’s t test. Values are reported as the mean ± SEM (SE of the mean).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Stimulation of AE by DHT
As expected, AE activity increased as a function of the dose of DHT (Fig. 1AGo). The basal level of AE activity in castrated (7 days) dog prostate was approximately 3 µmol/min·mg protein. AE activity was not significantly stimulated by 1 nM DHT; however, at 10 nM and 100 nM DHT, AE activity was significantly increased. Thus, DHT stimulates AE activity in a dose-dependent manner; and although a concentration of 100 nM may not represent a maximal response, this concentration was used as a reference in subsequent experiments.



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  		Figure 1. Effect of steroid hormones on AE activity. (A), DHT; (B), E2 or 3{alpha}-diol ± SHBG; ({blacksquare}), tissue incubated with dog SHBG for 3 h to saturate SHBG receptors before treatment with steroids; ({square}), no SHBG treatment; **, P < 0.05, compared with the control; *, P < 0.05, compared with the same treatment in the absence of SHBG. Each data point represents the mean ± SEM of six determinations derived from two independent experiments.

 
Stimulation of AE through the SHBG receptor complex
After preincubation with SHBG, to allow formation of the SHBG-RSHBG complex, treatment with E2 or 3{alpha}-diol led to an increase in AE activity similar to that observed with DHT (Fig. 1BGo). By contrast, in the absence of SHBG, E2 and 3{alpha}-diol did not stimulate AE activity. Thus, the stimulation of AE, caused by E2 and 3{alpha}-diol, required the SHBG-RSHBG complex.

The effects on AE protein were measured by Western blot using a specific anti-AE antibody. AE migrated as a 29-KDa molecular mass species on a 4–20% polyacrylamide gel under nonreducing conditions. The AE protein in prostate tissue treated with DHT, or SHBG plus E2, was increased substantially, relative to the respective controls (Fig. 2Go). In tissue treated with SHBG or E2 alone, the AE activity increased only slightly, compared with control.



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  		Figure 2. Western blot of prostate tissue homogenates treated with steroid hormones. Samples were resolved under nonreducing conditions on a 4–20% linear gradient polyacrylamide gel, followed by electrophoretic blotting on a PVDF membrane. AE, arginine esterase standard; lane 1, control; lane 2, DHT (100 nM); lane 3, DHT + hydroxyflutamide; lane 4, SHBG; lane 5, SHBG + E2; lane 6, E2 (lanes 1–6, 200 ng protein of tissue homogenate were loaded in each well). Similar results were obtained in two additional experiments.

 
Effect of AR antagonists on SHBG-mediated stimulation of AE activity.
Hydroxyflutamide (100 nM), a specific AR antagonist, inhibited the DHT-mediated increase in AE (Fig. 3Go). Similarly, the increased activity after treatment with SHBG+E2 or SHBG+3{alpha}-diol also was blocked by hydroxyflutamide (Fig. 3Go). Western blotting revealed parallel results in AE protein.



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  		Figure 3. Effect of hydroxyflutamide on AE activity. Prostate minces treated with steroid only or with 100 nM hydroxyflutamide (HF) plus steroid. The SHBG receptor of prostate tissue was saturated with dog SHBG before treatment with E2 and 3{alpha}-diol. ({square}), tissue treated in the absence of HF; ({blacksquare}), tissue treated in the presence of HF; control, vehicle only; *, P < 0.05, compared with the same treatment in the absence of HF. Each data bar represents the mean ± SEM of six determinations derived from two independent experiments.

 
Effect of an SHBG-cAMP pathway antagonist
In confirmation of our previous studies (3), intracellular cAMP levels were stimulated markedly by the combination of SHBG, E2, and 3{alpha}-diol (Fig. 4AGo). In a dose-dependent manner, 2MeOE2 inhibited the accumulation of cAMP stimulated by E2 or 3{alpha}-diol (Fig. 4AGo). Importantly, the stimulation of AE by E2 and 3{alpha}-diol also was blocked by 2MeOE2 (Fig. 4BGo). Thus, 2MeOE2 blocks both the accumulation of intracellular cAMP and the stimulation of AE activity that is initiated by E2 or 3{alpha}-diol and suggests that cAMP is a necessary intermediator between E2- or 3{alpha}-diol-SHBG-RSHBG and AE stimulation. Indeed, both the cAMP analog, 8-Br-cAMP, and the inducer of cAMP forskolin stimulated AE activity (Fig. 5Go).



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  		Figure 4. Effect of 2MeOE2 treatment on cAMP levels present in prostate tissue. (A), Concentration dependent on 2MeOE2 (nM) inhibition of cAMP accumulation induced by E2 and 3{alpha}-diol in the presence of SHBG. (B), Effect of 2MeOE2 on AE activity. Prostate tissue minces saturated with SHBG, were treated either with steroid hormone alone ({square}) or in the presence of 1 µM 2MeOE2 ({blacksquare}). Control, tissue AE activity without treatment; SHBG only, tissue saturated with SHBG; SHBG+E2, SHBG-saturated tissue treated with 100 nM E2 alone ({square}) or in the presence of 2MeOE2 ({blacksquare}); SHBG+3{alpha}-diol, SHBG-saturated tissue treated with 3{alpha}-diol alone ({square}) or in the presence of 2MeOE2 ({blacksquare}); *, P < 0.05, compared with the same treatment in the absence of 2MeOE2. Each data bar represents the mean ± SEM of six determinations derived from two independent experiments.

 


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  		Figure 5. Effect of stimulating the cAMP pathway on AE activity. AE activity was measured in the homogenates of prostate tissue treated with 100 nM DHT and compared with the effects of 50 µM forskolin (Fsk), a stimulator of cAMP production, or 50 µM 8-Br-cAMP. **, P < 0.05, compared with the control. Each data bar represents the mean ± SEM of six determinations derived from two independent experiments.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Androgens are important mediators of prostate growth, but although androgens require ARs to mediate their effects, the converse may not be true. Both in transformed cell lines and in appropriately transfected cells, evidence has been presented showing that the AR can be activated by substances other than steroids (19, 20, 21). However, the relevance of these observations to actual physiology has been problematical. The old observations that E2 and 3{alpha}-diol induced prostate hyperplasia in dogs (31, 32, 33, 34, 35), together with our demonstration that both these steroids caused increases in cAMP in dog prostate, led us to hypothesize that these events might be connected (3). We speculated that perhaps ARs in the prostate were being activated by a cAMP-mediated pathway.

To test our hypothesis, we investigated the effects of E2 and 3{alpha}-diol on an androgen-responsive protein in the dog prostate. AE is a dog prostate-specific protein under androgenic control that can be employed as a prostate marker, analogous to the use of PSA in humans (23, 24, 25, 26, 27, 28). We first confirmed that AE in dog prostate tissue was stimulated by DHT and that this effect could be antagonized by the specific AR antagonist, hydroxyflutamide. We then demonstrated that E2 and 3{alpha}-diol caused AE increase in prostate in the presence (but not in absence) of SHBG. The effects were not mediated by the estrogen receptor because, in the absence of SHBG, E2 alone had no effect, and 3{alpha}-diol does not bind to the estrogen receptor. The possible conversion of 3{alpha}-diol to DHT does not explain the effects of 3{alpha}-diol, because increases in AE required preincubation of prostate tissue with SHBG; 3{alpha}-diol alone was ineffective. 2MeOE2 a competitive inhibitor of E2 and 3{alpha}-diol binding to SHBG, blocked stimulation of cAMP by E2 and 3{alpha}-diol and prevented increases in AE caused by these steroids, suggesting that cAMP was involved in increasing AE. That 8-Br-cAMP and an inducer of cAMP (forskolin) also increased AE is consistent with this explanation. Because the AR selective antagonist, hydroxyflutamide, blocks E2, 3{alpha}-diol, and cAMP induction of AE, it seems that these effects are mediated through ARs. Furthermore, these results support the notion that ARs can be activated, even in the absence of androgens, by natural steroids that activate the cAMP pathway. Blockage of ligand-independent AR activation by antiandrogen is in agreement with several other recent reports.

Based on our findings, we propose a novel mechanism whereby E2 and 3{alpha}-diol can increase the production of androgen-responsive proteins in a physiologically relevant system. The AR, like other steroid hormone receptors, is a phosphoprotein (44, 45), and its activation state can potentially be modulated by phosphorylation-dephosphorylation, resulting in augmented or ligand-independent activation (17, 19, 21, 46, 47, 48, 49). The phosphorylation state of the AR has been shown to be increased upon hormone binding; however, changes in cAMP levels and activation of protein kinase A also have recently been implicated in causing ligand-independent activation of transfected ARs when expressed in either CV-1 or human prostate (PC-3) cells (17, 20, 21). Consistent with our results in normal prostate, it is therefore plausible that activation of the SHBG-RSHBG pathway can lead to androgen-independent AR activation via stimulation of protein kinase A. It is also possible that up-regulation of AR expression might occur via a cAMP response element present within the regulatory region of the AR gene (10, 13). This could potentially augment AE expression, causing an increase in AR concentrations and a corresponding increase in basal transcription.

A number of lines of evidence have implied a role for E2 in the pathogenesis of BPH or in androgen-independent progression of prostate cancer (31, 32, 33, 34, 35, 36, 37, 38). These studies indicate that E2 synergizes with 3{alpha}-diol, but not DHT, in induction of canine BPH. Because E2 and 3{alpha}-diol are the only two known steroids that activate the SHBG-RSHBG pathway in prostate tissue (3), and we have shown that both are capable of activating pathways normally considered androgen responsive, antagonism of the pathway by which SHBG leads to the induction of androgen-responsive genes may be a valuable therapeutic target for the treatment or prevention of BPH or prostate cancer. To our knowledge, this is the first demonstration in a physiologically relevant system that androgenic events can be observed in the complete absence of exogenous androgens.


   Acknowledgments
 
We thank Dr. Jean Y. Dubé for providing antibody, and Dr. Alan Partin for providing AE standard. We are grateful for valuable discussions and advice obtained from Drs. Sheila M. Cohen and Jeffrey H. Toney [Merck Research Laboratories (MRL)]. We thank Mr. Paul K. Cunningham and Mr. Donald F. Hora, Jr. (MRL-Laboratory Animal Resources) for their excellent technical assistance with the animal studies.

Received May 21, 1997.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Mendel CM 1989 The free hormone hypothesis: a physiologically based mathematical model. Endocr Rev 10:232–274[Abstract]
  2. Hryb DJ, Khan MS, Romas NA, Rosner W 1989 Solubilization and partial characterization of the sex hormone-binding globulin receptor from human prostate. J Biol Chem 264:5378–5383[Abstract/Free Full Text]
  3. Nakhla AM, Ding VDH, Khan MS, Romas NA, Rhodes L, Smith RG, Rosner W 1995 5{alpha}-androstan-3{alpha},17ß-diol is a hormone: stimulation of cAMP accumulation in human and dog prostate. J Clin Endocrinol Metab 80:2259–2262[Abstract]
  4. Nakhla AM, Khan MS, Romas NA, Rosner W 1994 Estradiol causes the rapid accumulation of cAMP in human prostate. Proc Natl Acad Sci USA 91:5402–5405[Abstract/Free Full Text]
  5. Nakhla AM, Khan MS, Rosner W 1990 Biologically active steroids activate receptor-bound human sex hormone-binding globulin to cause LNCaP cells to accumulate adenosine 3',5'-monophosphate. J Clin Endocrinol Metab 71:398–404[Abstract]
  6. Dumont JE, Jauniaux JC, Roger PP 1989 The cyclic AMP-mediated stimulation of cell proliferation. Trends Biochem Sci 14:67–71[CrossRef][Medline]
  7. Silberstein GB, Strickland P, Trumpbour V, Coleman S, Danie CW 1984 In vivo, cAMP stimulates growth and morphogenesis of mouse mammary ducts. Proc Natl Acad Sci USA 81:4950–4954[Abstract/Free Full Text]
  8. Sheffield LG, Welsch CW 1985 Cholera-toxin-enhanced growth of human breast cancer cell lines in vitro and in vivo: interaction with estrogen. Int J Cancer 36:479–483[Medline]
  9. Florio T, Perrino BA, Stork PJS 1996 Cyclic 3',5' adenosine monophosphate and cyclosporin A inhibit cellular proliferation and serine/threonine protein phosphatase activity in pituitary cells. Endocrinology 137:4409–4418[Abstract]
  10. Lindzey J, Grossmann M, Kumar MV, Tindall DJ 1993 Regulation of the 5'-flanking region of the mouse androgen receptor gene by cAMP and androgen. Mol Endocrinol 7:1530–1540[Abstract]
  11. Aronica SM, Kraus WL, Katzenellenbogen BS 1994 Estrogen action via the cAMP signaling pathway: stimulation of adenylate cyclase and cAMP-regulated gene transcription. Proc Natl Acad Sci USA 91:8517–8521[Abstract/Free Full Text]
  12. Tan Y, Low KG, Boccia C, Grossman J, Comb MJ 1994 Fibroblast growth factor and cyclic AMP (cAMP) synergistically activate gene expression at a cAMP response element. Mol Cell Biol 14:7546–7556[Abstract/Free Full Text]
  13. Mizokami A, Yeh SY, Chang C 1994 Identification of 3',5'-cyclic adenosine monophosphate response element and other cis-acting elements in the human androgen receptor gene promoter. Mol Endocrinol 8:77–88[Abstract]
  14. Chandra G, Cogswell JP, Miller LR, Godlevski MM, Stinnett SW, Noel SL, Kadwell SH, Kost TA, Gray JG 1996 Cyclic AMP signaling pathways are important in IL-1ß transcriptional regulation. J Immunol 155:4535–4543[Abstract]
  15. Daiter E, Omigbodun A, Wang S, Walinsky D, Strauss III JF, Hoyer JR, Coutifaris C 1996 Cell differentiation and endogenous cyclic adenosine 3',5'-monophosphate regulate osteopontin expression in human trophoblasts. Endocrinology 137:1785–1790[Abstract]
  16. Cho H, Aronica SM, Katzenellenbogen BS 1994 Regulation of progesterone receptor gene expression in MCF-7 breast cancer cells: a comparison of the effects of cyclic adenosine 3',5'-monophosphate, estradiol, insulin-like growth factor-1, and serum factors. Endocrinology 134:658–664[Abstract]
  17. Ikonen T, Palvimo JJ, Kallio PJ, Reinikainen P, Jänne OA 1994 Stimulation of androgen-regulated transactivation by modulators of protein phosphorylation. Endocrinology 135:1359–1366[Abstract]
  18. Blok LJ, Hoogerbrugge JW, Themmen AP, Baarends WM, Post M, Grootegoed JA 1992 Transient down-regulation of androgen receptor messenger ribonucleic acid (mRNA) expression in Sertoli cells by follicle-stimulating hormone is followed by up-regulation of androgen receptor mRNA and protein. Endocrinology 131:1343–1349[Abstract]
  19. Culig Z, Hobisch A, Cronauer MV, Hittmair A, Radmayr C, Bartsch G, Klocker H 1995 Activation of the androgen receptor by polypeptide growth factors and cellular regulators. World J Urol 13:285–289[Medline]
  20. Nazzareth LV, Weigel NL 1996 Activation of the human androgen receptor through a protein kinase A signaling pathway. J Biol Chem 271:19900–19907[Abstract/Free Full Text]
  21. Nazzareth LV, Mariani S, Lamb DL, Marcelli M, Weigel N 1996 Alternative mechanisms for activation of the androgen receptor in prostate cancer. Proc Keystone Symp on Lake Tahoe (article no. 433)
  22. Shirbiny AM 1994 Prostatic specific antigen. Adv Clin Chem 31:99–133[Medline]
  23. Juniewicz PE, Barbolt TA, Frenette EG, Dubé JY, Tremblay RR 1990 Effects of androgen and antiandrogen treatment on canine prostatic arginine esterase. Prostate 17:101–111[Medline]
  24. Dubé JY, Chapdelaine P, Tremblay RR 1983 Effects of testicular hormones on synthesis of soluble proteins by dog prostate slices. Can J Biochem Cell Biol 61:756–763[Medline]
  25. Frenette G, Dubé JY, Tremblay RR 1983 Effect of castration and steroid treatments on the activity of some hydrolytic enzymes in dog prostate. Prostate 4:383–390[Medline]
  26. Frenette G, Dubé JY, Lacoste D, Tremblay RR 1987 Radioimmunoassay in blood plasma of arginine esterase: the major secretory product of dog prostate. Prostate 10:145–152[Medline]
  27. Isaacs WB, Coffey DS 1984 The predominant protein of canine seminal plasma is an enzyme. J Biol Chem 259:11520–11526[Abstract/Free Full Text]
  28. Chapdelaine P, Potvin C, Ho-Kim MA, Larouche L, Bellemare G, Tremblay RR, Dubé JY 1988 Androgen regulation of canine prostatic arginine esterase mRNA using cloned cDNA. Mol Cell Endocrinol 56:63–70[CrossRef][Medline]
  29. Hryb DJ, Khan MS, Romas NA, Rosner W 1990 The control of the interaction of sex hormone-binding globulin with its receptor by steroid hormones. J Biol Chem 265:6048–6054[Abstract/Free Full Text]
  30. Mahendroo MS, Cala KM, Russell DW 1996 5{alpha}-reduced androgens play a key role in murine parturition. Mol Endocrinol 10:380–392[Abstract]
  31. Walsh PC, Wilson JD 1976 The induction of prostatic hypertrophy in the dog with androstanediol. J. Clin. Invest 57:1093–1097
  32. Juniewicz PE, Lemp BM, Barbolt TA, LaBrie TK, Batzold FH, Reel JR 1989 Dose-dependent hormonal induction of benign prostatic hyperplasia (BPH) in castrated dogs. Prostate 14:341–352[Medline]
  33. Coffey DS, Walsh PC 1990 Clinical and experimental studies of benign prostatic hyperplasia. Urol Clin North Am 17:461–475
  34. Funke PJ, Senge TH, Schenk B, Neumann F 1981 Histological and histochemical findings in prostates of castrated dogs after treatment with estradiol, tamoxifen androstanediol and cyprosterone acetate. In: Altwein JE, Bartsch G, Jacobi GH (eds) Antihormone-Bedeutung in der Urologie. W. Zuckerschwerdt Verlag, München, Germany, pp 51–55
  35. Jacobi GH, Moore RJ, Wilson JD 1978 Studies on the mechanism of 3{alpha}-androstanediol induced growth of the dog prostate. Endocrinology 102:1748–1755[Abstract]
  36. Habenicht UF, Tunn UW, Senge TH, Schröder FH, Schweikert HU, Bartsch G, El Etreby MF 1993 Management of benign prostatic hyperplasia with particular emphasis on aromatase inhibitors. J Steroid Biochem Mol Biol 44:557–563[CrossRef][Medline]
  37. Krieg M, Nass R, Tunu S 1993 Effect of aging on endogenous level of 5{alpha}-dihydrotestosterone, testosterone, estradiol, and estrone in epithelium and stroma of normal and hyperplastic human prostate. J Clin Endocrinol Metab 77:375–381[Abstract]
  38. Griffiths K, Davies P, Eaton CL, Harper ME, Turkes A, Peeling WB 1991 Endocrine factors in the initiation, diagnosis, and treatment of prostatic cancer. In: Voigt KD, Knabbe C (eds) Endocrine Dependent Tumors. Raven Press, Ltd., New York
  39. Nakhla AM, Romas NA, Rosner W 1997 Estradiol activates the prostate androgen receptor and PSA secretion through the intermediacy of sex hormone-binding globulin. J Biol Chem 272:6838–6841[Abstract/Free Full Text]
  40. Frenette G, Dubé JY, Tremblay RR 1985 Enzymatic characterization of arginine esterase from dog seminal plasma. Biochim Biophys Acta 838:270–276[Medline]
  41. Chapdelaine P, Dubé JY, Frenette G, Tremblay RR 1984 Identification of arginine esterase as the major androgen-dependent protein secreted by dog prostate and preliminary molecular characterization in seminal plasma. J Androl 5:206–210[Abstract/Free Full Text]
  42. Whitaker JR, Bender ML 1965 Kinetics of papain-catalyzed hydrolysis of {alpha}-N-benzoyl-L-arginine ethyl ester and {alpha}-N-benzoyl-L-argininamide. J Am Chem Soc 87:2728–2737[CrossRef][Medline]
  43. Isaacs WB, Shaper JH 1985 Isolation and characterization of the major androgen-dependent glycoprotein of canine prostatic fluid. J Biol Chem 256:6610–6615
  44. van Laar JH, Bolt-deVries J, Zegers ND, Trapman J, Brinkmann AO 1990 Androgen receptor heterogeneity and phosphorylation in human LNCaP cells. Biochem Biophys Res Commun 166:193–200[CrossRef][Medline]
  45. Moudgil VK 1990 Phosphorylation of steroid hormone receptors. Biochim Biophys Acta 1055:243–258[Medline]
  46. Kato S, Endoh H, Masuhiro Y, Kitamoto T, Uchiyama S, Sasaki H, Masushige S, Gotoh Y, Nishida E, Kawashima H, Metzger D, Chambon P 1995 Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase. Science 270:1491–1494[Abstract/Free Full Text]
  47. Arnold SF, Vorojeikina DP, Notides AC 1995 Phosphorylation of tyrosine 537 on the human estrogen receptor is required for binding to an estrogen response element. J Biol Chem 270:30205–30212[Abstract/Free Full Text]
  48. Bunone G, Briand PA, Miksicek RJ, Picard D 1996 Activation of the unliganded estrogen receptor by EGF involves the MAP kinase pathway and direct phosphorylation. EMBO J 15:2174–2183[Medline]
  49. van Laar JH, Berrevoets CA, Trapman J, Zegers ND, Brinkmann AO 1991 Hormone-dependent androgen receptor phosphorylation is accompanied by receptor transformation in human lymph node carcinoma of the prostate cells. J Biol Chem 266:3734–3738[Abstract/Free Full Text]



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