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Genetisches Institut (H.D., U.M., A.B.), Justus-Liebig-University, D-35392 Giessen, Germany; Department of Pharmacology (J.A.I.-L.), University of Michigan Medical School, Ann Harbor, Michigan 48109; and Forschungszentrum Karlsruhe (S.M., A.C.B.C.), Institut für Toxikologie und Genetik, 76021 Karlsruhe, Germany
Address all correspondence and requests for reprints to: Dr. Aria Baniahmad, Genetic Institute, Justus-Liebig-University, Heinrich-Buff-Ring 58–62, Giessen 35392, Germany. E-mail: aria.baniahmad{at}gen.bio.uni-giessen.de.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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This suggests that the association of SMRT with hAR is regulated at the level of cross-talk mechanisms and that ligand-independent receptor activation is due to corepressor dissociation. Taken together, we provide novel insights in AR regulation, antihormone action, and functional nuclear receptor-corepressor interaction.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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It has been suggested that amplification of the AR gene, activation of the signal transduction machinery, or changes in coactivator binding to AR lead to androgen-independent cancer cell growth. Furthermore, mutations in the AR gene have been implicated in the progression of prostate cancer from androgen-dependent to androgen-independent growth (6, 7). Signal transduction mechanisms that regulate the action of the AR in a ligand-independent manner, such as elevated levels of PKA, have also been reported (8, 9, 10), and these may play a role in the transition into androgen-independent growth of prostate cancer.
Thus, a general goal in prostate cancer therapy is to inhibit the AR-mediated transactivation in a long-term manner.
The AR is a member of the nuclear hormone receptor superfamily, which represents a large family of hormone-regulated transcription factors. Members of this superfamily share a common tripartite structure with a central DNA binding domain, which separates the receptor amino (N) terminus from the carboxy (C) terminus. The C terminus harbors the hormone binding domain (HBD) and the ligand-dependent transcriptional activation function (11, 12). The activity of nuclear receptors, in general, is modulated by associating proteins termed coactivators and corepressors. Whereas coactivators enhance the action of the liganded receptor, corepressors are thought to bind to the silencing domain, a region overlapping the hormone-binding domain (13), and to keep the receptor in an inactive state in the absence of hormone. Upon hormone binding, the corepressors dissociate, allowing the coactivators to bind and to exert their positive regulatory action. This model of corepressor action has been established mainly for the RARs and TRs. A typical example is the corepressor SMRT (silencing mediator for RA and TR) that was originally identified as a corepressor for the unliganded TR or RAR (14).
In contrast to other members of the nuclear hormone receptor superfamily, the major transactivation domains of the AR are localized at its N terminus (2, 15, 16, 17). The C terminus that serves as a transactivation domain for other steroid receptors has a very weak activity in the AR. It is therefore curious how binding of antiandrogens to the C terminus of the receptor can reduce the transactivation function at the N terminus of the AR.
In this communication, we demonstrate that the corepressor SMRT plays a role in the inhibition of androgen action by the antiandrogen cyproterone acetate (CPA). SMRT binds the N terminus of the AR inhibiting the transactivation function of the receptor by CPA. Receptor point mutants show that corepressor binding to the AR N terminus can be separated from the receptor-mediated transactivation. We also show that enhancement of the transactivation function of the AR achieved by signal transduction factors, such as PKA, correlate with the dissociation of SMRT from AR. These results together show the involvement of a corepressor in the regulation of the activity by the human AR (hAR).
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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).
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). In the absence of hormone VP16-SMRT led to an 4-fold increase in reporter gene activity. This induction is dependent on the presence of AR in the cells (not shown). In the presence of DHT and R1881, transactivation was increased a further 12- and 21-fold, respectively. Of the three antihormones tested, OH-F, CAS (bicalutamide), and CPA, an interaction of the AR with SMRT was observed only in the presence of CPA. This is shown by a further 25-fold increase in reporter activity when compared with the VP16 control. These data suggest that the corepressor SMRT interacts with the AR both in the presence of agonists and in the presence of the partial agonist CPA.
We then analyzed whether the overexpression of the corepressor SMRT might have an inhibitory effect on the transactivation induced by R1881 and CPA. For this purpose we transfected a full-length SMRT (14) expression vector into CV1 cells, together with the AR expression vector and the reporter MMTV-luc gene. As expected, addition of R1881 and CPA led to an increased reporter gene expression in the absence of coexpressed SMRT (Fig. 2A). Although coexpression of SMRT hardly affected basal promoter activity compared with an empty expression vector in the absence of R1881 or CPA, it reduced transactivation by both R1881 and CPA. Note that while SMRT strongly reduced CPA-mediated activation of the AR, its effect on R1881-induced transactivation was only mediocre. This suggests that the repressive effect of SMRT depends on the type of ligand, and the partial agonistic activity of CPA on the AR may be due to the low levels of SMRT in the recipient CV-1 cells (23).
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). In the presence of SMRT, an equimolar concentration of 10-9 M CPA resulted in a significant reduction of AR-mediated transactivation, and at 10-7 M CPA the R1881-induced transactivation mediated by AR was completely abrogated. The expression of AR is not changed by coexpression of full-length SMRT, by VP16 alone, or by the VP16-SMRT fusion determined by Western blotting (data not shown). Taken together, these results suggest that the level of CPA-mediated partial agonism of AR is regulated by the corepressor SMRT, and that CPA acts as a more efficient androgen antagonist in the presence of SMRT.
Response Element Specificity of AR-SMRT Interaction
PSA and probasin are used as important markers of prostate differentiation and prostate cancer growth, as both PSA and probasin expression are indicators of androgen action and AR functionality (24, 25, 26). We therefore wanted to analyze whether SMRT interacts with the AR in the context of natural promoters active in prostate such as the PSA and probasin promoters. Using the modified two-hybrid system we analyzed the interaction of VP16-SMRT with the AR on the following reporters, all of which contain response elements for the AR: PSA-luciferase, GRE2-tk-luciferase, ARR3-luciferase (probasin), and TAT-luciferase, and compared these with the MMTV-luc reporter (Fig. 3). Interestingly, we observed great differences in AR-SMRT interaction using these different response elements. Interaction of SMRT with AR is indicated as an enhancement of CPA-AR-mediated transactivation, comparing the values obtained with and without CPA using VP16 or VP-SMRT. A strong enhancement of transactivation was obtained using the natural promoters of the ARR3 (probasin) and the PSA genes in the presence of VP-SMRT. This effect is dependent on the presence of AR (not shown). Interestingly, both the double glucocorticoid response elements (GREs) in the vector GRE2-tk-luc and the TAT sequence exhibited no significant enhancement in the presence of the VP-SMRT fusion. The fold CPA-mediated induction is similar in the presence of VP or VP-SMRT, suggesting that CPA-bound AR does not recruit SMRT when AR is bound to these AR-responsive promoters.
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Detection of SMRT-hAR Complex by Coimmune Precipitation
To verify the interaction of SMRT with AR in the presence of CPA, we performed a coimmune precipitation using wild-type hAR and hemagglutin (HA)-tag alone or HA-tagged full-length SMRT coexpressed in HEK 293 cells in the presence of CPA. Anti-HA antibody was used for immune precipitation and the anti-AR antibody was used for Western detection (Fig. 4). We were able to detect coimmune-precipitated hAR only in the presence of SMRT. As controls the empty pSG5 vector was used in combination with the HA-SMRT expression vector and the empty HA vector in combination with the hAR expression vector. The expression of SMRT was controlled using HA antibody (not shown). A slower migrating unspecific band is present in the immune-precipitations (asterisk). LNCaP cell extracts were used as migration and detection control for hAR. Furthermore, we compared the effect of CPA on the AR-SMRT complex in coimmune precipitation experiments. The lower panel of Fig. 4 shows a moderate CPA-induced SMRT-AR interaction comparing the treatment with and without CPA, supporting the idea that CPA induces binding of SMRT to AR. As controls, we used both the empty HA vector and HA-SMRT alone. As input control AR-transfected HEK 293 cell extracts were used (input lane).
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). Truncation of the AR C terminus [
HBD; hAR amino acids (aa) 1–682] resulted in a hormone-independent transcriptionally active receptor. VP-SMRT expression led to a higher transactivation (compare VP16 with VP-SMRT and note the different scaling), suggesting that surprisingly the N terminus of AR is able to interact with SMRT. The N-terminal deletion (N-Term; hAR aa 505–919) lacked significant transcriptional activity in the presence of ligand, which confirms that the major transactivation function of AR is localized in its N terminus. This deletion also lacked interaction with SMRT. To control the functionality of this AR deletion, we generated an N-terminal VP16 fusion protein, replacing the AR N terminus with VP16 (VP-AR aa 505–919). This fusion exhibits hormone-dependent transcriptional activation but no effect of SMRT was observed (Fig. 5A). This confirms that the AR N terminus, and not the C terminus, of the hAR is the target for SMRT.
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). Because the first 33 aa of hAR were shown to be involved in intramolecular N- and C-terminal interaction (27), we wanted to know whether they influence SMRT-AR interaction. Therefore, we used internal deletions of hAR (Fig. 5B), which harbor the N-terminal interaction motif required to interact with its C terminus. A mutant containing an internal deletion from aa 39–171 bound SMRT in mammalian cells. However, the deletion mutant 39–328 did not bind SMRT (Fig. 5B). Thus, a similar observation was made using internal deletions. This indicates that the first 39 aa are not involved in SMRT binding and that the N-terminal sequences required for AR to interact with SMRT are localized between aa 171 and 328.
We then analyzed the effect of two point mutations localized in recently identified negative regulatory regions in the N-terminal region of AR (28) on their ability to interact with SMRT using the modified mammalian two-hybrid experiment. We analyzed mutant K385E or K518E either singly or in combination. In experiments with the mutant constructs individually or combined, we observe a strongly reduced interaction with SMRT compared with the wild-type AR (Fig. 5C).
In agreement with this finding, we examined the effect of full-length SMRT on various AR deletions and found that SMRT reduced the agonistic activity of CPA on those AR deletions that showed interaction with SMRT. Although the expression of full-length SMRT strongly reduced the agonistic activity of CPA on the wild-type AR, AR39–171, and AR 171-E, only a marginal reduction of the agonistic activity of CPA was observed with the double mutant K385E/K518-E and the N-terminal AR mutants lacking the interaction with SMRT (Fig. 5D). Taken together, this indicates that the binding and inhibitory effect of SMRT is dependent on the AR N terminus and at least overlaps the negative regulatory regions of AR, with the region between 385 and 518 also contributing to the functional interaction with SMRT.
SMRT Binds to the AR N-Terminus in Vitro
To analyze the interaction of AR with SMRT in vitro and to verify our observation that SMRT binds to the N terminus of hAR, we performed glutathione-S-transferase (GST) pull-down experiments. Bacterially expressed GST or GST-C-SMRT, a fusion of the C-terminal 422 aa of SMRT, were incubated with in vitro translated and 35S-methionine labeled full-length hAR in the presence of CPA or N-terminal receptor deletions (Fig. 6). In this assay the wild-type hAR bound specifically to GST-SMRT but not to GST alone. If instead of the wild-type AR, only the N terminus (1–505) was radioactively labeled and used in this assay, an interaction with GST-SMRT was still observed, which confirmed our previous data. A fragment of the N terminus encompassing aa 1–328 showed a significant but weaker interaction with SMRT. Neither the mutant AR 1–171, nor, as a negative control, the unrelated protein luciferase interacted with SMRT (Fig. 6, lower panel). Taken together, this suggests that the first 328 aa of hAR are sufficient to interact with SMRT but further sequences of the AR N terminus may be required to strongly enhance the interaction of SMRT with the AR N terminus.
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The Interaction of hAR with SMRT in the Presence of CPA Is Controlled by cAMP
Because it is known that factors that increase the intracellular levels of cAMP positively modulate the transcriptional activity of AR (8, 9), we investigated whether cAMP can relieve the binding of SMRT to AR. We first added 8-bromo-cAMP (8-Br-cAMP), a cAMP analog, in the modified mammalian two-hybrid system with hAR (Fig. 7A). Addition of 8-Br-cAMP does not affect the basal promoter activity in the absence of CPA. However, treatment with 8-Br-cAMP resulted in a significant reduction in the fold activation in the presence of VP16-SMRT as compared with in the absence of 8-Br-cAMP, which indicates that treatment with 8-Br-cAMP leads to a decrease in SMRT-AR interaction.
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). In cotransfection experiments with the catalytic subunit of PKA, we made similar observations as we did with 8-Br-cAMP. PKA did not have a significant effect on basal promoter activity. However, coexpression of PKA resulted in a strong reduction in reporter activity in the presence of VP16-SMRT, suggesting that overexpression of PKA leads to the dissociation of SMRT from the CPA-bound AR. Taken together, these results show that increasing the intracellular levels of cAMP or coexpression of PKA down-regulates the interaction of SMRT with AR.
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DISCUSSION |
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Here, we show that at least one of the antagonists, CPA, functions as an androgen antagonist by inducing the association of the corepressor SMRT with the AR. This corepressor strongly reduces the transcriptional activity of the receptor when bound to the AR in the presence of CPA. Similar observations were made for the PR using NCoR and specific antiprogestins such as RU486 and ZK 98299, as well as for the ER using SMRT and the antiestrogen hydroxytamoxifen (18, 19, 20, 29).
In our studies we showed that the partial agonistic activity of CPA in CV1 cells is most likely due to a reduced level of SMRT in these cells. Accordingly, coexpression of SMRT resulted in a decrease of CPA-mediated agonism in these cells. Importantly, coexpression of SMRT leads to an enhancement of the antagonistic activity of CPA in the presence of androgen. We therefore conclude that the level of SMRT regulates the action of the antiandrogen CPA. SMRT does not interact with AR in the presence of the antiandrogens OH-F and CAS, indicating that their regulatory activities are based on other mechanisms.
Another proposed mechanism for antiandrogen resistance and tumor regrowth is the activation of the signal transduction machinery (3, 7, 8, 9, 10). On the molecular level the activation of the signal transduction pathway and phosphorylation cascades may regulate corepressor-nuclear receptor binding. Our results showing that PKA induces the dissociation of AR from SMRT support this notion.
Mechanisms of SMRT-AR Functionality
Our data show that the C terminus of SMRT interacts with the N terminus of AR. Although both R1881 and CPA induce interaction of hAR with SMRT, our data indicate that there is a functional difference of the corepressor SMRT bound either to the agonist- or antagonist-liganded AR. Either the interaction leads to a functional difference of SMRT itself, or the presence of coactivators modulate the effect mediated by SMRT. This is in agreement with our finding (Fig. 2A) that the corepressor SMRT only weakly affects the transcriptional activity of agonist-bound AR. This may also indicate that the agonist-induced transcriptional activity of AR by recruitment of coactivators overrides the repressive effect of SMRT (30, 31, 32).
For both the in vitro GST pull-down and the mammalian interaction system we found that the C terminus of SMRT, which harbors the two receptor interaction domains (22), is sufficient for the interaction with AR. Interestingly, both receptor interacting domains of SMRT were shown to be required to bind to nonsteroid receptors, such as TRs and RARs as well as to orphan receptors, such as Rev-Erb (33). In these cases, however, it is the HBD of the receptors that interacts with the C terminus of SMRT. Our finding that the C terminus of SMRT interacts with the N terminus of the AR is therefore unique.
Recently, it was shown that several steroid receptors harbor negative regulatory regions in their N termini when mutated, leading to an increase in receptor-mediated transactivation (28, 34, 35). A small sequence motif encompassing the following consensus amino acid sequence P-X (0-4) -I/V-K-X-E-X(0-4)-P is conserved among receptors for steroids and other transcription factors. Mutations of these sequences in AR led to an enhancement of AR-mediated transcriptional activity. Our findings that SMRT functionally interacts with the AR N terminus and that mutations in this negative regulatory region of the AR abolish interaction with SMRT make these sequences functionally relevant also in negative regulation by antiandrogens. As several coactivators have been shown to mediate AR transactivation function through interaction with the N terminus of AR, binding of SMRT to this region presumably either competes for coactivator binding or the equilibrium of activation, and repression is shifted to a more repressive state when corepressors bind.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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In Vitro Translation Vectors
The AR was translated using pSG5-AR (16) with the coupled in vitro transcription-translation TNT kit (Promega Corp., Madison, WI). The vectors pSGAR 1–171, pSG-AR 1–328, and pSG-AR 505 were generated by deleting the coding sequences from AflII to BglII, Kpn2I to BglII, and Acc65I to BglII, respectively.
Mammalian Expression Vectors
The expression vectors for AR [pSG-AR; pSG-ARHBD; (16)] and all AR deletions were generated using standard cloning techniques with restriction enzyme digests. The internal deletions of AR were generated by deleting AR sequences with Cfr9 and AflII (aa 39–171) or with Cfr9I and Eco47III (aa 39–328) and insertion of a small oligonucleotide to keep the reading frame intact. Clones were verified by in vitro translation. The mammalian expression vectors for VP16, VP-SMRT, and pCMX-SMRT (21) were kindly provided by Ron Evans (The Salk Institute, La Jolla, CA). Full-length pHA-SMRT was constructed by in-frame insertion of SMRT cDNA (14) in the pMTII-HA vector. The reporters MMTV-luc (16), ARR3-Luc kindly provided by Dr. R. J. Matusik (Vanderbilt University, Nashville, TN) (24), TAT3-Luc (28), GRE2-Luc (16), and PSA-Luc (25) contain the luciferase gene as reporter gene.
Cell Culture
CV1 and HEK-293 cells were grown in DMEM with 10% FCS at 37 C/5% CO2. Cotransfections were carried out using the CaPO4-method as described earlier (36). hAR expression vector (1 µg) was cotransfected with 5 µg of indicated reporter plasmid. For the modified mammalian two-hybrid experiments, 1 µg of either VP16-C-SMRT, VP16 expression plasmids, full-length SMRT, or empty expression plasmid was used. For PKA coexpression studies, 1 µg of PKA expression plasmid was cotransfected, and charcoal-treated 10% FCS was used. All transfection assays shown were done in independent duplicate or triplicate sets. Each set was repeated at least two more times. At least two different double CsCl gradient-purified plasmid preparations were used. The error bars represent the deviation of the mean value. For hormonal studies 10-7 M hormone was added except when otherwise stated. Where indicated, cells were treated with 10-4 M 8-Br-cAMP. pCMV-ß-galactosidase was cotransfected as internal control for transfection efficiency.
Coimmune Precipitation
HEK-293 cells were cotransfected with full-length hAR expression vector together with either HA or HA-SMRT expression vector coding for the HA-tagged full-length SMRT. Hormone was added (10-7 M CPA) immediately after transfection. After 48 h, cells were lysed on ice in lysis buffer containing 50 mM Tris-HCl (pH 7.4), 100 mM NaCl, 5 mM CaCl2, 5 mM MgCl2, 1% Nonidet P-40, 1%, Triton X-100, and 10-7 M CPA. Cell debris was pelleted at 13,000 rpm at 4 C for 10 min. Purified HA monoclonal antibody (1.5 µg) (12C5 m-
HA) was added to each cell extract and incubated at 4 C overnight. Cell extracts were incubated for 2 h with 15 µl of protein A/G-agarose beads (Sigma, St. Louis, MO) at 4 C. Beads were washed five times with washing buffer [50 mM Tris-HCl, (pH 7.4), 100 mM NaCl, 5 mM CaCl2, 5 mM MgCl2, 0.1% Nonidet P-40, and 10-7 M CPA], and subjected to SDS-PAGE. Western analysis was performed by using anti-AR antibody (F39.4.1, BioGenex Laboratories, Inc., San Ramon, CA) and the enhanced chemiluminescence detection method (Amersham Pharmacia Biotech, Arlington Heights, IL).
GST Pull-Down Experiments
Bacterial expression of GST or GST-C-SMRT, encompassing the C-terminal 422 aa, was performed by induction of gene expression with 0.2 mM isopropyl-ß-D-thiogalactopyranoside for 3 h at 37 C in the BL21(lys) bacterial strain. Purification of the GST fusion proteins and interaction studies with in vitro translated, 35S-methionine-labeled nuclear hormone receptors (TNT kit from Promega Corp.) were as described previously (36). In each experiment, the amount of the input lane was 10% of that incubated with the glutathione beads (Pharmacia Biotech, Piscataway, NJ). The SDS-PAGEs were stained with Coomassie brilliant blue to ensure equal loading of GST fusion proteins. The bound and labeled proteins were visualized by fluorography. For full-length AR, 10-7 M CPA was used during translation and interaction studies.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Abbreviations: aa, Amino acids; 8-Br-cAMP, 8-bromo-cAMP; CAS, casodex; CPA, cyproterone acetate; DHT, dihydrotestosterone; GRE, glucocorticoid response element; GST, glutathione-S-transferase; HA, hemagglutin; hAR, human AR; HBD, hormone-binding domain; MMTV-luc, mouse mammary tumor virus-luciferase; OH-F, hydroxyflutamide; PSA, prostatespecific antigen; SMRT, silencing mediator for retinoic acid and thyroid hormone receptor.
Received for publication June 1, 2001. Accepted for publication December 6, 2001.
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REFERENCES |
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silencing by the AF2/
c activation domain can be overcome by the corepressor SMRT, but not by N-CoR. Mol Endocrinol 12:504–512. Mol Endocrinol 12:248–2624/c/AF-2 of the thyroid hormone receptor relieves silencing of the retinoic acid receptor silencer core independent of both 4 activation function and full dissociation of corepressors. Mol Cell Biol 17:4259–4271[Abstract]This article has been cited by other articles:
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  M. Eisold, M. Asim, H. Eskelinen, T. Linke, and A. Baniahmad Inhibition of MAPK-signaling pathway promotes the interaction of the corepressor SMRT with the human androgen receptor and mediates repression of prostate cancer cell growth in the presence of antiandrogens J. Mol. Endocrinol., May 1, 2009; 42(5): 429 - 435. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. C. Hodgson, H. C. Shen, A. N. Hollenberg, and S. P. Balk Structural basis for nuclear receptor corepressor recruitment by antagonist-liganded androgen receptor Mol. Cancer Ther., October 1, 2008; 7(10): 3187 - 3194. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. Moehren, M. Papaioannou, C. A. Reeb, A. Grasselli, S. Nanni, M. Asim, D. Roell, I. Prade, A. Farsetti, and A. Baniahmad Wild-type but not mutant androgen receptor inhibits expression of the hTERT telomerase subunit: a novel role of AR mutation for prostate cancer development FASEB J, April 1, 2008; 22(4): 1258 - 1267. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. M. Dehm and D. J. Tindall Androgen Receptor Structural and Functional Elements: Role and Regulation in Prostate Cancer Mol. Endocrinol., December 1, 2007; 21(12): 2855 - 2863. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Y. Kim, O. G. Park, J. W. Lee, and Y. C. Lee One- plus Two-hybrid System, a Novel Yeast Genetic Selection for Specific Missense Mutations Disrupting Protein/Protein Interactions Mol. Cell. Proteomics, October 1, 2007; 6(10): 1727 - 1740. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. C. Hodgson, I. Astapova, A. N. Hollenberg, and S. P. Balk Activity of Androgen Receptor Antagonist Bicalutamide in Prostate Cancer Cells Is Independent of NCoR and SMRT Corepressors Cancer Res., September 1, 2007; 67(17): 8388 - 8395. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. Moehren, M. Papaioannou, C. A. Reeb, W. Hong, and A. Baniahmad Alien Interacts with the Human Androgen Receptor and Inhibits Prostate Cancer Cell Growth Mol. Endocrinol., May 1, 2007; 21(5): 1039 - 1048. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. J Burd, L. M Morey, and K. E Knudsen Androgen receptor corepressors and prostate cancer Endocr. Relat. Cancer, December 1, 2006; 13(4): 979 - 994. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Wu, H. Kawate, K. Ohnaka, H. Nawata, and R. Takayanagi Nuclear Compartmentalization of N-CoR and Its Interactions with Steroid Receptors. Mol. Cell. Biol., September 1, 2006; 26(17): 6633 - 6655. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.-G. Yoon and J. Wong The Corepressors Silencing Mediator of Retinoid and Thyroid Hormone Receptor and Nuclear Receptor Corepressor Are Involved in Agonist- and Antagonist-Regulated Transcription by Androgen Receptor Mol. Endocrinol., May 1, 2006; 20(5): 1048 - 1060. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. M. Butler, M. M. Centenera, P. J. Neufing, G. Buchanan, C. S. Y. Choong, C. Ricciardelli, K. Saint, M. Lee, A. Ochnik, M. Yang, et al. Suppression of Androgen Receptor Signaling in Prostate Cancer Cells by an Inhibitory Receptor Variant Mol. Endocrinol., May 1, 2006; 20(5): 1009 - 1024. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Chen, M. Nomura, H. Morinaga, E. Matsubara, T. Okabe, K. Goto, T. Yanase, H. Zheng, J. Lu, and H. Nawata Modulation of Androgen Receptor Transactivation by FoxH1: A NEWLY IDENTIFIED ANDROGEN RECEPTOR COREPRESSOR J. Biol. Chem., October 28, 2005; 280(43): 36355 - 36363. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Zhang, X.-W. Wang, D. Jelovac, T. Nakanishi, M.-h. Yu, D. Akinmade, O. Goloubeva, D. D. Ross, A. Brodie, and A. W. Hamburger The ErbB3-binding protein Ebp1 suppresses androgen receptor-mediated gene transcription and tumorigenesis of prostate cancer cells PNAS, July 12, 2005; 102(28): 9890 - 9895. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. L. Hultman, N. V. Krasnoperova, S. Li, S. Du, C. Xia, J. D. Dietz, D. S. Lala, D. J. Welsch, and X. Hu The Ligand-Dependent Interaction of Mineralocorticoid Receptor with Coactivator and Corepressor Peptides Suggests Multiple Activation Mechanisms Mol. Endocrinol., June 1, 2005; 19(6): 1460 - 1473. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Wang and S. S. Simons Jr. Corepressor Binding to Progesterone and Glucocorticoid Receptors Involves the Activation Function-1 Domain and Is Inhibited by Molybdate Mol. Endocrinol., June 1, 2005; 19(6): 1483 - 1500. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. C. Hodgson, I. Astapova, S. Cheng, L. J. Lee, M. C. Verhoeven, E. Choi, S. P. Balk, and A. N. Hollenberg The Androgen Receptor Recruits Nuclear Receptor CoRepressor (N-CoR) in the Presence of Mifepristone via Its N and C Termini Revealing a Novel Molecular Mechanism for Androgen Receptor Antagonists J. Biol. Chem., February 25, 2005; 280(8): 6511 - 6519. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. S. Hilgarth, L. A. Murphy, H. S. Skaggs, D. C. Wilkerson, H. Xing, and K. D. Sarge Regulation and Function of SUMO Modification J. Biol. Chem., December 24, 2004; 279(52): 53899 - 53902. [Full Text] [PDF]
|
|
|
|
|
|
D.-Y. Lin, H.-I Fang, A.-H. Ma, Y.-S. Huang, Y.-S. Pu, G. Jenster, H.-J. Kung, and H.-M. Shih Negative Modulation of Androgen Receptor Transcriptional Activity by Daxx Mol. Cell. Biol., December 15, 2004; 24(24): 10529 - 10541. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. C. Whitaker, S. Hanrahan, N. Totty, S. C. Gamble, J. Waxman, A. C. B. Cato, H. C. Hurst, and C. L. Bevan Androgen Receptor Is Targeted to Distinct Subcellular Compartments in Response to Different Therapeutic Antiandrogens Clin. Cancer Res., November 1, 2004; 10(21): 7392 - 7401. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Masiello, S.-Y. Chen, Y. Xu, M. C. Verhoeven, E. Choi, A. N. Hollenberg, and S. P. Balk Recruitment of {beta}-Catenin by Wild-Type or Mutant Androgen Receptors Correlates with Ligand-Stimulated Growth of Prostate Cancer Cells Mol. Endocrinol., October 1, 2004; 18(10): 2388 - 2401. [Abstract] [Full Text] [PDF]
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H. I Scher, G. Buchanan, W. Gerald, L. M Butler, and W. D Tilley Targeting the androgen receptor: improving outcomes for castration-resistant prostate cancer Endocr. Relat. Cancer, September 1, 2004; 11(3): 459 - 476. [Abstract] [Full Text] [PDF]
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Q. Wang, J. A. Blackford Jr., L.-N. Song, Y. Huang, S. Cho, and S. S. Simons Jr. Equilibrium Interactions of Corepressors and Coactivators with Agonist and Antagonist Complexes of Glucocorticoid Receptors Mol. Endocrinol., June 1, 2004; 18(6): 1376 - 1395. [Abstract] [Full Text] [PDF]
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L. Callewaert, G. Verrijdt, A. Haelens, and F. Claessens Differential Effect of Small Ubiquitin-Like Modifier (SUMO)-ylation of the Androgen Receptor in the Control of Cooperativity on Selective Versus Canonical Response Elements Mol. Endocrinol., June 1, 2004; 18(6): 1438 - 1449. [Abstract] [Full Text] [PDF]
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C.-C. Tsai, H.-Y. Kao, A. Mitzutani, E. Banayo, H. Rajan, M. McKeown, and R. M. Evans Ataxin 1, a SCA1 neurodegenerative disorder protein, is functionally linked to the silencing mediator of retinoid and thyroid hormone receptors PNAS, March 23, 2004; 101(12): 4047 - 4052. [Abstract] [Full Text] [PDF]
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 C. L. Smith and B. W. O'Malley Coregulator Function: A Key to Understanding Tissue Specificity of Selective Receptor Modulators Endocr. Rev., February 1, 2004; 25(1): 45 - 71. [Abstract] [Full Text] [PDF]
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Y. Zhang, Y. Yang, S. Yeh, and C. Chang ARA67/PAT1 Functions as a Repressor To Suppress Androgen Receptor Transactivation Mol. Cell. Biol., February 1, 2004; 24(3): 1044 - 1057. [Abstract] [Full Text] [PDF]
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N. Schrantz, J. d. S. Correia, B. Fowler, Q. Ge, Z. Sun, and G. M. Bokoch Mechanism of p21-activated Kinase 6-mediated Inhibition of Androgen Receptor Signaling J. Biol. Chem., January 16, 2004; 279(3): 1922 - 1931. [Abstract] [Full Text] [PDF]
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L.-N. Song, M. Coghlan, and E. P. Gelmann Antiandrogen Effects of Mifepristone on Coactivator and Corepressor Interactions with the Androgen Receptor Mol. Endocrinol., January 1, 2004; 18(1): 70 - 85. [Abstract] [Full Text] [PDF]
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C. Geserick, H.-A. Meyer, K. Barbulescu, and B. Haendler Differential Modulation of Androgen Receptor Action by Deoxyribonucleic Acid Response Elements Mol. Endocrinol., September 1, 2003; 17(9): 1738 - 1750. [Abstract] [Full Text] [PDF]
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I. U. Agoulnik, W. C. Krause, W. E. Bingman III, H. T. Rahman, M. Amrikachi, G. E. Ayala, and N. L. Weigel Repressors of Androgen and Progesterone Receptor Action J. Biol. Chem., August 15, 2003; 278(33): 31136 - 31148. [Abstract] [Full Text] [PDF]
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C. J. Loy, K. S. Sim, and E. L. Yong Filamin-A fragment localizes to the nucleus to regulate androgen receptor and coactivator functions PNAS, April 15, 2003; 100(8): 4562 - 4567. [Abstract] [Full Text] [PDF]
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 L. Jia, J. Kim, H. Shen, P. E. Clark, W. D. Tilley, and G. A. Coetzee Androgen Receptor Activity at the Prostate Specific Antigen Locus: Steroidal and Non-Steroidal Mechanisms Mol. Cancer Res., March 1, 2003; 1(5): 385 - 392. [Abstract] [Full Text] [PDF]
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G. Liao, L.-Y. Chen, A. Zhang, A. Godavarthy, F. Xia, J. C. Ghosh, H. Li, and J. D. Chen Regulation of Androgen Receptor Activity by the Nuclear Receptor Corepressor SMRT J. Biol. Chem., February 7, 2003; 278(7): 5052 - 5061. [Abstract] [Full Text] [PDF]
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J. Reid, I. Murray, K. Watt, R. Betney, and I. J. McEwan The Androgen Receptor Interacts with Multiple Regions of the Large Subunit of General Transcription Factor TFIIF J. Biol. Chem., October 18, 2002; 277(43): 41247 - 41253. [Abstract] [Full Text] [PDF]
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