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Bert W. O'malley - One of the best experts on this subject based on the ideXlab platform.

  • The dynamics of nuclear receptors and nuclear receptor Coregulators in the pathogenesis of endometriosis
    Human reproduction update, 2014
    Co-Authors: Sang Jun Han, Bert W. O'malley
    Abstract:

    background: Endometriosis is defined as the colonization and growth of endometrial tissue at anatomic sites outside the uterine cavity. Up to 15% of reproductive-aged women in the USA suffer from painful symptoms of endometriosis, such as infertility, pelvic pain, menstrual cycle abnormalities and increased risk of certain cancers. However, many of the current clinical treatments for endometriosis are not sufficiently effect- ive and yield unacceptable side effects. There is clearly an urgent need to identify new molecular mechanisms that critically underpin the initiation and progression of endometriosis in order to develop more specific and effective therapeutics which lack the side effects of current therapies. The aim of this review is to discuss how nuclear receptors (NRs) and their Coregulators promote the progression of endometriosis. Understanding the pathogenic molecular mechanisms for the genesis and maintenance of endometriosis as modulated by NRs and Coregulators can reveal new thera- peutic targets for alternative endometriosis treatments. methods: This review was prepared using published gene expression microarray data sets obtained from patients with endometriosis and published literature on NRs and their Coregulators that deal with endometriosis progression. Using the above observations, our current under- standing of how NRs and NR Coregulators are involved in the progression of endometriosis is summarized. results: Aberrant levels of NRs and NR Coregulators in ectopic endometriosis lesions are associated with the progression of endometriosis. As an example, endometriotic cell-specific alterations in gene expression are correlated with a differential methylation status of the genome com- pared with the normal endometrium. These differential epigenetic regulations can generate favorable cell-specific NR and coregulator milieus for endometriosis progression. Genetic alterations, such as single nucleotide polymorphisms and insertion/deletion polymorphisms of NR and cor- egulator genes, are frequently detected in ectopic lesions compared with the normal endometrium. These genetic variations impart new molecu- lar properties to NRs and Coregulators to increase their capacity to stimulate progression of endometriosis. Finally, post-translational modifications of NR Coregulators, such as proteolytic processing, generate endometriosis-specific isoforms. Compared with the unmodified Coregulators, these coregulator isoforms have unique functions that enhance the pathogenesis of endometriosis.

  • Nuclear receptor Coregulators: modulators of pathology and therapeutic targets
    Nature Reviews Endocrinology, 2012
    Co-Authors: David M. Lonard, Bert W. O'malley
    Abstract:

    The nuclear receptor superfamily includes transcription factors that transduce steroid, thyroid and retinoid hormones and other ligands in conjunction with Coregulators. To date, over 350 Coregulators have been reported in the literature, and advances in proteomic analyses of coregulator protein complexes have revealed that a far greater number of coregulator-interacting proteins also exist. Coregulator dysfunction has been implicated in diverse pathological states, genetic syndromes and cancer. A hallmark of disease related to the disruption of normal coregulator function is the pleiotropic effect on animal physiology, which is frequently manifested as the dysregulation of metabolic and neurological systems. Coregulators have broad physiological and pathological functions that make them promising new drug targets for diseases such as hormone-dependent cancers. Advances in proteomics, genomics and transcriptomics have provided novel insights into the biology of Coregulators at a system-wide level and will lead the way to a new understanding of how Coregulators can be evaluated in the context of complex and multifaceted genetic factors, hormones, diet, the environment and stress. Ultimately, better knowledge of the associations that exist between coregulator function and human diseases is expected to expand the indications for the use of future coregulator-targeted drugs. To date, more than 350 nuclear receptor Coregulators have been reported in the literature and a larger number of coregulator-interacting proteins have also been identified. Coregulators have been implicated in diverse pathological states, genetic syndromes and cancer. This Review focuses on their broad physiological and pathological functions and their promise as new drug targets for diseases such as hormone-dependent cancers. Coregulators interact with nuclear receptors and other transcription factors to alter chromatin and stimulate (coactivators) or repress (corepressors) gene expression Over 350 Coregulators have been identified in the literature, but proteomic studies indicate that this number is a gross underestimate Many Coregulators have been implicated in the physiology of reproduction, energy metabolism, inherited human genetic diseases and cancer Coregulators are receiving increasing attention as important drug targets for diseases including cancer, inflammatory disorders and genetic syndromes related to their dysfunction Proteomic, genomic and transcriptomic characterization of Coregulators will enable their physiological and pathological roles to be better realized in the context of diverse endocrine, environmental, dietary and stress conditions

  • Nuclear receptor Coregulators: modulators of pathology and therapeutic targets
    Nature reviews. Endocrinology, 2012
    Co-Authors: David M. Lonard, Bert W. O'malley
    Abstract:

    The nuclear receptor superfamily includes transcription factors that transduce steroid, thyroid and retinoid hormones and other ligands in conjunction with Coregulators. To date, over 350 Coregulators have been reported in the literature, and advances in proteomic analyses of coregulator protein complexes have revealed that a far greater number of coregulator-interacting proteins also exist. Coregulator dysfunction has been implicated in diverse pathological states, genetic syndromes and cancer. A hallmark of disease related to the disruption of normal coregulator function is the pleiotropic effect on animal physiology, which is frequently manifested as the dysregulation of metabolic and neurological systems. Coregulators have broad physiological and pathological functions that make them promising new drug targets for diseases such as hormone-dependent cancers. Advances in proteomics, genomics and transcriptomics have provided novel insights into the biology of Coregulators at a system-wide level and will lead the way to a new understanding of how Coregulators can be evaluated in the context of complex and multifaceted genetic factors, hormones, diet, the environment and stress. Ultimately, better knowledge of the associations that exist between coregulator function and human diseases is expected to expand the indications for the use of future coregulator-targeted drugs.

  • Uterine Development and Fertility Are Dependent on Gene Dosage of the Nuclear Receptor Coregulator REA
    Endocrinology, 2012
    Co-Authors: Sunghee Park, Bert W. O'malley, Sangyeon Yoon, Yuechao Zhao, Seong Eun Park, Lan Liao, John P. Lydon, Francesco J. Demayo, Milan K. Bagchi
    Abstract:

    Although the effectiveness of nuclear hormone-receptor complexes is known to depend on coregulator partner proteins, relatively little is known about the roles of Coregulators in uterine development and early stages of pregnancy and implantation. Because conventional genetic deletion of the coregulator, repressor of estrogen receptor activity (REA), was embryonic lethal, we here study REA conditional knockout mice generated by cre-loxP recombination, in which REA function was abrogated only in progesterone receptor-expressing tissues, to define the roles of REA in postembryonic stages and in a tissue-specific manner. We find that REA has gene dose-dependent activity impacting uterine development and fertility. Conditional homozygous mutant (REAd/d) mice developed to adulthood and showed normal ovarian function, but females were infertile with severely compromised uterine development and function characterized by cell cycle arrest, apoptosis, and altered adenogenesis (endometrial gland morphogenesis), resu...

  • The Year in Basic Science: nuclear receptors and Coregulators.
    Molecular endocrinology (Baltimore Md.), 2008
    Co-Authors: Bert W. O'malley
    Abstract:

    This article highlights the most significant scientific achievements of June 2007 to June 2008 in nuclear receptors (NRs) and Coregulators. These molecules are the subjects of nine studies in three key areas of endocrinology: molecular endocrinology, endocrine metabolism, and endocrine pathology. In each case, the relevant NR or coregulator was found to play an integral role in the study, whether in elucidating a formerly unknown pathway or in initiating or facilitating a disease process. As more NRs and Coregulators are researched, more therapeutic approaches to human disease can potentially be developed.

R. Kiplin Guy - One of the best experts on this subject based on the ideXlab platform.

  • Quantification of the vitamin D receptor-coregulator interaction.
    Biochemistry, 2009
    Co-Authors: Arnaud Teichert, Leggy A. Arnold, R. Kiplin Guy, Steve Otieno, Yuko Oda, Indre Augustinaite, Tim R. Geistlinger, Richard W. Kriwacki, Daniel D Bikle
    Abstract:

    The vitamin D receptor (VDR) regulates a diverse set of genes that control processes including bone mineral homeostasis, immune function, and hair follicle cycling. Upon binding to its natural ligand, 1alpha,25(OH)(2)D(3), the VDR undergoes a conformational change that allows the release of corepressor proteins and the binding of coactivator proteins necessary for gene transcription. We report the first comprehensive evaluation of the interaction of the VDR with a library of coregulator binding motifs in the presence of two ligands, the natural ligand 1alpha,25(OH)(2)D(3) and a synthetic, nonsecosteroidal agonist LG190178. We show that the VDR has relatively high affinity for the second and third LxxLL motifs of SRC1, SRC2, and SRC3 and second LxxLL motif of DRIP205. This pattern is distinct in comparison to other nuclear receptors. The pattern of VDR-coregulator binding affinities was very similar for the two agonists investigated, suggesting that the biologic functions of LG190178 and 1alpha,25(OH)(2)D(3) are similar. Hairless binds the VDR in the presence of ligand through a LxxLL motif (Hr-1), repressing transcription in the presence and absence of ligand. The VDR binding patterns identified in this study may be used to predict functional differences among different tissues expressing different sets of Coregulators, thus facilitating the goal of developing tissue- and gene-specific vitamin D response modulators.

  • Coregulator Interactions with the Thyroid Hormone Receptor
    Molecular & cellular proteomics : MCP, 2005
    Co-Authors: Jamie Moore, R. Kiplin Guy
    Abstract:

    The thyroid hormone receptor (TR) directly regulates the transcription of thyroid hormone-responsive genes in response to changing levels of thyroid hormone. Mechanistically TR utilizes a complex set of binding interactions, with hormone, response elements, and coregulatory proteins, to provide specific local control of patterns of transcriptional response that are partially responsible for inducing the tissue-selective responses to the circulating hormone. One of the apparently dominant phenomena in the regulation of thyroid hormone responses is the protein interactions between TR and its Coregulators. This review summarizes the current state of knowledge with respect to the identity of these Coregulators, their interaction with TR, and the consequences of those interactions.

  • Quantitative proteomics of the thyroid hormone receptor-coregulator interactions.
    The Journal of biological chemistry, 2004
    Co-Authors: Jamie Moore, Sarah J. Galicia, Andrea C. Mcreynolds, Ngoc Ha Nguyen, Thomas S. Scanlan, R. Kiplin Guy
    Abstract:

    Abstract The thyroid hormone receptor regulates a diverse set of genes that control processes from embryonic development to adult homeostasis. Upon binding of thyroid hormone, the thyroid receptor releases corepressor proteins and undergoes a conformational change that allows for the interaction of coactivating proteins necessary for gene transcription. This interaction is mediated by a conserved motif, termed the NR box, found in many Coregulators. Recent work has demonstrated that differentially assembled coregulator complexes can elicit specific biological responses. However, the mechanism for the selective assembly of these coregulator complexes has yet to be elucidated. To further understand the principles underlying thyroid receptor-coregulator selectivity, we designed a high-throughput in vitro binding assay to measure the equilibrium affinity of thyroid receptor to a library of potential Coregulators in the presence of different ligands including the endogenous thyroid hormone T3, synthetic thyroid receptor β-selective agonist GC-1, and antagonist NH-3. Using this homogenous method several coregulator NR boxes capable of associating with thyroid receptor at physiologically relevant concentrations were identified including ones found in traditional coactivating proteins such as SRC1, SRC2, TRAP220, TRBP, p300, and ARA70; and those in Coregulators known to repress gene activation including RIP140 and DAX-1. In addition, it was discovered that the thyroid receptor-coregulator binding patterns vary with ligand and that this differential binding can be used to predict biological responses. Finally, it is demonstrated that this is a general method that can be applied to other nuclear receptors and can be used to establish rules for nuclear receptor-coregulator selectivity.

Peter J. Leedman - One of the best experts on this subject based on the ideXlab platform.

  • Breast cancer prognosis predicted by nuclear receptor-coregulator networks.
    Molecular oncology, 2014
    Co-Authors: Tram B Doan, Peter J. Leedman, Natalie A. Eriksson, Dinny Graham, John W. Funder, Evan R. Simpson, Elizabeth Kuczek, Colin Clyne, Wayne D. Tilley, Peter J. Fuller
    Abstract:

    Although molecular signatures based on transcript expression in breast cancer samples have provided new insights into breast cancer classification and prognosis, there are acknowledged limitations in current signatures. To provide rational, pathway-based signatures of disrupted physiology in cancer tissues that may be relevant to prognosis, this study has directly quantitated changed gene expression, between normal breast and cancer tissue, as a basis for signature development. The nuclear receptor (NR) family of transcription factors, and their Coregulators, are fundamental regulators of every aspect of metazoan life, and were rigorously quantified in normal breast tissues and ERα positive and ERα negative breast cancers. Coregulator expression was highly correlated with that of selected NR in normal breast, particularly from postmenopausal women. These associations were markedly decreased in breast cancer, and the expression of the majority of Coregulators was down-regulated in cancer tissues compared with normal. While in cancer the loss of NR-coregulator associations observed in normal breast was common, a small number of NR (Rev-ERBβ, GR, NOR1, LRH-1 and PGR) acquired new associations with Coregulators in cancer tissues. Elevated expression of these NR in cancers was associated with poorer outcome in large clinical cohorts, as well as suggesting the activation of ERα -related, but ERα-independent, pathways in ERα negative cancers. In addition, the combined expression of small numbers of NR and Coregulators in breast cancer was identified as a signature predicting outcome in ERα negative breast cancer patients, not linked to proliferation and with predictive power superior to existing signatures containing many more genes. These findings highlight the power of predictive signatures derived from the quantitative determination of altered gene expression between normal breast and breast cancers. Taken together, the findings of this study identify networks of NR-coregulator associations active in normal breast but disrupted in breast cancer, and moreover provide evidence that signatures based on NR networks disrupted in cancer can provide important prognostic information in breast cancer patients.

  • The RNA coregulator SRA, its binding proteins and nuclear receptor signaling activity.
    IUBMB life, 2008
    Co-Authors: Shane M. Colley, Kavitha R. Iyer, Peter J. Leedman
    Abstract:

    Nuclear receptor (NR) Coregulators are key modulators of hormone signaling. Discovery of steroid receptor RNA activator (SRA), a coregulator that is active as a RNA, transformed thinking in the field of hormone action. The subsequent identification of SRA-binding coregulator proteins, including p68, SHARP and more recently SLIRP, has provided important insight into SRA's mechanism of action and potentially offers new opportunities to target NR signaling pathways for therapeutic gain. Here we outline advances in the field of NR coregulator biology, with a bias on recent progress in understanding SRA-protein interactions.

  • The RNA Coregulator SRA, its Binding Proteins and Nuclear Receptor Signalling Activity
    2007
    Co-Authors: Shane M. Colley, Peter J. Leedman
    Abstract:

    Nuclear receptor (NR) Coregulators are key modulators of hormone signalling. The discovery of Steroid receptor RNA Activator (SRA), a coregulator that is active as an RNA, transformed thinking in the field of hormone action. The subsequent identification of SRA-binding coregulator proteins, including p72, SHARP and more recently SLIRP, has provided important insight into SRA's mechanism of action, and potentially offers new opportunities to target NR signalling pathways for therapeutic gain. This review outlines advances in the field of NR coregulator biology, with an emphasis on recent progress in understanding SRA-protein interactions.

Elizabeth M Wilson - One of the best experts on this subject based on the ideXlab platform.

  • androgen receptor regulation by histone methyltransferase suppressor of variegation 3 9 homolog 2 and melanoma antigen a11
    Molecular and Cellular Endocrinology, 2017
    Co-Authors: Emily B Askew, John T. Minges, Amanda B Parris, Elizabeth M Wilson
    Abstract:

    Abstract Androgen receptor (AR) transcriptional activity depends on interactions between the AR NH2-terminal region and transcriptional Coregulators. A yeast two-hybrid screen of a human testis library using predicted α-helical NH2-terminal fragment AR-(370-420) as bait identified suppressor of variegation 3-9 homolog 2 (SUV39H2) histone methyltransferase as an AR interacting protein. SUV39H2 interaction with AR and the AR coregulator, melanoma antigen-A11 (MAGE-A11), was verified in two-hybrid, in vitro glutathione S-transferase affinity matrix and coimmunoprecipitation assays. Fluorescent immunocytochemistry colocalized SUV39H2 and AR in the cytoplasm without androgen, in the nucleus with androgen, and with MAGE-A11 in the nucleus independent of androgen. Chromatin immunoprecipitation using antibodies raised against SUV39H2 demonstrated androgen-dependent recruitment of AR and SUV39H2 to the androgen-responsive upstream enhancer of the prostate-specific antigen gene. SUV39H2 functioned cooperatively with MAGE-A11 to increase androgen-dependent AR transcriptional activity. SUV39H2 histone methyltransferase is an AR coactivator that increases androgen-dependent transcriptional activity through interactions with AR and MAGE-A11.

  • Androgen receptor regulation by histone methyltransferase Suppressor of variegation 3-9 homolog 2 and Melanoma antigen-A11
    Molecular and cellular endocrinology, 2016
    Co-Authors: Emily B Askew, John T. Minges, Amanda B Parris, Suxia Bai, Elizabeth M Wilson
    Abstract:

    Androgen receptor (AR) transcriptional activity depends on interactions between the AR NH2-terminal region and transcriptional Coregulators. A yeast two-hybrid screen of a human testis library using predicted α-helical NH2-terminal fragment AR-(370-420) as bait identified suppressor of variegation 3-9 homolog 2 (SUV39H2) histone methyltransferase as an AR interacting protein. SUV39H2 interaction with AR and the AR coregulator, melanoma antigen-A11 (MAGE-A11), was verified in two-hybrid, in vitro glutathione S-transferase affinity matrix and coimmunoprecipitation assays. Fluorescent immunocytochemistry colocalized SUV39H2 and AR in the cytoplasm without androgen, in the nucleus with androgen, and with MAGE-A11 in the nucleus independent of androgen. Chromatin immunoprecipitation using antibodies raised against SUV39H2 demonstrated androgen-dependent recruitment of AR and SUV39H2 to the androgen-responsive upstream enhancer of the prostate-specific antigen gene. SUV39H2 functioned cooperatively with MAGE-A11 to increase androgen-dependent AR transcriptional activity. SUV39H2 histone methyltransferase is an AR coactivator that increases androgen-dependent transcriptional activity through interactions with AR and MAGE-A11.

  • primate specific melanoma antigen a11 regulates isoform specific human progesterone receptor b transactivation
    Journal of Biological Chemistry, 2012
    Co-Authors: Shifeng Su, John T. Minges, Amanda J. Blackwelder, Steven L Young, Gail Grossman, L. Yuan, Elizabeth M Wilson
    Abstract:

    Progesterone acting through the progesterone receptor (PR) and its Coregulators prepares the human endometrium for receptivity to embryo implantation and maintains pregnancy. The menstrual cycle-dependent expression of melanoma antigen-A11 (MAGE-11) in the mid-secretory human endometrium suggested a novel function in human PR signaling. Here we show that MAGE-11 is an isoform-specific coregulator responsible for the greater transcriptional activity of human PR-B relative to PR-A. PR was recruited to progesterone response regions of progesterone-regulated FK506-binding protein 5 (FKBP5) immunophilin and small Ras family G protein cell growth inhibitor RASD1 genes. Expression of MAGE-11 lentivirus shRNA in human endometrial Ishikawa cells expressing PR-B showed that MAGE-11 is required for isoform-specific PR-B up-regulation of FKBP5. In contrast, MAGE-11 was not required for progesterone up-regulation of RASD1 in endometrial cells expressing the PR-A/B heterodimer. Target gene specificity of PR-B depended on the synergistic actions of MAGE-11 and p300 mediated by the unique PR-B NH2-terminal 110LLXXVLXXLL119 motif that interacts with the MAGE-11 F-box region in a phosphorylation- and ubiquitinylation-dependent manner. A progesterone-dependent mechanism is proposed in which MAGE-11 and p300 increase PR-B up-regulation of the FKBP5 gene. MAGE-11 down-regulates PR-B, similar to the effects of progesterone, and interacts with FKBP5 to stabilize a complex with PR-B. We conclude that the coregulator function of MAGE-11 extends to isoform-specific regulation of PR-B during the cyclic development of the human endometrium.

Chawnshang Chang - One of the best experts on this subject based on the ideXlab platform.

  • The Use of Phage Display Technique for the Isolation of Androgen Receptor Interacting Peptides with (F/W)XXL(F/W) and FXXLY New Signature Motifs
    Journal of Biological Chemistry, 2003
    Co-Authors: Cheng Lung Hsu, Yuh-ling Chen, Yueh-chiang Hu, Hank Lin, Shuyuan Yeh, Huei Ju Ting, Xin Wang, Chawnshang Chang
    Abstract:

    Early studies suggested that the signature motif, LXXLL, within steroid hormone receptor p160 Coregulators may play important roles for the mediation of receptor-coregulator interaction. Interestingly, several androgen receptor (AR) Coregulators, such as ARA70 and ARA55, may not use such a unique motif to mediate their coregulator activity. Here we apply the phage display technique to identify some new signature motifs, (F/W)XXL(F/W) and FXXLY (where F is phenylalanine, W is tryptophan, L is leucine, Y is tyrosine, and X is any amino acid) that can influence the interaction between AR and AR Coregulators. Sequence analyses found that several AR Coregulators, such as ARA70, ARA55, ARA54, and FHL2, contain FXXL(F/Y) motifs. Both glutathione S-transferase pull-down assays and transient transfection reporter assays demonstrate that these AR Coregulators may use the FXXL(F/Y) motif to interact with AR and exert their AR coregulator activity. Exchanging the amino acid of Phe, Trp, or Tyr in this newly identified signature motif cluster may influence these peptides to interact with AR. The motif-containing peptides, as well as ARA70 or ARA54, may require selective flanking sequences for the better interaction with AR. In addition to influencing the AR transactivation, these motifs in AR-interacting peptides/proteins were also able to influence the AR N-/C-terminal interaction. Together, our data suggest that AR interacting peptides and/or AR Coregulators may utilize the (F/W)XXL(F/W) and FXXLY motifs to mediate their interaction with AR and exert their influences on the AR transactivation.

  • Androgen Receptor (AR) Coregulators: An Overview
    Endocrine reviews, 2002
    Co-Authors: Cynthia A. Heinlein, Chawnshang Chang
    Abstract:

    The biological action of androgens is mediated through the androgen receptor (AR). Androgen-bound AR functions as a transcription factor to regulate genes involved in an array of physiological processes, most notably male sexual differentiation and maturation, and the maintenance of spermatogenesis. The transcriptional activity of AR is affected by Coregulators that influence a number of functional properties of AR, including ligand selectivity and DNA binding capacity. As the promoter of target genes, Coregulators participate in DNA modification, either directly through modification of histones or indirectly by the recruitment of chromatin-modifying complexes, as well as functioning in the recruitment of the basal transcriptional machinery. Aberrant coregulator activity due to mutation or altered expression levels may be a contributing factor in the progression of diseases related to AR activity, such as prostate cancer. AR demonstrates distinct differences in its interaction with Coregulators from other steroid receptors due to differences in the functional interaction between AR domains, possibly resulting in alterations in the dynamic interactions between coregulator complexes.

  • Identification and Characterization of a Novel Androgen Receptor Coregulator ARA267-α in Prostate Cancer Cells
    The Journal of biological chemistry, 2001
    Co-Authors: Xin Wang, Cheng Lung Hsu, Shuyuan Yeh, Liang Wang, Tzuying Chiang, Yue Yang, Yinglu Guo, Chawnshang Chang
    Abstract:

    Abstract The androgen receptor (AR) is a member of the steroid receptor superfamily that binds to the androgen response element to regulate target gene transcription. AR may need to interact with some selected Coregulators for maximal or proper androgen function. Here we report the isolation of a new AR coregulator with a calculated molecular mass of 267 kDa named the androgen receptor-associated protein 267-α (ARA267-α). ARA267-α contains 2427 amino acids, including one Su(var)3-9,Enhancer-of-zeste, and Trithorax (SET) domain, two LXXLL motifs, three nuclear translocation signal (NLS) sequences, and four plant homodomain (PHD) finger domains. Northern blot analyses reveal that ARA267-α is expressed predominantly in the lymph node as 13- and 10-kilobase transcripts. HepG2 is the only cell line tested that does not express ARA267-α. Yeast two-hybrid and glutathione S-transferase pull-down assays show that both the N and C terminus of ARA267-α interact with the AR DNA- and ligand-binding domains. Unlike other Coregulators, such as CBP, which enhance the interaction between the N and C terminus of AR, we found that ARA267-α had little influence on the interaction between the N and C terminus of AR. Luciferase and chloramphenicol acetyltransferase assays show that ARA267-α can enhance AR transactivation in a dihydrotestosterone-dependent manner in PC-3 and H1299 cells. ARA267-α can also enhance AR transactivation with other Coregulators, such as ARA24 or PCAF, a histone acetylase, in an additive manner. Together, our data demonstrate that ARA267-α is a new AR coregulator containing the SET domain with an exceptionally large molecular mass that can enhance AR transactivation in prostate cancer cells.

  • Identification and characterization of androgen receptor associated Coregulators in prostate cancer cells.
    Journal of biological regulators and homeostatic agents, 2001
    Co-Authors: Erik R. Sampson, Shuyuan Yeh, Hong-chiang Chang, Wang X, Chawnshang Chang
    Abstract:

    The androgen receptor (AR) is a member of the nuclear receptor (NR) superfamily that mediates the effects of androgens on target tissues. Over the last decade, it has become apparent that NRs require accessory factors for optimal activation of target gene expression. Numerous NR Coregulators have been identified, with diverse structures and potential mechanisms of coregulation, creating an increasingly complicated picture of NR action. Due to the expanding complexity of the coregulator field, this review will focus on the AR ligand-binding domain (LBD) and N-terminal interacting proteins identified by our lab. The LBD-interacting proteins ARA70, ARA55 and ARA54 were first characterized and ARA70 was found to have a relatively higher specificity for the AR in human prostate cancer DU145 cells. Characterization of the functional relationship between the AR and these Coregulators indicated that ARA70 and ARA55 could enhance the androgenic effects of 17beta-estradiol (E2) and hydroxyflutamide (HF), an antiandrogen commonly used in the treatment of prostate cancer. ARA160, an AR N-terminal interacting protein also known as TATA element modulatory factor (TMF), was subsequently shown to cooperate with ARA70 in enhancing AR activity. Another AR N-terminal interacting protein, ARA24, interacted with the poly-Q tract, a region within the N-terminus of the AR linked to Kennedy's disease (X-linked spinal and bulbar muscular atrophy). More recently, our lab has identified ARA267, a SET domain containing protein, and supervillin, an F-actin binding protein, as AR Coregulators. Collectively, the data from these studies indicate that these Coregulators are necessary for optimal AR transactivation. Interruption of the interaction between AR and these proteins may serve as a new therapeutic target in the treatment of prostate cancer.

  • Functional analysis of androgen receptor N-terminal and ligand binding domain interacting Coregulators in prostate cancer
    Journal of the Formosan Medical Association = Taiwan yi zhi, 2000
    Co-Authors: Shuyuan Yeh, Cheng Lung Hsu, Yuh-ling Chen, Erik R. Sampson, Dong Kun Lee, Eungseok Kim, Hong-chiang Chang, Saleh Altuwaijri, Chawnshang Chang
    Abstract:

    Several new androgen receptor (AR) Coregulators, including ARA70, ARA55, ARA54, ARA160 and ARA24, associated with the N-terminal or the ligand-binding domain (LBD) of AR, have been identified by our group. We first identified the AR-LBD Coregulators ARA70, ARA55, and ARA54. Our previous reports suggest that ARA70 can enhance the androgenic activity of 17 beta-estradiol (E2) and antiandrogens toward AR. It is of interest to compare and determine if the specificity of sex hormones and antiandrogens can be modulated by different Coregulators. Our results indicate that, ARA70 is the best coregulator for increasing the androgenic activity of E2. Only ARA70 and ARA55 were able to significantly increase the androgenic activity of hydroxyflutamide, the active metabolite of a widely-used antiandrogen for the treatment of prostate cancer. Furthermore, our results suggest that among the LBD Coregulators, ARA70 has a relatively high specificity for AR in the human prostate cancer cell line DU145. Together, our data suggest that the androgenic activity of some sex hormones and antiandrogens can be modulated by selective AR coactivators. In addition to the AR-LBD associated proteins, ARA24 and ARA160 have been identified as AR Coregulators, interacting with the AR N-terminal instead of the LBD. Functional analysis revealed that the AR N-terminal coregulator ARA160 could cooperate with the AR LBD-associated coregulator ARA70. Our data indicate that ARA24 could also interact with AR, and that this binding is decreased by an expanding poly-glutamine (Q) length within AR. The length of the poly-Q stretch in the AR N-terminal domain is inversely correlated with the transcriptional activity of AR. Our data suggest that optimal AR transactivation may require interaction of AR with AR Coregulators. The identification of factors or peptides that can interrupt androgen-mediated AR-ARA interactions may be useful in the development of better antiandrogens for treating androgen-related diseases, such as prostate cancer.