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      Gonadotropin-Releasing Hormone Functionally Antagonizes Testosterone Activation of the Human Androgen Receptor in Prostate Cells through Focal Adhesion Complexes Involving Hic-5

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          Abstract

          Gonadotropin-releasing hormone (GnRH) analogs constitute the most widely employed medical treatment for prostatic cancer. The predominant mechanism of action is presumed to be via the inhibition of gonadotropins and resultant decrease in androgen. However, GnRH analogs have also been shown to directly inhibit prostate cancer cells both in vitro and in vivo through antiproliferative cell cycle arrest and stimulation of apoptosis. Since the GnRH receptor has been shown to affect sex steroid hormone receptor function, we considered that part of GnRH analog actions on prostate cells may be mediated through modulation of the human androgen receptor. Using a model HEK293 cell line expressing the GnRH receptor, we demonstrated a novel signalling pathway of the GnRH receptor that induces nuclear translocation of the androgen receptor that renders it transcriptionally inactive. This mechanism involves the calcium-dependent tyrosine kinase Pyk2, the non-receptor tyrosine kinase c-Src and the focal adhesion protein/steroid receptor co-factor, Hic-5. In this setting there is a GnRH-induced association and nuclear translocation of the androgen receptor with Hic-5. GnRH-induced Pyk2 activation opposed the association of Hic-5 with androgen receptor as overexpression of a dominant negative Pyk2 enhanced the GnRH-induced nuclear translocation of a green fluorescent protein-tagged human androgen receptor. GnRH-induced c-Src activation resulted in the phosphorylation of expressed Hic-5 and promoted its association with the human androgen receptor. In contrast to testosterone, GnRH-induced nuclear translocation did not transcriptionally activate the androgen receptor. We then demonstrated that GnRH can also stimulate androgen receptor mobilization in human prostate PC3, BPH-1 and LNCaP cells, and in cultured rat ventral prostate cells through the same mechanism. To determine if GnRH could antagonize androgen effects in normal tissue, we examined the effect of GnRH on rat ventral prostate organ cultures and demonstrated that GnRH can functionally antagonize the actions of testosterone on prostate cell proliferation and tissue growth. This antagonism of testosterone action by GnRH may underlie in part the capacity of GnRH receptor activation to inhibit prostate tumor growth.

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          Most cited references 35

          • Record: found
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          • Article: not found

          Pharmacology and functions of metabotropic glutamate receptors.

           J P Pin,  P. Conn (1996)
          In the mid to late 1980s, studies were published that provided the first evidence for the existence of glutamate receptors that are not ligand-gated cation channels but are coupled to effector systems through GTP-binding proteins. Since those initial reports, tremendous progress has been made in characterizing these metabotropic glutamate receptors (mGluRs), including cloning and characterization of cDNA that encodes a family of eight mGluR subtypes, several of which have multiple splice variants. Also, tremendous progress has been made in developing new highly selective mGluR agonists and antagonists and toward determining the physiologic roles of the mGluRs in mammalian brain. These findings have exciting implications for drug development and suggest that the mGluRs provide a novel target for development of therepeutic agents that could have a significant impact on neuropharmacology.
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            Gonadotropin-releasing hormone receptors.

            GnRH and its analogs are used extensively for the treatment of hormone-dependent diseases and assisted reproductive techniques. They also have potential as novel contraceptives in men and women. A thorough delineation of the molecular mechanisms involved in ligand binding, receptor activation, and intracellular signal transduction is kernel to understanding disease processes and the development of specific interventions. Twenty-three structural variants of GnRH have been identified in protochordates and vertebrates. In many vertebrates, three GnRHs and three cognate receptors have been identified with distinct distributions and functions. In man, the hypothalamic GnRH regulates gonadotropin secretion through the pituitary GnRH type I receptor via activation of G(q). In-depth studies have identified amino acid residues in both the ligand and receptor involved in binding, receptor activation, and translation into intracellular signal transduction. Although the predominant coupling of the type I GnRH receptor in the gonadotrope is through productive G(q) stimulation, signal transduction can occur via other G proteins and potentially by G protein-independent means. The eventual selection of intracellular signaling may be specifically directed by variations in ligand structure. A second form of GnRH, GnRH II, conserved in all higher vertebrates, including man, is present in extrahypothalamic brain and many reproductive tissues. Its cognate receptor has been cloned from various vertebrate species, including New and Old World primates. The human gene homolog of this receptor, however, has a frame-shift and stop codon, and it appears that GnRH II signaling occurs through the type I GnRH receptor. There has been considerable plasticity in the use of different GnRHs, receptors, and signaling pathways for diverse functions. Delineation of the structural elements in GnRH and the receptor, which facilitate differential signaling, will contribute to the development of novel interventive GnRH analogs.
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              • Record: found
              • Abstract: found
              • Article: not found

              Regulation of tyrosine kinase cascades by G-protein-coupled receptors.

              Mitogenic signaling by G-protein-coupled receptors (GPCRs) involves tyrosine phosphorylation of adaptor proteins and assembly of multiprotein Ras activation complexes. Over the past three years, three types of scaffolds for GPCR-directed complex assembly have been identified: transactivated receptor tyrosine kinases (RTKs), integrin-based focal adhesions, and GPCRs themselves. Nonreceptor tyrosine kinases play an important role in each case. The processes of GPCR desensitization and sequestration via clathrin-coated pits are also involved in signaling through the RTK- and GPCR-based scaffolds.
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                Author and article information

                Journal
                NEN
                Neuroendocrinology
                10.1159/issn.0028-3835
                Neuroendocrinology
                S. Karger AG
                0028-3835
                1423-0194
                2006
                March 2007
                28 March 2007
                : 84
                : 5
                : 285-300
                Affiliations
                aMedical Research Council Human Reproductive Sciences Unit, The Queen’s Medical Research Institute, and bArdana Bioscience, Edinburgh, UK
                Article
                98402 Neuroendocrinology 2006;84:285–300
                10.1159/000098402
                17202804
                © 2007 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 11, References: 56, Pages: 16
                Categories
                GnRH, Gonadotropins, Gonadal Steroids and Reproduction

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