title: Specific properties of a C-terminal truncated androgen receptor detected in hormone refractory prostate cancer.
abstract: Mutations in the human androgen receptor (AR) gene that lead to C-terminus truncated AR variants are frequently detected in prostate cancer (PC). These AR variants lack both the ligand-binding domain (LBD) and the AF-2 region. The aim of this study was to delineate the alternative mechanisms that lead to the activation of such AR variants as they are unresponsive to hormone stimulation, and to outline consequences of the loss of the LBD/AF-2 region on their functional properties. By using an MMTV-luciferase reporter construct and LY294002, UO126, or ZD1839, inhibitor of PI3K, MEK1/2, and EGFR signaling pathway respectively, we demonstrated that phosphorylation was required for full transcriptional activities of one these AR variants, the Q640X mutant AR. Western-blot analyses confirmed that these inhibitors affect the phosphorylation status of this AR variant. Furthermore, studies of the intranuclear colocalization of the Q640X AR with cofactors, such as CBP, GRIP-1, and c-Jun, reveal that the transcriptional complex that forms around the mutant AR is different to that formed around the wild type AR. We demonstrated that CBP and c-Jun are highly recruited by the mutant AR, and this leads to an unexpected activation of AP-1, NFAT, and NFkappaB transcriptional activities. Similar enhanced activities of these transcription factors were not observed with the wild type AR. The importance of the LBD/AF-2 for the regulation of AR transcriptional activities, the impact of the presence of such AR variants on PC cells proliferation and survival, and on progression to androgen independence are discussed.
authors.affiliation: Laboratoire de Cancerologie Experimentale et de Radiobiologie, Strasbourg, France.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Lapouge
authors.forename: Gemma
authors.initials: G
authors.lastname: Marcias
authors.forename: Eva
authors.initials: E
authors.lastname: Erdmann
authors.forename: Pascal
authors.initials: P
authors.lastname: Kessler
authors.forename: Marion
authors.initials: M
authors.lastname: Cruchant
authors.forename: Sebastian
authors.initials: S
authors.lastname: Serra
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Bergerat
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Céraline
mesh_terms: D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D014644:Genetic Variation; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011944:Receptors, Androgen / Q000235:genetics* / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
chemical_list: D066246:ErbB Receptors; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011944:Receptors, Androgen; D018808:Transcription Factor AP-1; C410798:AR protein, human; C482128:MAP2K2 protein, human; C512478:EGFR protein, human; C482125:MAP2K1 protein, human