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Androgen Receptor

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Albert O. Brinkmann – One of the best experts on this subject based on the ideXlab platform.

  • The Androgen Receptor in prostate cancer.
    Pathology Research and Practice, 2011
    Co-Authors: Jan Trapman, Albert O. Brinkmann

    Abstract:

    Summary The Androgen Receptor is a member of the family of nuclear Receptors. In its activated form as an Androgen Receptor ligand complex (the ligand can either be testosterone or 5a-dihydrotestosterone), the Androgen Receptor is able to regulate a specific expression of target genes. The Androgen Receptor is expressed at high levels in male reproductive tissues. Mutations in the Androgen Receptor gene are the molecular cause of the Androgen insensitivity syndrome, which is characterized by an aberrant male or an apparently female phenotype. Expansion of a CAG-repeat, encoding a polymorphic glutamine stretch is the cause of a rare motor neuron disease (Kennedy’s disease). Hormonal therapy is the treatment of choice for metastatic prostate cancer. Hormone refractory prostate tumors in general still express Androgen Receptor. In a proportion of the late stage prostate tumors, somatic mutations in the Androgen Receptor gene have been described. Mutations can result in diminished ligand specificity of the Androgen Receptor. Furthermore, it has been hypothesized that ligand independent mechanisms can also be involved in Androgen Receptor activation.

  • In situ photolabelling of the human Androgen Receptor.
    Journal of Steroid Biochemistry, 2003
    Co-Authors: Albert O. Brinkmann, George G J M Kuiper, J. Bolt-de Vries, Eppo Mulder

    Abstract:

    In situ photoaffinity labelling of the human Androgen Receptor has been performed in the LNCaP (Lymph Node Carcinoma of the Prostate) cell line. The covalently labelled Receptors were identified by SDS-PAGE. Intact LNCaP cells, incubated with [3H]-R1881 and subsequently irradiated with u.v. light and directly solubilized in SDS-buffer, revealed two photolabelled protein bands at 110 and 50 kDa. Irradiation of intact cells and subsequent isolation of nuclei followed by extraction with 0.5 M NaCl resulted in one major photolabelled protein band at 110 kDa. The labelling of this band could be completely suppressed by a 100-fold molar excess of non-radioactive R1881. Photolabelling of Androgen Receptors in a cytosolic preparation of LNCaP cells after anion exchange chromatography resulted in a much lower labelling efficiency compared with the in situ labelling procedure, although the Androgen Receptor was purified 100-fold. The steroid binding domain of the human Androgen Receptor has been partially mapped with chymotrypsin and S. aureus V8 protease digestion. Proteolytic digestion with chymotrypsin of purified photoaffinity-labelled 110 kDa human Androgen Receptor resulted in the generation of a 15 kDa peptide which still contains the covalently linked hormone. It is concluded that the in situ photoaffinity labelling technique can be applied successfully for characterization of the steroid binding domain of Androgen Receptors in prostate cancer cells and in other Androgen target cells. Furthermore, it was demonstrated that the human Androgen Receptor is a monomer with a molecular mass of 110 kDa, of which the steroid binding site is confined to a 15 kDa domain.

  • Androgen Receptor abnormalities
    The Journal of Steroid Biochemistry and Molecular Biology, 2003
    Co-Authors: Albert O. Brinkmann, George G J M Kuiper, C. Ris-stalpers, H. C. J. Van Rooij, Gabriela Romalo, Mark Trifiro, Eppo Mulder, Leonard Pinsky, H.u. Schweikert, Jan Trapman

    Abstract:

    The human Androgen Receptor is a member of the superfamily of steroid hormone Receptors. Proper functioning of this protein is a prerequisite for normal male sexual differentiation and development. The cloning of the human Androgen Receptor cDNA and the elucidation of the genomic organization of the corresponding gene has enabled us to study Androgen Receptors in subjects with the clinical manifestation of Androgen insensitivity and in a human prostate carcinoma cell line (LNCaP). Using PCR amplification, subcloning and sequencing of exons 2-8, we identified a G—-T mutation in the Androgen Receptor gene of a subject with the complete form of Androgen insensitivity, which inactivates the splice donor site at the exon 4/intron 4 boundary. This mutation causes the activation of a cryptic splice donor site in exon 4, which results in the deletion of 41 amino acids from the steroid binding domain. In two other independently arising cases we identified two different nucleotide alterations in codon 686 (GAC; aspartic acid) located in exon 4. One mutation (G—-C) results in an aspartic acid—-histidine substitution (with negligible Androgen binding), whereas the other mutation (G—-A) leads to an aspartic acid—-asparagine substitution (normal Androgen binding, but a rapidly dissociating Androgen Receptor complex). Sequence analysis of the Androgen Receptor in human LNCaP-cells (lymph node carcinoma of the prostate) revealed a point mutation (A—-G) in codon 868 in exon 8 resulting in the substitution of threonine by alanine. This mutation is the cause of the altered steroid binding specificity of the LNCaP-cell Androgen Receptor. The functional consequences of the observed mutations with respect to protein expression, specific ligand binding and transcriptional activation, were established after transient expression of the mutant Receptors in COS and HeLa cells. These findings illustrate that functional errors in the human Androgen Receptor have an enormous impact on phenotype and fertility.

Michael J. Mcphaul – One of the best experts on this subject based on the ideXlab platform.

  • Functional analysis of the human Androgen Receptor promoter.
    Molecular and Cellular Endocrinology, 1996
    Co-Authors: Karen K Takane, Michael J. Mcphaul

    Abstract:

    Although Androgen Receptor levels vary widely during development, our previous studies have suggested that a single promoter is active in a number of human and rat tissues and cell lines. To examine the elements controlling Androgen Receptor expression, we performed deletion mapping and site-directed mutagenesis of the human Androgen Receptor promoter and assayed these promoter fusions in human cell lines that produce the Androgen Receptor as well as those deficient in the Androgen Receptor, both in the presence and absence of Androgen. Our studies identify a region (-74 to +87) surrounding the site of transcription initiation that constitutes the core of the Androgen Receptor promoter. When assayed in T47D cells (an AR-expressing cell line), this segment was sufficient to direct the expression of reporter genes at levels similar to that observed for larger promoter fragments, and further deletions led to an appreciable loss of promoter activity. DNA sequences surrounding this region appear to modulate the activity of this minimal promoter in a cooperative fashion. Site-directed mutagenesis and mobility shift assays demonstrated the importance of regulatory regions upstream of the transcription initiation site including an SP1 binding site and two segments with similarities to consensus HLH protein binding sites (E-boxes). Androgen treatment did not cause a decrease in activity of any of the transiently transfected promoter fusions tested, suggesting that the promoter does not contain the information necessary for autoregulation or that a posttranscriptional or posttranslational mechanism is responsible for the regulation of AR mRNA by ligand. Furthermore, the Androgen Receptor promoter fusions displayed differing transcriptional activities when transfected into two cell lines deficient in Androgen Receptor expression suggesting heterogeneity in the mechanisms responsible for this deficiency.

  • Mutations of the Androgen Receptor coding sequence are infrequent in patients with isolated hypospadias.
    The Journal of Clinical Endocrinology and Metabolism, 1995
    Co-Authors: A Alléra, J D Wilson, M A Herbst, James E. Griffin, Hans U. Schweikert, Michael J. Mcphaul

    Abstract:

    Androgen Receptor defects can cause severe hypospadias. To examine the possibility that Androgen Receptor defects are a common cause of such deficiencies, we have determined the coding sequence of the Androgen Receptor gene in nine patients with severe hypospadias. The analysis of the Androgen Receptor coding sequence predicts a normal amino acid sequence for the Androgen Receptor of eight of the nine patients, indicating that the observed defects in virilization are infrequently caused by mutations of the open-reading frame of the Androgen Receptor. These findings demonstrate the importance of family history and endocrine studies in identifying patients likely to harbor coding sequence mutations in the Androgen Receptor gene, and they serve to focus attention on other genes that may influence Androgen action in this group of patients.

  • The Androgen Receptor of the urogenital tract of the fetal rat is regulated by Androgen
    Molecular and Cellular Endocrinology, 1994
    Co-Authors: Frans M. Bentvelsen, Michael J. Mcphaul, J D Wilson, Fredrick W. George

    Abstract:

    Abstract To provide insight into Androgen-mediated virilization, we measured the Androgen Receptor in tissues of male and female rat fetuses prior to and during the period of phenotypic sex differentiation. Western immunoblotting was performed utilizing an antibody directed against the 21 amino-terminal segment of the Androgen Receptor. In immunoblots prepared from urogenital tract tissues of day 17 male and female fetal rats, this antibody specifically recognizes a 11 OK protein band characteristic of the Androgen Receptor. Androgen Receptor levels were low to undetectable in a variety of non-urogenital tract tissues. After day 18 of fetal development, the amount of Androgen Receptor decreased in female urogenital tissues, and by day 22 the amount of immunoreactive Androgen Receptor was higher in the male urogenital sinus and tubercle than in the corresponding tissues of the female. Administration of 5α-dihydrotestosterone to pregnant rats at a dose of 50 mg/kg body weight per day from day 12 to day 22 caused an increase in immunoreactive Androgen Receptor in the female urogenital sinus and tubercle to levels approaching those in male tissues. Administration of the Androgen antagonist flutamide (100 mg/kg body weight per day) during the same interval caused a reduction in Androgen Receptor level in the urogenital sinus and tubercle of the male. These findings suggest that Androgens modulate the amount of Androgen Receptor in the embryonic urogenital tract either by inducing the proliferation of Androgen-responsive cells or by increasing Androgen Receptor levels in individual cells.

Jan Trapman – One of the best experts on this subject based on the ideXlab platform.

  • The Androgen Receptor in prostate cancer.
    Pathology Research and Practice, 2011
    Co-Authors: Jan Trapman, Albert O. Brinkmann

    Abstract:

    Summary The Androgen Receptor is a member of the family of nuclear Receptors. In its activated form as an Androgen Receptor ligand complex (the ligand can either be testosterone or 5a-dihydrotestosterone), the Androgen Receptor is able to regulate a specific expression of target genes. The Androgen Receptor is expressed at high levels in male reproductive tissues. Mutations in the Androgen Receptor gene are the molecular cause of the Androgen insensitivity syndrome, which is characterized by an aberrant male or an apparently female phenotype. Expansion of a CAG-repeat, encoding a polymorphic glutamine stretch is the cause of a rare motor neuron disease (Kennedy’s disease). Hormonal therapy is the treatment of choice for metastatic prostate cancer. Hormone refractory prostate tumors in general still express Androgen Receptor. In a proportion of the late stage prostate tumors, somatic mutations in the Androgen Receptor gene have been described. Mutations can result in diminished ligand specificity of the Androgen Receptor. Furthermore, it has been hypothesized that ligand independent mechanisms can also be involved in Androgen Receptor activation.

  • Evolution of the Androgen Receptor pathway during progression of prostate cancer.
    Cancer Research, 2006
    Co-Authors: Peter J. M. Hendriksen, Jan Trapman, Natasja Dits, Koichi Kokame, Antoine Veldhoven, Wytske M. Van Weerden, Chris H. Bangma, Guido Jenster

    Abstract:

    The present work focused on the potential involvement of selective adaptations of the Androgen Receptor pathway in the initiation and progression of prostate cancer. We defined the Androgen Receptor pathway by selecting 200 genes that were Androgen responsive in prostate cancer cell lines and/or xenografts. This Androgen Receptor pathway gene signature was then used for profiling prostate cancer xenografts and patient-derived samples. Approximately half of the Androgen Receptor pathway genes were up-regulated in well-differentiated prostate cancer compared with normal prostate. Functionally distinct parts of the Androgen Receptor pathway were specifically down-regulated in high-grade cancers. Unexpectedly, metastases have down-regulated the vast majority of Androgen Receptor pathway genes. The significance of this progressive down-regulation of Androgen Receptor pathway genes was shown for a few Androgen Receptor-regulated genes. Lower mRNA expression of HERPUD1, STK39, DHCR24, and SOCS2 in primary prostate tumors was correlated with a higher incidence of metastases after radical prostatectomy. HERPUD1 mRNA expression predicted the occurrence of metastases almost perfectly. In vitro experiments showed that overexpression of the stress response gene HERPUD1 rapidly induces apoptosis. Based on the functions of the genes within the distinct subsets, we propose the following model. Enhanced Androgen Receptor activity is involved in the early stages of prostate cancer. In well-differentiated prostate cancer, the Androgen Receptor activates growth-promoting as well as growth-inhibiting and cell differentiation genes resulting in a low growth rate. The progression from low-grade to high-grade prostate carcinoma and metastases is mediated by a selective down-regulation of the Androgen Receptor target genes that inhibit proliferation, induce differentiation, or mediate apoptosis.

  • Androgen Receptor abnormalities
    The Journal of Steroid Biochemistry and Molecular Biology, 2003
    Co-Authors: Albert O. Brinkmann, George G J M Kuiper, C. Ris-stalpers, H. C. J. Van Rooij, Gabriela Romalo, Mark Trifiro, Eppo Mulder, Leonard Pinsky, H.u. Schweikert, Jan Trapman

    Abstract:

    The human Androgen Receptor is a member of the superfamily of steroid hormone Receptors. Proper functioning of this protein is a prerequisite for normal male sexual differentiation and development. The cloning of the human Androgen Receptor cDNA and the elucidation of the genomic organization of the corresponding gene has enabled us to study Androgen Receptors in subjects with the clinical manifestation of Androgen insensitivity and in a human prostate carcinoma cell line (LNCaP). Using PCR amplification, subcloning and sequencing of exons 2-8, we identified a G—-T mutation in the Androgen Receptor gene of a subject with the complete form of Androgen insensitivity, which inactivates the splice donor site at the exon 4/intron 4 boundary. This mutation causes the activation of a cryptic splice donor site in exon 4, which results in the deletion of 41 amino acids from the steroid binding domain. In two other independently arising cases we identified two different nucleotide alterations in codon 686 (GAC; aspartic acid) located in exon 4. One mutation (G—-C) results in an aspartic acid—-histidine substitution (with negligible Androgen binding), whereas the other mutation (G—-A) leads to an aspartic acid—-asparagine substitution (normal Androgen binding, but a rapidly dissociating Androgen Receptor complex). Sequence analysis of the Androgen Receptor in human LNCaP-cells (lymph node carcinoma of the prostate) revealed a point mutation (A—-G) in codon 868 in exon 8 resulting in the substitution of threonine by alanine. This mutation is the cause of the altered steroid binding specificity of the LNCaP-cell Androgen Receptor. The functional consequences of the observed mutations with respect to protein expression, specific ligand binding and transcriptional activation, were established after transient expression of the mutant Receptors in COS and HeLa cells. These findings illustrate that functional errors in the human Androgen Receptor have an enormous impact on phenotype and fertility.