Cell-line and tissue-specific signatures of androgen receptor-coregulator transcription.

Department of Pediatric and Adolescent Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany.
Journal of Molecular Medicine (Impact Factor: 4.74). 12/2006; 84(11):919-31. DOI: 10.1007/s00109-006-0081-1
Source: PubMed

ABSTRACT Normal genital skin fibroblasts (GSF) and the human prostate carcinoma cell line LNCaP have been used widely as cell culture models of genital origin to study androgen receptor (AR) signaling. We demonstrate that LNCaP shows a reproducible response to androgens as assessed using cDNA-microarrays representing approximately 32,000 unique human genes, whereas several independent GSF strains are virtually unresponsive. We show that LNCaP cells express markedly higher AR protein levels likely contributing to the observed differences of androgen responsiveness. However, previous data suggested that AR-expression levels alone do not determine androgen responsiveness of human GSF compared to LNCaP. We hypothesized that cell-specific differences in expression levels of AR coregulators might contribute to differences in androgen responsiveness and might be found by comparing LNCaP and GSFs. Using the Canadian McGill-database of AR coregulators ( ), we identified 61 AR-coregulator genes represented by 282 transcripts on our microarray platform that was used to measure transcript profiles of LNCaP and GSF cells. Baseline expression levels of 48 AR-coregulator transcripts representing 33 distinct genes showed significant differences between GSF and LNCaP, four of which we confirmed by reverse transcriptase polymerase chain reaction. Compared to LNCaP, GSFs displayed significant upregulation of AR coregulators that can function as repressors of AR-transactivation, such as caveolin 1. Analysis of a recently published comprehensive dataset of 115 microarrays representing 35 different human tissues revealed tissue-specific signatures of AR coregulators that segregated with ontogenetically related groups of tissues (e.g., lymphatic system and genital tissues, brain). Our data demonstrate the existence of cell-line and tissue-specific expression patterns of molecules with documented AR coregulatory functions. Therefore, differential expression patterns of AR coregulators could modify tissue-specificity and diversity of androgen actions in development, physiology, and disease.

Download full-text


Available from: James D Brooks, Aug 05, 2014
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Paediatric endocrinology is a medical specialty dealing with variations of physical growth and sexual development in childhood. Genetic anomalies that can cause disorders of sexual development in children are rare. Given this, sharing and collaboration on the small number of cases that occur is needed by clinical experts in the field. The EU-funded EuroDSD project ( is one such collaboration involving clinical centres and clinical and genetic experts across Europe. Through the establishment of a virtual research environment (VRE) supporting sharing of data and a variety of clinical and bioinformatics analysis tools, EuroDSD aims to provide a research infrastructure for research into disorders of sex development. Security, ethics and information governance are at the heart of this infrastructure. This paper describes the infrastructure that is being built and the inherent challenges in security, availability and dependability that must be overcome for the enterprise to succeed.
    9th IEEE/ACM International Symposium on Cluster Computing and the Grid, CCGrid 2009, Shanghai, China, 18-21 May 2009; 01/2009
  • [Show abstract] [Hide abstract]
    ABSTRACT: Störungen der Geschlechtsentwicklung (Disorders of sex development, DSD) umfassen eine sehr heterogene Gruppe angeborener Abweichungen der geschlechtlichen Determinierung und Differenzierung, die früher auch als "Intersexualität" bezeichnet wurden. Hierzu gehören sowohl chromosomale als auch monogen vererbte Störungen, die entweder primär genetisch oder aber hormonell zu einer Abweichung der Geschlechtsentwicklung führen. Bei einem Großteil der Fälle ist jedoch auch heute noch keine genaue kausale Zuordnung möglich. Die Geburt eines Kindes mit einer genitalen Fehlbildung stellt daher weiterhin eine große Herausforderung für alle Beteiligten dar. Im Vordergrund stehen neben der Diagnosestellung vor allem die Beratung und Begleitung der Betroffenen bzw. der Eltern durch ein qualifiziertes Team aus Ärzten verschiedenster Fachrichtungen sowie psychosozialen Experten. Der vorliegende Beitrag erläutert zunächst die Grundlagen der sexuellen Determinierung und Differenzierung mit den molekulargenetischen Ursachen der Abweichungen. Anschließend gehen wir auf die im Jahr 2005 verabschiedete internationale Nomenklatur zu DSD, die daraus folgende Klassifikation sowie auf diagnostische Maßnahmen und Fragen der Entscheidungsfindung ein. Neue Forschungsthemen werden vorgestellt. Disorders of sex development (DSD) include a heterogeneous group of heritable disorders of sex determination and differentiation, formerly termed "intersexuality". This includes chromosomal as well as monogenic disorders, which inhibit or change primarily genetic or endocrine pathways of normal sex development. However, in most patients affected, no definitive cause for the disorder can be found. Therefore, the birth of a child with ambiguous genitalia still represents an enormous challenge. For the structuring of diagnostic procedures, for decision making and also for therapeutic interventions a highly specialized team of physicians of different subspecialties and of experts for psychosocial care is needed to counsel parents and patients accordingly. This manuscript shall explain the genetic and molecular origins of DSD, the new DSD nomenclature, the consecutive classification and steps for diagnosis. New scientific topics on DSD are presented.
    Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz 12/2007; 50(12):1569-1577. DOI:10.1007/s00103-007-0393-5 · 1.01 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The androgen receptor (AR) and attendant signaling program regulates key components of prostate organogenesis, contributes to normal physiological functions, and influences organ-specific pathologies that include benign prostate hypertrophy and carcinoma. AR signaling regulates genetic programs in both epithelium and in cells comprising the stromal compartment of the prostate. Given that multiple cellular and tissue effects are attributable to AR signaling, increased knowledge of the AR-regulated gene expression network is central to an understanding of prostate function in health and disease. Androgen-responsive gene expression can be regulated at the level of transcription, RNA processing, RNA stability, protein translation, or protein stability. The products of these genes form part of a network of biochemical interactions leading to physiological consequences for prostate development and pathology. This review focuses on recent advances in the identification of genes regulated by androgens and the AR and provides context for their potential influence on normal prostate physiology and mechanisms of disease.