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: 5.11). 12/2006; 84(11):919-31. DOI: 10.1007/s00109-006-0081-1
Source: PubMed


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 ( http://www.mcgill.ca/androgendb ), 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.

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Available from: James D Brooks, Aug 05, 2014
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    • "If the coregulators act in concert, up to 2.5 × 1013 potential distinct coregulator-receptor complexes might be possible according to Lonard and O’Malley [35]. The differential expression pattern of coregulators will be highly cell specific and thereby lead to a cell-specific modification pattern of androgen action [36] (Figure 2). "
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    • "The first discrepancy may be related to decreased ability of ligand-bound AR to interact with the machinery necessary for nuclear import in HeLa cells, or to the presence of a competing androgen-binding protein in the cytosol but not the nucleus of HeLa, so that higher concentrations of androgen would be necessary to complete functions that take place in the cytoplasm, such as nuclear import, but not in the nucleus, such as hyperspeckling or transcriptional activity. The third discrepancy may be related to decreased transcriptional activity in GSF reported by others [39], or to the preponderance in these cell lines of AR co-repressors [40]. "
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    • "We hypothesize that the different sets of AR co-regulators between LNCAP and PC3-AR cells can explain the difference in the AR response programs between the PC3-AR and the LNCaP models. Cell-line and tissue-specific androgen receptor-coregulators have been documented by Bebermeier et al. [33]. "
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