Cell-line and tissue-specific signatures of androgen receptor-coregulator transcription
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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.
KeywordsAndrogen receptor Coregulator Corepressor Coactivator Microarray
The study was supported by the Deutsche Forschungsgemeinschaft (DFG) (grants Ho 2073/2-1, 2-2 and KFO 111/1-1, and 1-2, projects C and D to P.M.H.) with support by the Medical Faculty of Lübeck of the University of Schleswig-Holstein, Germany (P.M.H and O.H.), and the Doris Duke Charitable Foundation (J.D.B.). We thank Genevieve Vidanes, Nicole Homburg, Christine Marschke, Erika Meinecke, and Dagmar Struve for excellent technical assistance. We also thank the scientists and staff of the Stanford Microarray Facility and the Stanford Microarray Database.
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