Cell-line and tissue-specific signatures of androgen receptor-coregulator transcription
Cell-line and tissue-specific signatures of androgen receptor-coregulator transcription
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DOI：
10.1007/s00109-006-0081-1
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发表时间：
2006-11-01
影响因子：
4.7
通讯作者：
Holterhus, Paul-Martin
中科院分区：
文献类型：
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作者：
Bebermeier, Jan-Hendrik;Brooks, James D.;Holterhus, Paul-Martin
正常生殖器皮肤成纤维细胞（GSF）和人前列腺癌细胞LNCaP已被广泛用作生殖器起源的细胞培养模型来研究雄激素受体（AR）信号传导。我们证明LNCaP对雄激素表现出可重复的反应，通过使用代表大约32,000个独特人类基因的dna微阵列进行评估，而一些独立的GSF菌株实际上没有反应。我们发现LNCaP细胞表达明显更高的AR蛋白水平，可能导致观察到的雄激素反应性差异。然而，先前的数据表明，与LNCaP相比，ar表达水平本身并不能决定人类GSF的雄激素反应性。我们假设AR共调节因子的表达水平的细胞特异性差异可能导致雄激素反应的差异，并且可能通过比较LNCaP和gsf来发现。利用加拿大mcgill - AR共调节因子数据库（http://www.mcgill.ca/androgendb），我们在微阵列平台上鉴定了61个AR共调节基因，这些基因由282个转录本代表，用于测量LNCaP和GSF细胞的转录本谱。代表33个不同基因的48个ar共调节转录物的基线表达水平在GSF和LNCaP之间显示出显著差异，其中4个我们通过逆转录酶聚合酶链反应证实。与LNCaP相比，GSFs表现出AR共调节因子的显著上调，这些共调节因子可以作为AR交易激活的抑制因子，如caveolin 1。对最近发表的代表35种不同人体组织的115个微阵列的综合数据集的分析揭示了与个体相关组织群（例如淋巴系统和生殖器组织、大脑）分离的AR共调节因子的组织特异性特征。我们的数据表明存在细胞系和组织特异性表达模式的分子与记录AR协同调节功能。因此，AR共调节因子的差异表达模式可以改变雄激素在发育、生理和疾病中的组织特异性和多样性。
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.