The role of hepatocyte nuclear factor-3α (forkhead box A1) and androgen receptor in transcriptional regulation of prostatic genes
The role of hepatocyte nuclear factor-3α (forkhead box A1) and androgen receptor in transcriptional regulation of prostatic genes
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DOI：
10.1210/me.2003-0020
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发表时间：
2003-08-01
影响因子：
--
通讯作者：
Matusik, RJ
中科院分区：
文献类型：
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作者：
Gao, N;Zhang, JF;Matusik, RJ
雄激素和间充质因子是前列腺上皮发育和功能活动的重要细胞外信号。对参与前列腺分化的上皮内决定因子知之甚少。在这里，我们发现肝细胞核因子- 3α (hnf - 3α)是一种内胚层发育因子，对于雄激素受体（AR）介导的前列腺基因激活至关重要。两个HNF-3顺式调控元件在大鼠前盆腔（PB）基因启动子中被鉴定出来，每一个都紧连着一个雄激素反应元件。值得注意的是，在前列腺特异性抗原（PSA）基因核心增强子中观察到类似的HNF-3和AR结合位点组织，提示其具有共同的功能机制。破坏这些HNF-3基序的突变显著地消除了PB和PSA活性的最大雄激素诱导。在表达内源性HNF-3alpha的LNCaP细胞中，过表达c端缺失的突变体HNF-3alpha会抑制雄激素诱导的启动子活性。体内染色质免疫沉淀显示，hnf - 3α在PSA增强子上的占据可以发生在雄激素缺乏的情况下，在配体结合的AR募集之前。通过免疫沉淀检测到hnf - 3α和AR的物理相互作用，并通过谷胱甘肽- s转移酶下拉确认。这种相互作用是通过AR的dna结合域/铰链区和HNF-3alpha的叉头结构域直接介导的。此外，在表达分化标志物（PSA和PB）的人和小鼠前列腺上皮细胞中，HNF-3alpha表达强烈，但HNF-3beta或HNF-3gamma不表达。综上所述，这些数据支持一个模型，其中来自细胞谱系和细胞外环境的调节线索协调建立了前列腺分化反应。
Androgens and mesenchymal factors are essential extracellular signals for the development as well as the functional activity of the prostate epithelium. Little is known of the intraepithelial determinants that are involved in prostatic differentiation. Here we found that hepatocyte nuclear factor-3alpha (HNF-3alpha), an endoderm developmental factor, is essential for androgen receptor (AR)-mediated prostatic gene activation. Two HNF-3 cis-regulatory elements were identified in the rat probasin (PB) gene promoter, each immediately adjacent to an androgen response element. Remarkably, similar organization of HNF-3 and AR binding sites was observed in the prostate-specific antigen (PSA) gene core enhancer, suggesting a common functional mechanism. Mutations that disrupt these HNF-3 motifs significantly abolished the maximal androgen induction of PB and PSA activities. Overexpressing a mutant HNF-3alpha deleted in the C-terminal region inhibited the androgen-induced promoter activity in LNCaP cells where endogenous HNF-3alpha is expressed. Chromatin immunoprecipitation revealed in vivo that the occupancy of HNF-3alpha on PSA enhancer can occur in an androgen-depleted condition, and before the recruitment of ligand-bound AR. A physical interaction of HNF-3alpha and AR was detected through immunoprecipitation and confirmed by glutathione-S-transferase pull-down. This interaction is directly mediated through the DNA-binding domain/hinge region of AR and the forkhead domain of HNF-3alpha. In addition, strong HNF-3alpha expression, but not HNF-3beta or HNF-3gamma, is detected in both human and mouse prostatic epithelial cells where markers (PSA and PB) of differentiation are expressed. Taken together, these data support a model in which regulatory cues from the cell lineage and the extracellular environment coordinately establish the prostatic differentiated response.