Nuclear receptor interaction protein, a coactivator of androgen receptors (AR), is regulated by AR and Sp1 to feed forward and activate its own gene expression through AR protein stability.
Nuclear receptor interaction protein, a coactivator of androgen receptors (AR), is regulated by AR and Sp1 to feed forward and activate its own gene expression through AR protein stability.
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DOI：
10.1093/nar/gkm942
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发表时间：
2008-01
影响因子：
14.9
通讯作者：
Chen SL
中科院分区：
文献类型：
--
作者：
Chen PH;Tsao YP;Wang CC;Chen SL
以前，我们发现了一种新的基因，核受体相互作用蛋白（NRIP），一种转录辅因子，可以增强AR驱动的PSA启动子活性在前列腺癌细胞中的配体依赖性方式。在这里，我们研究了NRIP监管。我们从NRIP基因的转录起始位点克隆了一个413 bp的片段，该片段具有很强的启动子活性，TATA较少且富含GC，并且基于DNA序列，包含一个雄激素反应元件（ARE）和三个Sp1结合位点（Sp1-1，Sp1-2，Sp1-3）。瞬时启动子荧光素酶测定，染色质免疫沉淀和小RNA干扰分析映射ARE和Sp1-2结合位点参与NRIP启动子激活，这意味着NRIP是AR或Sp1的靶基因。AR通过ARE与NRIP启动子结合，并通过AR-Sp1复合物形成间接通过Sp1结合位点与NRIP启动子结合。因此，ARE和Sp1结合位点内的NRIP启动子可以响应雄激素诱导。更有趣的是，NRIP通过与AR形成复合物来保护AR蛋白免受蛋白酶体降解，从而发挥前馈作用增强AR驱动的NRIP启动子活性。这是第一次证明NRIP是一种新的AR靶基因，并且NRIP表达通过AR蛋白的稳定性前馈并激活其自身的表达。
Previously, we found a novel gene, nuclear receptor interaction protein (NRIP), a transcription cofactor that can enhance an AR-driven PSA promoter activity in a ligand-dependent manner in prostate cancer cells. Here, we investigated NRIP regulation. We cloned a 413-bp fragment from the transcription initiation site of the NRIP gene that had strong promoter activity, was TATA-less and GC-rich, and, based on DNA sequences, contained one androgen response element (ARE) and three Sp1-binding sites (Sp1-1, Sp1-2, Sp1-3). Transient promoter luciferase assays, chromatin immunoprecipitation and small RNA interference analyses mapped ARE and Sp1-2-binding sites involved in NRIP promoter activation, implying that NRIP is a target gene for AR or Sp1. AR associates with the NRIP promoter through ARE and indirectly through Sp1-binding site via AR–Sp1 complex formation. Thus both ARE and Sp1-binding site within the NRIP promoter can respond to androgen induction. More intriguingly, NRIP plays a feed-forward role enhancing AR-driven NRIP promoter activity via NRIP forming a complex with AR to protect AR protein from proteasome degradation. This is the first demonstration that NRIP is a novel AR-target gene and that NRIP expression feeds forward and activates its own expression through AR protein stability.
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