Tip60 and histone deacetylase 1 regulate androgen receptor activity through changes to the acetylation status of the receptor.
Tip60 and histone deacetylase 1 regulate androgen receptor activity through changes to the acetylation status of the receptor.
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DOI：
10.1074/jbc.m203423200
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发表时间：
2002-07-19
影响因子：
4.8
通讯作者：
Robson, CN
中科院分区：
文献类型：
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作者：
Gaughan, L;Logan, IR;Robson, CN
雄激素受体（AR）是核激素受体超家族的一员，被认为在前列腺癌的发展中起着重要作用。AR是一种激素依赖性转录因子，可激活许多雄激素应答基因的表达。含有组蛋白乙酰转移酶的蛋白质通过激发组蛋白乙酰化，促进启动子进入转录机制，从而增加了包括核激素受体在内的几种转录因子的活性。相反，组蛋白去乙酰化酶（hdac）已被确定可以降低组蛋白乙酰化水平，并与各种转录因子的转录抑制有关。我们之前已经证明Tip60 （tat相互作用蛋白，60 kDa）是AR的一个良好的共激活蛋白。在这里，我们表明Tip60直接使AR乙酰化，我们证明这是Tip60介导的转录的必要条件。为了确定AR功能抑制的机制，我们证明了AR活性被HDAC1的组蛋白去乙酰化酶活性特异性下调。此外，通过哺乳动物双杂交和免疫沉淀实验，我们发现AR和HDAC1相互作用，提示HDAC1直接下调AR活性。在染色质免疫沉淀实验中，我们提供了AR、Tip60和HDAC1在内源性AR响应的PSA启动子上形成三聚体复合物的证据，这表明AR的乙酰化和去乙酰化是调节转录活性的重要机制。
The androgen receptor (AR), a member of the nuclear hormone receptor superfamily, is thought to play an important role in the development of prostate cancer. The AR is a hormone-dependent transcription factor that activates expression of numerous androgen-responsive genes. Histone acetyltransferase-containing proteins have been shown to increase activity of several transcription factors, including nuclear hormone receptors, by eliciting histone acetylation, which facilitates promoter access to the transcriptional machinery. Conversely, histone deacetylases (HDACs) have been identified which reduce levels of histone acetylation and are associated with transcriptional repression by various transcription factors. We have previously shown tat Tip60 (Tat-interactive protein, 60 kDa) is a bona fie co-activator protein for the AR. Here we show that Tip60 directly acetylates the AR, which we demonstrate is a requisite for Tip60-mediated transcription. To define a mechanism for repression of AR function, we demonstrate that AR activity is specifically down-regulated by the histone deacetylase activity of HDAC1. Furthermore, using both mammalian two-hybrid and immunoprecipitation experiments, we show that AR and HDAC1 interact, suggestive of a direct role for down-regulation of AR activity by HDAC1. In chromatin immunoprecipitation assays, we provide evidence that AR, Tip60, and HDAC1 form a trimeric complex upon the endogenous AR-responsive PSA promoter, suggesting that acetylation and deacetylation of the AR is an important mechanism for regulating transcriptional activity.