Regulation of androgen receptor and histone deacetylase 1 by Mdm2-mediated ubiquitylation.
Regulation of androgen receptor and histone deacetylase 1 by Mdm2-mediated ubiquitylation.
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DOI：
10.1093/nar/gki141
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发表时间：
2005
影响因子：
14.9
通讯作者：
Robson CN
中科院分区：
文献类型：
--
作者：
Gaughan L;Logan IR;Neal DE;Robson CN
雄激素受体（AR）是核激素受体转录因子家族的一员，在调节雄激素依赖性和非依赖性肿瘤形成相关基因的表达中起关键作用。AR的调节是通过含组蛋白乙酰转移酶（HAT）的共激活蛋白或组蛋白去乙酰化酶1 （HDAC1）的交替结合来实现的。控制AR稳定性的因素也可能构成一个重要的调节机制，这一观点已被发现证实，AR是mdm2介导的泛素化和蛋白水解的直接靶点。通过染色质免疫沉淀（ChIP）和re-ChIP分析，我们发现在LNCaP前列腺癌细胞中，Mdm2与AR和HDAC1在活性雄激素反应性PSA启动子上相关。此外，我们证明了mdm2介导的AR和HDAC1的修饰催化了蛋白质的不稳定并减弱了AR的活性，这表明AR和HDAC1的泛素化可能是调节AR功能的另一种机制。我们还发现，HDAC1和Mdm2协同作用，减少AR共激活因子Tip60的HAT活性减弱的AR介导的转录，这表明乙酰化状态和受体泛素化在AR调节中存在相互作用。总之，我们的数据表明Mdm2在调节AR转录体组分中的新作用。
The androgen receptor (AR) is a member of the nuclear hormone receptor family of transcription factors and plays a critical role in regulating the expression of genes involved in androgen-dependent and -independent tumour formation. Regulation of the AR is achieved by alternate binding of either histone acetyltransferase (HAT)-containing co-activator proteins, or histone deacetylase 1 (HDAC1). Factors that control AR stability may also constitute an important regulatory mechanism, a notion that has been confirmed with the finding that the AR is a direct target for Mdm2-mediated ubiquitylation and proteolysis. Using chromatin immunoprecipitation (ChIP) and re-ChIP analyses, we show that Mdm2 associates with AR and HDAC1 at the active androgen-responsive PSA promoter in LNCaP prostate cancer cells. Furthermore, we demonstrate that Mdm2-mediated modification of AR and HDAC1 catalyses protein destabilization and attenuates AR sactivity, suggesting that ubiquitylation of the AR and HDAC1 may constitute an additional mechanism for regulating AR function. We also show that HDAC1 and Mdm2 function co-operatively to reduce AR-mediated transcription that is attenuated by the HAT activity of the AR co-activator Tip60, suggesting interplay between acetylation status and receptor ubiquitylation in AR regulation. In all, our data indicates a novel role for Mdm2 in regulating components of the AR transcriptosome.
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