SHP represses transcriptional activity via recruitment of histone deacetylases
SHP represses transcriptional activity via recruitment of histone deacetylases
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DOI：
10.1021/bi047308d
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发表时间：
2005-04-26
期刊：
影响因子：
2.9
通讯作者：
Jalaguier, S
中科院分区：
文献类型：
--
作者：
Gobinet, J;Carascossa, S;Jalaguier, S
孤儿受体短异源二聚体伴侣（SHP）是许多核受体的共同伴侣，在许多不同的生理事件中发挥重要作用。在以前的研究中，我们描述了SHP作为雄激素受体（AR）的强阻遏物。在此，我们讨论了其负活性对转录的作用机制。我们首先研究了SHP的内在阻遏潜力，并将两个核心阻遏结构域定位于氨基酸170-210和210-240。从GST下拉分析，我们证明了SHP和不同的组蛋白脱乙酰酶（HDACs）之间的直接相互作用，以及HDAC 1和SHP抑制结构域之间的强相互作用。我们通过显示它们的免疫共沉淀进一步支持了SHP和HDAC 1之间相互作用的证据，并提供了包含AR、SHP和HDAC 1的三元复合物存在的证据。使用HDAC活性的特异性抑制剂----阿司他丁A（TSA），证实HDAC对SHP的内在反式阻遏活性有显著贡献。最后，我们发现TSA逆转了SHP诱导的AR抑制，进一步强调了SHP和HDAC之间相互作用的相关性。后一种作用以非常相似的方式影响SHP介导的雌激素受体α（ER α）反式激活的抑制。总之，我们的研究结果表明，SHP介导的大部分抑制作用，通过招募HDAC，并表明，SHP的生理作用可能会受到HDAC抑制剂。
The orphan receptor short heterodimer partner (SHP) is a common partner for a great number of nuclear receptors, and it plays an important role in many diverse physiological events. In a previous study, we described SHP as a strong repressor of the androgen receptor (AR). Herein, we addressed the mechanism of action of its negative activity on transcription. We first investigated the intrinsic repressive potential of SHP and mapped two core repressive domains to the amino acids 170-210 and 210-240. From GST pull-down assays, we demonstrated a direct interaction between SHP and diverse histone deacetylases (HDACs) as well as a strong interaction between HDAC1 and SHP inhibitory domains. We further supported the evidence for an interaction between SHP and HDAC1 by showing their co-immunoprecipitation and provided evidence for the existence of a ternary complex comprising AR, SHP, and HDAC1. The use of trichostatin A (TSA), a specific inhibitor of HDAC activity, confirmed that HDACs significantly contribute to the intrinsic transrepressive activity of SHP. Finally, we showed that TSA reversed SHP-induced repression of AR, further emphasizing the relevance of the interaction between SHP and HDACs. This latter action affected in a very similar manner SHP-mediated repression of estrogen receptor alpha (ER alpha) transactivation. Altogether, our results indicate that SHP mediates most of its repressive effect through recruitment of HDACs and suggest that the physiological actions of SHP could be affected by HDAC inhibitors.