Pax6 represses androgen receptor-mediated transactivation by inhibiting recruitment of the coactivator SPBP.
Pax6 represses androgen receptor-mediated transactivation by inhibiting recruitment of the coactivator SPBP.
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PAX6通过抑制共激活因子SPBP的募集来抑制雄激素受体介导的反式激活。
DOI：
10.1371/journal.pone.0024659
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Johansen T
中科院分区：
文献类型：
--
作者：
Elvenes J;Thomassen EI;Johnsen SS;Kaino K;Sjøttem E;Johansen T
雄激素受体（AR）在男性生殖系统的发育和维持以及前列腺癌的病因学中具有中心作用。最近有报道称，转录因子Pax 6可作为AR的阻遏物，并在前列腺癌细胞中高度甲基化。SPBP是一种转录调节因子，以前已被证明可以增强Pax 6的活性。在这项研究中，我们已经确定SPBP作为AR的转录共激活因子。我们还表明，Pax 6抑制SPBP介导的增强AR活性的AR靶基因probasin启动子，一个镇压，部分逆转SPBP的表达增加。增强Pax 6的表达减少了与probasin启动子相关的SPBP的量，当在HeLa细胞中通过ChIP测定时。我们绘制了AR和SPBP，AR和Pax 6的DNA结合结构域的相关蛋白质之间的相互作用。进一步的结合研究表明，Pax 6和SPBP竞争结合AR。这些结果表明，Pax 6通过置换和/或抑制共激活因子向AR靶启动子的募集来抑制AR活性。了解AR辅激活因子的抑制机制可以产生用于治疗前列腺癌的分子靶向药物。
The androgen receptor (AR) has a central role in development and maintenance of the male reproductive system and in the etiology of prostate cancer. The transcription factor Pax6 has recently been reported to act as a repressor of AR and to be hypermethylated in prostate cancer cells. SPBP is a transcriptional regulator that previously has been shown to enhance the activity of Pax6. In this study we have identified SPBP to act as a transcriptional coactivator of AR. We also show that Pax6 inhibits SPBP-mediated enhancement of AR activity on the AR target gene probasin promoter, a repression that was partly reversed by increased expression of SPBP. Enhanced expression of Pax6 reduced the amount of SPBP associated with the probasin promoter when assayed by ChIP in HeLa cells. We mapped the interaction between both AR and SPBP, and AR and Pax6 to the DNA-binding domains of the involved proteins. Further binding studies revealed that Pax6 and SPBP compete for binding to AR. These results suggest that Pax6 represses AR activity by displacing and/or inhibiting recruitment of coactivators to AR target promoters. Understanding the mechanism for inhibition of AR coactivators can give rise to molecular targeted drugs for treatment of prostate cancer.
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