CCAR1, a key regulator of mediator complex recruitment to nuclear receptor transcription complexes.
CCAR1, a key regulator of mediator complex recruitment to nuclear receptor transcription complexes.
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DOI：
10.1016/j.molcel.2008.08.001
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发表时间：
2008-08-22
期刊：
影响因子：
16
通讯作者：
Stallcup, Michael R.
中科院分区：
文献类型：
--
作者：
Kim, Jeong Hoon;Yang, Catherine K.;Heo, Kyu;Roeder, Robert G.;An, Woojin;Stallcup, Michael R.
DNA结合的转录因子募集许多共激活蛋白来重塑染色质并激活转录。据信介体复合物将RNA聚合酶II募集到大多数蛋白质编码基因。通常认为，介体亚基与DNA结合转录因子的相互作用负责介体募集到启动子。然而，我们在这里报告说，核受体（NR）的中介招聘需要一个新的辅激活蛋白，CCAR 1（细胞周期和凋亡调节因子1）。CCAR 1与介体和p160共激活因子复合物的组分相关联，并响应于适当的激素被募集到内源性NR靶基因。内源性CCAR 1水平的降低抑制了乳腺癌细胞内源性NR靶基因的表达，抑制了乳腺癌细胞内源性NR靶基因的表达。因此，CCAR 1调节关键增殖诱导基因的表达。CCAR 1还作为p53共激活因子发挥作用，表明其在转录调控中具有更广泛的作用。
DNA-bound transcription factors recruit many coactivator proteins to remodel chromatin and activate transcription. The Mediator complex is believed to recruit RNA polymerase II to most protein-encoding genes. It is generally assumed that interaction of Mediator subunits with DNA-binding transcription factors is responsible for Mediator recruitment to promoters. However, we report here that Mediator recruitment by nuclear receptors (NR) requires a new coactivator protein, CCAR1 (cell cycle and apoptosis regulator 1). CCAR1 associates with components of the Mediator and p160 coactivator complexes and is recruited to endogenous NR target genes in response to the appropriate hormone. Reduction of endogenous CCAR1 levels inhibited hormone-induced expression of endogenous NR target genes, hormone-induced recruitment of Mediator components and RNA polymerase II to target gene promoters, and estrogen-dependent growth of breast cancer cells. Thus, CCAR1 regulates expression of key proliferation inducing genes. CCAR1 also functions as a p53 coactivator, suggesting a broader role in transcriptional regulation.
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