CoAA, a nuclear receptor coactivator protein at the interface of transcriptional coactivation and RNA splicing
CoAA, a nuclear receptor coactivator protein at the interface of transcriptional coactivation and RNA splicing
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DOI：
10.1128/mcb.24.1.442-453.2004
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发表时间：
2004-01-01
影响因子：
5.3
通讯作者：
O'Malley, BW
中科院分区：
文献类型：
--
作者：
Auboeuf, D;Dowhan, DH;O'Malley, BW
我们已经证明，类固醇激素以启动子依赖的方式协调控制基因转录活性和剪接决定。我们的假设是，参与调控启动子转录活性的激素招募的辅助调节因子的子集也直接参与替代RNA剪接决定。为了深入了解转录辅助调节因子控制剪接决定的分子机制，我们将注意力集中在最近发现的辅助激活因子CoAA上。这种异质性核核糖核蛋白(HnRNP)样蛋白与转录辅助调节因子TRBP相互作用，TRBP是一种通过与激活的核受体相互作用而招募到靶向启动子的蛋白质。利用不同启动子驱动的转录和剪接报告基因，我们观察到CoAA以启动子优先的方式介导转录和剪接效应。我们将CoAA的活性与其他hnRNP相关蛋白的活性进行了比较，这些蛋白质像CoAA一样，含有两个N-端RNA识别基序(RRMS)，后面跟着一个C-端辅助结构域，并且要么参与了转录控制，要么没有参与转录控制。通过将CoAA RRMS或CoAA辅助结构域与所选蛋白质的相应结构域互换，我们发现CoAA的RRMS和辅助结构域根据启动子的不同而不同地参与转录。这有助于在类固醇激素作用过程中CoAA介导的RNA剪接中的启动子优先效应。
We have shown that steroid hormones coordinately control gene transcriptional activity and splicing decisions in a promoter-dependent manner. Our hypothesis is that a subset of hormonally recruited coregulators involved in regulation of promoter transcriptional activity also directly participate in alternative RNA splicing decisions. To gain insight into the molecular mechanisms by which transcriptional coregulators could control splicing decisions, we focused our attention on a recently identified coactivator, CoAA. This heterogeneous nuclear ribonucleoprotein (hnRNP)-like protein interacts with the transcriptional coregulator TRBP, a protein recruited to target promoters through interactions with activated nuclear receptors. Using transcriptional and splicing reporter genes driven by different promoters, we observed that CoAA mediates transcriptional and splicing effects in a promoter-preferential manner. We compared the activity of CoAA to the activity of other hnRNP-related proteins that, like CoAA, contain two N-terminal RNA recognition motifs (RRMs) followed by a C-terminal auxiliary domain and either have or have not been implicated in transcriptional control. By swapping either CoAA RRMs or the CoAA auxiliary domain with the corresponding domains of the proteins selected, we showed that depending on the promoter, the RRMs and the auxiliary domain of CoAA are differentially engaged in transcription. This contributes to the promoter-preferential effects mediated by CoAA on RNA splicing during the course of steroid hormone action.