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首页> 外文期刊>Molecular and Cellular Biology >Developmentally Essential Protein Flightless I Is a Nuclear Receptor Coactivator with Actin Binding Activity
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Developmentally Essential Protein Flightless I Is a Nuclear Receptor Coactivator with Actin Binding Activity

机译：发育必需的蛋白质，不会飞行的我是具有肌动蛋白结合活性的核受体共激活因子。

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Hormone-activated nuclear receptors (NR) activate transcription by recruiting multiple coactivator complexes to the promoters of target genes. One important coactivator complex includes a p160 coactivator (e.g., GRIP1, SRC-1, or ACTR) that binds directly to activated NR, the histone acetyltransferase p300 or CBP, and the arginine-specific histone methyltransferase CARM1. We previously demonstrated that the coactivator function of CARM1 depends both on the methyltransferase activity and on additional unknown proteins that bind to CARM1. In this study a yeast two-hybrid screen for proteins that bind CARM1 identified the protein Flightless I (Fli-I), which has essential roles in Drosophila and mouse development. Fli-I bound to CARM1, GRIP1, and NRs and cooperated synergistically with CARM1 and GRIP1 to enhance NR function. Fli-I bound poorly to and did not cooperate with PRMT1, a CARM1-related protein arginine methyltransferase that also functions as an NR coactivator. The synergy between GRIP1, CARM1, and Fli-I required the methyltransferase activity of CARM1. The C-terminal AD1 (binding site for p300/CBP) and AD2 (binding site for CARM1) activation domains of GRIP1 contributed to the synergy but were less stringently required than the N-terminal region of GRIP1, which is the binding site for Fli-I. Endogenous Fli-I was recruited to the estrogen-regulated pS2 gene promoter of MCF-7 cells in response to the hormone, and reduction of endogenous Fli-I levels by small interfering RNA reduced hormone-stimulated gene expression by the endogenous estrogen receptor. A fragment of Fli-I that is related to the actin binding protein gelsolin enhanced estrogen receptor activity, and mutations that reduced actin binding also reduced the coactivator function of this Fli-I fragment. These data suggest that Fli-I may facilitate interaction of the p160 coactivator complex with other coactivators or coactivator complexes containing actin or actin-like proteins.
机译：激素激活的核受体（NR）通过募集多个共激活复合物到目标基因的启动子来激活转录。一种重要的共激活因子复合物包括直接与激活的NR结合的p160共激活因子（例如GRIP1，SRC-1或ACTR），组蛋白乙酰转移酶p300或CBP以及精氨酸特异性组蛋白甲基转移酶CARM1。我们以前证明了CARM1的共激活功能取决于甲基转移酶活性和与CARM1结合的其他未知蛋白。在这项研究中，对结合CARM1的蛋白质进行了酵母双杂交筛选，鉴定出了Flightless I（Fli-I）蛋白质，该蛋白质在果蝇和小鼠发育中具有重要作用。 Fli-1与CARM1，GRIP1和NR结合，并与CARM1和GRIP1协同作用以增强NR功能。 Fli-1与PRMT1的结合较弱，并且不与PRMT1结合，PRMT1是一种CARM1相关蛋白精氨酸甲基转移酶，也可作为NR共激活剂。 GRIP1，CARM1和Fli-1之间的协同作用需要CARM1的甲基转移酶活性。 GRIP1的C末端AD1（p300 / CBP的结合位点）和AD2（CARM1的结合位点）激活域有助于协同作用，但比GRIP1的N末端区域（Fli的结合位点）所需的严格性低。 -一世。响应激素，将内源性Fli-1募集到MCF-7细胞的雌激素调节的pS2基因启动子上，通过小分子干扰RNA降低内源性Fli-1水平可降低内源性雌激素受体刺激激素刺激的基因表达。与肌动蛋白结合蛋白凝溶胶蛋白有关的Fli-1片段增强了雌激素受体活性，而降低了肌动蛋白结合的突变也降低了该Fli-1片段的共激活功能。这些数据表明，Fli-1可以促进p160共激活物复合物与其他包含肌动蛋白或肌动蛋白样蛋白的共激活物或共激活物复合物的相互作用。

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