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维甲酸受体活性中受体相互作用蛋白140的特性分析

Characterization of receptor-interacting protein 140 in retinoid receptor activities.

作者信息

Lee C H, Wei L N

机构信息

Department of Pharmacology, University of Minnesota Medical School, Minneapolis, Minnesota 55455, USA.

出版信息

J Biol Chem. 1999 Oct 29;274(44):31320-6. doi: 10.1074/jbc.274.44.31320.

Abstract

Receptor-interacting protein 140 (RIP140) contains multiple receptor interaction domains and interacts with retinoic acid receptors in a ligand-dependent manner. Nine LXXLL receptor-interacting motifs are organized into two clusters within this molecule, each differentially interacting with retinoic acid receptor (RAR) and retinoid X receptor (RXR). RAR interacts with the 5' cluster, whereas RXR interacts with both clusters. Additionally, a third ligand-dependent receptor-interacting domain is assigned to the very C terminus of this molecule, which contains no LXXLL motif. In mammalian cells, receptor heterodimerization is required for efficient interaction of RAR/RXR with RIP140. Furthermore, the heterodimeric, holoreceptors cooperatively interact with RIP140, which requires the activation function 2 domains of both receptors. By using different retinoic acid reporter systems, it is demonstrated that RIP140 strongly suppresses retinoic acid induction of reporter activities, but coactivator SRC-1 enhances it. Furthermore, an intrinsic repressive activity of RIP140 is demonstrated in a GAL4 fusion system. Unlike receptor corepressor, which interacts with antagonist-bound RAR/RXRs, RIP140 does not interact with antagonist-occupied RAR/RXR dimers. These data suggest that RIP140 represents a third coregulator category that is able to suppress the activation of certain agonist-bound hormone receptors.

摘要

受体相互作用蛋白140(RIP140)含有多个受体相互作用结构域,并以配体依赖的方式与视黄酸受体相互作用。九个LXXLL受体相互作用基序在该分子内组织成两个簇,每个簇与视黄酸受体(RAR)和视黄醇X受体(RXR)有不同的相互作用。RAR与5'簇相互作用,而RXR与两个簇都相互作用。此外,第三个配体依赖的受体相互作用结构域位于该分子的最C末端,该末端不含LXXLL基序。在哺乳动物细胞中,RAR/RXR与RIP140的有效相互作用需要受体异二聚化。此外,异二聚体全受体与RIP140协同相互作用,这需要两个受体的激活功能2结构域。通过使用不同的视黄酸报告系统,证明RIP140强烈抑制报告基因活性的视黄酸诱导,但共激活因子SRC-1增强了这种诱导。此外,在GAL4融合系统中证明了RIP140的内在抑制活性。与与拮抗剂结合的RAR/RXR相互作用的受体共抑制因子不同,RIP140不与拮抗剂占据的RAR/RXR二聚体相互作用。这些数据表明,RIP140代表了第三类共调节因子,能够抑制某些激动剂结合的激素受体的激活。

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