Hatchell Esme C, Colley Shane M, Beveridge Dianne J, Epis Michael R, Stuart Lisa M, Giles Keith M, Redfern Andrew D, Miles Lauren E C, Barker Andrew, MacDonald Louisa M, Arthur Peter G, Lui James C K, Golding Jemma L, McCulloch Ross K, Metcalf Cecily B, Wilce Jackie A, Wilce Matthew C J, Lanz Rainer B, O'Malley Bert W, Leedman Peter J
Laboratory for Cancer Medicine, The University of Western Australia Centre for Medical Research, Western Australian Institute for Medical Research, Western Australia.
Mol Cell. 2006 Jun 9;22(5):657-68. doi: 10.1016/j.molcel.2006.05.024.
Steroid receptor RNA activator (SRA), the only known RNA coactivator, augments transactivation by nuclear receptors (NRs). We identified SLIRP (SRA stem-loop interacting RNA binding protein) binding to a functional substructure of SRA, STR7. SLIRP is expressed in normal and tumor tissues, contains an RNA recognition motif (RRM), represses NR transactivation in a SRA- and RRM-dependent manner, augments the effect of Tamoxifen, and modulates association of SRC-1 with SRA. SHARP, a RRM-containing corepressor, also binds STR7, augmenting repression with SLIRP. SLIRP colocalizes with SKIP (Chr14q24.3), another NR coregulator, and reduces SKIP-potentiated NR signaling. SLIRP is recruited to endogenous promoters (pS2 and metallothionein), the latter in a SRA-dependent manner, while NCoR promoter recruitment is dependent on SLIRP. The majority of the endogenous SLIRP resides in the mitochondria. Our data demonstrate that SLIRP modulates NR transactivation, suggest it may regulate mitochondrial function, and provide mechanistic insight into interactions between SRA, SLIRP, SRC-1, and NCoR.
类固醇受体RNA激活剂（SRA）是唯一已知的RNA共激活因子，可增强核受体（NRs）的反式激活作用。我们鉴定出SLIRP（SRA茎环相互作用RNA结合蛋白）与SRA的一个功能亚结构STR7结合。SLIRP在正常组织和肿瘤组织中均有表达，含有一个RNA识别基序（RRM），以SRA和RRM依赖的方式抑制NR反式激活，增强他莫昔芬的作用，并调节SRC-1与SRA的结合。SHARP是一种含RRM的共抑制因子，也与STR7结合，与SLIRP一起增强抑制作用。SLIRP与另一个NR共调节因子SKIP（位于14号染色体q24.3）共定位，并减少SKIP增强的NR信号传导。SLIRP被募集到内源性启动子（pS2和金属硫蛋白），后者以SRA依赖的方式募集，而NCoR启动子的募集则依赖于SLIRP。大多数内源性SLIRP存在于线粒体中。我们的数据表明SLIRP调节NR反式激活，提示其可能调节线粒体功能，并为SRA、SLIRP、SRC-1和NCoR之间的相互作用提供了机制上的见解。
