Mokecular Mechanism of Nuclear Receptor-mediated Chromatin Remodeling

核受体（Nuclear receptors，NR）被认为通过两种类型的共激活复合物以配体依赖的方式调节其靶基因的转录：第一种包括组蛋白乙酰基转移酶（HAT），如CBP/p300、PCAF或p160蛋白家族，而第二种是大的多蛋白复合物，称为DRIP/TRAP/SMCC，没有HAT活性。在这里，我们确定了一个大的人（h）多蛋白辅激活因子复合物激活转录所必需的雌激素受体α（Erα）。该复合物含有GCN 5 HAT、c-Myc相互作用蛋白TRRAP/PAF 400、30 kDa TATA结合蛋白（TBP）相关因子（TAF_<11>30）和其它亚基，类似于已知的TFTC（含无TBP的TAF<11>_）型HAT复合物（hTFTC、hPCAF、hSTAGA和酵母佐贺）。Erα或其他NR与TRRAP的三个LXXLL基序之间存在直接和配体依赖性的相互作用。TRRAP与GCN 5共表达可增强Erα的转运功能，纯化的GCN 5 HAT复合物可增强配体Erα的转运功能。此外，反义TRRAP RNA的表达抑制乳腺癌细胞的雌激素依赖性细胞生长。因此，分离的TFTC型HAT复合物充当NR功能的第三类共激活剂复合物。

Nuclear receptors (NRs) ware thought to regulate transcription of their target genes in a ligand-dependent way through two types of co-activator complexes : The first includes histone acetyl transferases (HATs), such as CBP/p300, PCAF or the p160 family of proteins, while the second is large multiprotein complexes, called DRIP/TRAP/SMCC without HAT activity. Here we identified a large human (h) multiprotein co-activator complex necessary for activation of transcription by the estrogen receptor a (Erα). This complex contains the GCN5 HAT, the c-Myc interacting protein TRRAP/PAF400, the 30 kDa TATA binding protein (TBP) associated factor (TAF_<11>30), and other subunits, similarly to known TFTC (TBP-free TAF_<11>-containing)-type HAT complexes (hTFTC, hPCAF, hSTAGA and yeast SAGA). Direct and ligand-dependent interactions between Erα, or other NRs, and three LXXLL motifs of TRRAP were identified. In the cells Erα transaction was enhanced by co-expression of TRRAP with GCN5, and the purified GCN5 HAT complex potentiated the transaction function of liganded Erα in vitro. Moreover, expression of anti-sense TRRAP RNA inhibited oestrogen-dependent cell growth of breast cancer cells. Thus, the isolated TFTC-type HAT complex acts as a third class of co-activator complex for NR function.