Regulation Code by Nuclear Receptor Coactivator ASC-2

描述（由申请人提供）：转录激活是“共激活子代码”的一种功能，其中多个共激活子根据单个靶基因和细胞类型的背景以组合方式起作用。我们最近纯化并表征了一种名为ASCOM （ASC-2复合体）的新型转录辅激活子复合物，本提案侧重于ASCOM介导核受体（nr）转录激活的详细分子机制。该复合体的ASC-2组分是在该实验室和至少五个其他实验室独立分离的NR辅助激活蛋白。ASCOM还含有ALR-1/MLL2 （Trx/ALL-1/ mll1相关蛋白）及其剪接异构体ALR-2、alr样蛋白HALR （MLL3）、ASH2、Rb结合蛋白RBQ-3等。ALRol/ALR-2和HALR具有组蛋白甲基转移酶（HMT）活性，ASCOM代表了第一个与这一重要组蛋白修饰功能相关的NR共激活子复合物。该建议的中心假设是ASCOM与SRC/CBP、TRAP/DRIP、Swi/Snf和N-CoR/SMRT/HDAC等其他复合体一起作为rna转录激活的关键介质。本文拟研究1)ASCOM不同成分在NR转录激活过程中的详细生化功能，2)ASCOM与其他共激活因子在NR转录激活过程中的组合共激活子代码，重点研究Swi/Snf和CBP/p300。我们最近使用转基因小鼠对ASC-2的生物学功能进行了表征，发现了ASC-2在许多重要过程中的潜在作用，包括脂质和胆固醇稳态的代谢调节。基因扩增以及ASC-2和其他ASCOM成分在几种人类癌症中的表达改变也表明在肿瘤发生中起作用。因此，我们相信这里提出的研究不仅将为充分理解rna调节转录的分子机制提供重要的一步，而且还可能为治疗重要的人类疾病提供新的治疗方法。

DESCRIPTION (provided by applicant): Transcriptional activation is a function of a "coactivator code" in which multiple coactivators function in a combinatorial manner dictated by the context of the individual target gene and cell type. We have recently purified and characterized a novel transcriptional coactivator complex called ASCOM (for the ASC-2 complex), and this proposal focuses on the detailed molecular mechanisms by which ASCOM mediates transcriptional activation by nuclear receptors (NRs). The ASC-2 component of this complex is an NR coactivator protein independently isolated in this and at least five other laboratories. ASCOM also contains ALR-1/MLL2 (Trx/ALL-1/MLLl-related protein) and its splicing isoform ALR-2, ALR-like protein HALR (MLL3), ASH2, the Rb binding protein RBQ-3 and others. ALRol/ALR-2 and HALR exhibit histone methyltransferase (HMT) activity, and ASCOM represents the first NR coactivator complex associated with this important histone modification function. The central hypothesis of this proposal is that ASCOM, along with other complexes such as SRC/CBP, TRAP/DRIP, Swi/Snf and N-CoR/SMRT/HDAC, serves as a key mediator of transcriptional activation by NRs. Studies are proposed to test 1) the detailed biochemical function of different constituents of ASCOM during NR transcriptional activation and 2) the combinatorial coactivator code of ASCOM with other coactivators in NR transactivation, with an emphasis on Swi/Snf and CBP/p300. Our recent characterization of the biological functions of ASC-2 using transgenic mice has identified potential roles in many important processes, including metabolic regulation of lipid and cholesterol homeostasis. Gene-amplification as well as alterations of expression of ASC-2 and other ASCOM components in several human cancers also suggest a role in tumorigenesis. Thus, we believe that the studies proposed here will not only provide an important step toward fully understanding the molecular mechanisms by which NRs regulate transcription but could also lead to novel therapeutic approaches to the treatment of important human diseases.