Regulation Code by Nuclear Receptor Coactivator ASC-2

描述（由申请人提供）：转录激活是“共激活因子密码”的功能，其中多个共激活因子以由个体靶基因和细胞类型的背景决定的组合方式起作用。我们最近纯化和表征了一种新的转录辅激活因子复合物称为ASCOM（ASC-2复合物），该建议侧重于详细的分子机制，ASCOM介导的核受体（NR）的转录激活。该复合物的ASC-2组分是在本实验室和至少五个其他实验室中独立分离的NR共激活蛋白。ASCOM还含有ALR-1/MLL 2（Trx/ALL-1/MLL 1相关蛋白）及其剪接同种型ALR-2、ALR样蛋白HALR（MLL 3）、ASH 2、Rb结合蛋白RBQ-3等。ALRol/ALR-2和HALR表现出组蛋白甲基转移酶（HMT）活性，ASCOM代表了第一个与这种重要的组蛋白修饰功能相关的NR共激活因子复合物。该提议的中心假设是ASCOM与其他复合物如SRC/CBP、TRAP/DRIP、Swi/Snf和N-CoR/SMRT/HDAC一起沿着充当NR转录激活的关键介体。建议进行研究以测试1）ASCOM的不同组分在NR转录激活过程中的详细生化功能和2）ASCOM与NR反式激活中的其他共激活因子的组合共激活因子代码，重点是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，确定了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组分在几种人类癌症中的表达改变也表明在肿瘤发生中的作用。因此，我们相信，这里提出的研究不仅将提供一个重要的一步，充分了解的分子机制，其中核受体调节转录，但也可能导致新的治疗方法来治疗重要的人类疾病。

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.