Regulation Code by Nuclear Receptor Coactivator ASC-2

描述(申请人提供)：转录激活是“辅激活子密码”的一种功能，其中多个辅激活子以一种组合的方式发挥作用，这种方式取决于单个靶基因和细胞类型的背景。我们最近纯化并鉴定了一个新的转录辅助激活因子复合体，称为ASCOM(针对ASC-2复合体)，这一建议侧重于Ascom介导核受体(NRs)转录激活的详细分子机制。该复合体的ASC-2组分是一个在这个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/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和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，而ASCOM代表了与这一重要的组蛋白修饰功能相关的第一个NR辅活化子复合体。这一提议的中心假设是，Ascom与其他复合体如SRC/CBP、TRAP/Drop、Swi/SNF和N-COR/SMRT/HDAC一起，是NRS转录激活的关键调节因子。研究内容包括：1)Ascom不同组分在NR转录激活过程中的详细生化功能；2)Ascom与其他辅激活子在NR转录激活过程中的组合共激活编码，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，已经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。在几种人类癌症中，基因扩增以及ASC-2和其他ASCOM成分表达的变化也表明在肿瘤发生中发挥了作用。因此，我们相信，这里提出的研究不仅将为全面理解NRs调控转录的分子机制提供重要的一步，而且还可能导致治疗重要人类疾病的新的治疗方法。

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.