Mechanisms of transcription coregulator usage by the target of rapamycin pathway

描述（由申请人提供）：营养和能量可用性是驱动细胞生长和增殖的关键决定因素。然而，营养和能量水平传递到控制细胞生长和增殖的基因表达机制的机制仍然知之甚少。雷帕霉素靶蛋白（target of rapamycin，TOR）信号通路是一条从芽殖酵母到人类的进化保守的信号通路，它响应于营养和能量水平来调控细胞生长和增殖所必需的基因表达。这一途径在许多疾病中失调，包括癌症、糖尿病、肥胖和多种神经综合征。因此，职权范围对人类健康至关重要。该提案将使用芽殖酵母模型系统来研究TOR通路如何向进化上保守的转录共调控复合物Ccr 4-Not发出信号，以调控细胞生长和增殖所必需的基因表达过程。Ccr 4-Not是哺乳动物胚胎发育和胚胎干细胞维持所必需的，Ccr 4-Not缺陷与癌症、肥胖和心血管疾病有关。因此，确定TOR如何利用Ccr 4-Not调节基因表达将具有广泛的生物医学意义。本提案的目的I将描述TOR如何调节Ccr 4-Not磷酸化和复合物组成。目的II将阐述TOR如何调控Ccr 4-Not调控组蛋白基因表达，这是DNA复制和细胞增殖的必要步骤。目的III将分析TOR如何利用Ccr 4-Not来促进核糖体RNA的表达和加工，这是一个重要的TOR调节过程，是核糖体产生和最终蛋白质合成所必需的。在完成该提案后，将定义TOR途径如何通过Ccr 4-Not转录共调节复合物发出信号以控制细胞生长和增殖所必需的基因表达。

DESCRIPTION (provided by applicant): Nutrient and energy availability are key determinants for driving cell growth and proliferation. However, the mechanisms by which nutrient and energy levels are transmitted to the gene expression machinery controlling cell growth and proliferation are still poorly understood. The target of rapamycin (TOR) pathway is an evolutionarily conserved signaling pathway found from budding yeast to man. TOR responds to nutrient and energy levels to control gene expression necessary for cell growth and proliferation. This pathway is deregulated in many diseases, including cancer, diabetes, obesity and multiple neurological syndromes. As such, TOR is of fundamental importance to human health. This proposal will use a budding yeast model system to examine how the TOR pathway signals to the evolutionarily conserved transcriptional co-regulatory complex, Ccr4-Not, to regulate gene expression processes essential for cell growth and proliferation. Ccr4-Not is required for mammalian embryogenesis and embryonic stem cell maintenance and Ccr4-Not defects are linked to cancer, obesity and cardiovascular disease. Therefore, defining how TOR utilizes Ccr4-Not to regulate gene expression will have wide-ranging biomedical implications. Aim I of this proposal will be to delineate how TOR regulates Ccr4-Not phosphorylation and complex composition. Aim II will address how TOR regulation of Ccr4-Not controls histone gene expression which is a necessary step in DNA replication and cell proliferation. Aim III will analyze how TOR uses Ccr4-Not to promote the expression and processing of ribosomal RNAs, an essential TOR-regulated process necessary for ribosome production and ultimately, protein synthesis. Upon the completion of this proposal, how the TOR pathway signals through the Ccr4-Not transcriptional co-regulatory complex to control gene expression essential for cell growth and proliferation will have been defined.