Mechanisms of transcription coregulator usage by the target of rapamycin pathway

描述(由申请人提供)：营养和能量供应是推动细胞生长和增殖的关键决定因素。然而，营养和能量水平被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(TOR)途径的靶点是一条从萌芽酵母到人的进化保守的信号通路。Tor对营养和能量水平做出反应，以控制细胞生长和增殖所需的基因表达。这一途径在许多疾病中都被解除了调控，包括癌症、糖尿病、肥胖症和多种神经综合征。因此，TOR对人类健康至关重要。本提案将使用萌芽酵母模型系统来研究TOR途径如何向进化上保守的转录共调控复合体CCR4-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。CCR4-NOT是哺乳动物胚胎发育和胚胎干细胞维持所必需的，CCR4-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CCR4-Not来调控基因表达将具有广泛的生物医学意义。这项提案的目的一将描述TOR如何调节CCR4-而不是磷酸化和复杂成分。AIM II将阐述CCR4-NOT的TOR调控如何控制组蛋白基因的表达，这是DNA复制和细胞增殖中的一个必要步骤。目的III将分析TOR如何利用CCR4-Not促进核糖体RNA的表达和加工，这是TOR调节核糖体生产和最终蛋白质合成所必需的过程。在这一提议完成后，TOR通路如何通过CCR4-NOT转录共调控复合体来控制细胞生长和增殖所必需的基因表达将被定义。

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.