Mechanisms of transcription coregulator usage by the target of rapamycin pathway

雷帕霉素通路靶标使用转录共调节因子的机制

• 批准号: 8552300
• 负责人: Ronald Laribee
• 金额: $ 27万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-13 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8552300
• 关键词: Address; Affect; Automobile Driving; Binding; Biochemical; Biogenesis; Cardiovascular Diseases; Cell Maintenance; Cell Proliferation; Cell physiology; Cells; Chromatin; Complex; DNA biosynthesis; Data; Defect; Diabetes Mellitus; Disease; Embryonic Development; Environment; Epigenetic Process; Eukaryotic Cell; Gene Expression; Gene Expression Process; Gene Mutation; Genes; Genetic Transcription; Health; Histones; Human; Lead; Link; Malignant Neoplasms; Messenger RNA; Metabolic Diseases; Microarray Analysis; Modeling; Neurologic; Normal Cell; Nuclear Export; Nutrient; Obesity; Pathway interactions; Phosphorylation; Phosphotransferases; Polymerase; Process; Production; Protein Biosynthesis; Protein Complex Subunit; Proteomics; RNA Processing; RNA chemical synthesis; Recruitment Activity; Regulation; Ribosomal DNA; Ribosomal RNA; Ribosomes; Role; S Phase; Saccharomycetales; Signal Pathway; Signal Transduction; Sirolimus; Stimulus; Syndrome; Testing; Transcription Elongation; Transcription Initiation; Yeast Model System; Yeasts; cell growth; detection of nutrient; embryonic stem cell; histone modification; human disease; mRNA Decay; man; public health relevance; research study; response; ubiquitin ligase

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.

描述（由申请人提供）：营养和能量的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。雷帕霉素靶点（TOR）途径是一种进化保守的从芽殖酵母到人类的信号通路。TOR对营养和能量水平作出反应，以控制细胞生长和增殖所需的基因表达。在许多疾病中，包括癌症、糖尿病、肥胖症和多种神经系统综合征，这种途径都不受控制。因此，TOR对人类健康至关重要。本研究将使用出芽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体Ccr4-Not发出信号，以调节细胞生长和增殖所必需的基因表达过程。Ccr4-Not是哺乳动物胚胎发生和胚胎干细胞维持所必需的，而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调节基因表达将具有广泛的生物医学意义。本提案的目的1将是描述TOR如何调节Ccr4-Not磷酸化和复合物组成。目的II将讨论TOR调控Ccr4-Not如何控制组蛋白基因表达，这是DNA复制和细胞增殖的必要步骤。Aim 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调节核糖体产生和最终蛋白质合成所必需的重要过程。在完成这一提议后，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。