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: 9109664
• 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/9109664
• 关键词: Address; Affect; Automobile Driving; Binding; Biochemical; Biogenesis; Cardiovascular Diseases; Cell Maintenance; Cell Proliferation; Cell physiology; Cells; Chromatin; Complex; DNA Sequence Alteration; DNA biosynthesis; Data; Defect; Diabetes Mellitus; Disease; Embryonic Development; Environment; Eukaryotic Cell; Gene Expression; Gene Expression Process; 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; epigenetic regulation; histone modification; human disease; mRNA Decay; man; 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）：养分和能量可用性是驱动细胞生长和增殖的关键决定因素。但是，将营养和能级传播到控制细胞生长和增殖的基因表达机制的机制仍然很少了解。雷帕霉素（TOR）途径的靶标是从萌芽酵母到人发现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必需的基因表达。该途径在许多疾病中受到失调，包括癌症，糖尿病，肥胖和多种神经系统综合征。因此，Tor对人类健康至关重要。该提案将使用萌芽的酵母模型系统来检查TOR途径如何信号向进化保守的转录共调节复合物CCR4-NOT来调节基因表达过程对细胞生长和增殖必不可少。 CCR4-not是哺乳动物胚胎发生和胚胎干细胞维持所必需的，CCR4不存在与癌症，肥胖和心血管疾病有关。因此，定义TOR如何利用CCR4来调节基因表达将具有广泛的生物医学含义。该提案的目的是描述TOR如何调节CCR4-不磷酸化和复杂组成。 AIM II将解决CCR4的TOR调节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如何使用CCR4-not-不是促进核糖体RNA的表达和加工，这是核糖体产生及最终蛋白质合成所必需的TOR调节过程。该提案完成后，将如何通过CCR4信号信号来控制细胞生长和增殖必不可少的基因表达。