Ras and TOR Signaling in Yeast

酵母中的 Ras 和 TOR 信号转导

• 批准号: 9029609
• 负责人: JAMES R. BROACH
• 金额: $ 46.84万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9029609
• 关键词: Address; Behavior; Binding; Binding Sites; Cell Cycle Regulation; Cell Proliferation; Cell Survival; Cell physiology; Cells; Chromatin Structure; Common Core; Cues; Cyclic AMP-Dependent Protein Kinases; Development; Diabetes Mellitus; Disease; Environment; Equilibrium; Eukaryotic Cell; Event; Future; Genes; Genetic Screening; Genomics; Growth; Human Biology; Individual; Knowledge; Lead; Malignant Neoplasms; Metabolism; Modeling; Noise; Nucleosomes; Nutrient; Outcome; Pathway interactions; Play; Population; Process; Property; Regulation; Research; Resources; Role; Saccharomyces; Signal Pathway; Signal Transduction; Sirolimus; Starvation; Stress; Structure; System; Testing; Yeasts; biological adaptation to stress; cell growth; cohort; detection of nutrient; genome-wide; genome-wide analysis; in vivo; metabolic profile; novel; programs; promoter; public health relevance; ras Proteins; response; transcription factor

 DESCRIPTION (provided by applicant): All cells respond to nutrients, environmental stresses and other external signals both by adjusting their transcriptional and metabolic profiles to make optimum use of the available nutrients and by selecting a developmental program that maximizes their potential for survival under the existing environmental conditions. An elaborate nutrient- and stress-sensing network allows cells to adapt rapidly to the ever changing environment. In particular, two main nutrient sensing conduits in yeast - the Ras/protein kinase A (PKA) pathway and the target of rapamycin (TORC1) pathway - connect internal cellular processes with nutrient status to regulate growth-specific events and modulate stress responses. We propose to continue our studies on these pathways and processes with particular focus on the stress response and quiescence. Stress response. We have determined that activation of the stress response inhibits cell growth and that nutrient pathways abrogate that inhibition as a critical function in stimulating cell proliferation. We propose to determine hw stress impinges on growth. In addition, our studies have demonstrated the critical role of noise in regulation of the stress response, which imparts quite diverse behaviors to genetically identical cells. We have suggested that this allows individual cells in a population to hedge their bets against an uncertain future, and hypothesis we plan to test directly. A variety of different stresses elicit a common core stress response and we will continue to identify the signaling pathways responsible for these diverse input and test whether most or all of the stresses filter through a common sensing mechanism. On the other hand, different stresses activate different, albeit overlapping, cohorts of genes, at least in part by directing binding of Msn2 to different promoters. We will test whether this is achieved through indirect cooperativity in which binding of one transcription factor unmasks the binding site for a second factor through nucleosome displacement, a model recently proposed but untested in vivo. Quiescence. Cells spend the vast majority of their lifetime in a quiescent, non-growing state and yet our understanding of this stat is woefully lacking. We plan to rectify this shortcoming by elucidating a number of quiescence properties, including the large scale genome organization and the global chromatin structure of quiescent cells and to ascertain the extent to which these novel structures contribute to the long term survival of cells under starvation conditions. Our studies address difficult but fundamental questions regarding the means by which cells balance growth versus survival in an uncertain environment and how information acquisition through signaling pathways inform that balancing act. We focus on yeast cells but our studies inform critical issues of human biology, particularly in evaluating the role of signaling networks in regulating metabolism and development and how perturbations in these signaling networks could lead to untoward outcomes resulting in cancer and other diseases.

 描述(由申请人提供)：所有细胞对营养物质、环境压力和其他外部信号的反应都是通过调整它们的转录和代谢特征以最佳地利用可用的营养物质，并通过选择在现有环境条件下最大化其生存潜力的发育计划来实现的。一个复杂的营养和压力感应网络使细胞能够迅速适应不断变化的环境。特别是，酵母中的两个主要营养传感通道-RAS/蛋白激酶A(PKA)途径和雷帕霉素靶标(TORC1)途径-将细胞内部过程与营养状态联系起来，以调节生长特定事件和调节应激反应。我们建议继续对这些途径和过程进行研究，特别是应激反应和静止。压力反应。我们已经确定，应激反应的激活抑制了细胞的生长，营养途径取消了这种抑制作为刺激细胞增殖的关键功能。我们建议确定HW应激对生长的影响。此外，我们的研究还证明了噪声在调节应激反应中的关键作用，应激反应赋予遗传相同的细胞相当不同的行为。我们已经提出，这允许群体中的单个细胞对冲他们的 押注于不确定的未来，以及我们计划直接测试的假设。各种不同的应激引起共同的核心应激反应，我们将继续确定负责这些不同输入的信号通路，并测试大多数或所有应激是否通过共同的感知机制进行渗透。另一方面，不同的压力激活了不同的基因群，尽管是重叠的，至少部分是通过引导MSN2与不同的启动子结合来实现的。我们将测试这是否通过间接协同作用实现，在间接协同作用中，一个转录因子的结合通过核小体置换揭示第二个因子的结合部位，这是最近提出的一个模型，但尚未在体内进行测试。宁静。细胞一生中的大部分时间都处于静止、不生长的状态，但我们对这种状态的了解严重不足。我们计划通过阐明一些静止的特性来纠正这一缺点，包括静止细胞的大规模基因组组织和全局染色质结构，并确定这些新结构在多大程度上有助于细胞在饥饿条件下的长期存活。我们的研究解决了困难但基本的问题，即细胞如何在不确定的环境中平衡生长和生存，以及通过信号通路获得的信息如何影响这种平衡行为。我们专注于酵母细胞，但我们的研究为人类生物学的关键问题提供了信息，特别是在评估信号网络在调节新陈代谢和发育中的作用以及这些信号网络中的扰动如何导致导致癌症和其他疾病的不良后果方面。