Ras and TOR Signaling in Yeast

 描述（由申请人提供）：所有细胞都通过调整其转录和代谢谱以最佳利用可用的营养物质以及通过选择在现有环境条件下最大化其存活潜力的发育程序来响应营养物质、环境应激和其他外部信号。一个精心设计的营养和压力传感网络使细胞能够迅速适应不断变化的环境。特别是，在酵母中的两个主要的营养传感管道-Ras/蛋白激酶A（PKA）途径和雷帕霉素的目标（TORC 1）途径-连接内部细胞过程与营养状态，以调节生长特异性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，特别关注应激反应和静止。压力反应。我们已经确定，应激反应的激活抑制细胞生长，并且营养途径消除了作为刺激细胞增殖的关键功能的抑制。我们建议确定hw应力对生长的影响。此外，我们的研究已经证明了噪音在调节应激反应中的关键作用，这赋予了遗传上相同的细胞相当不同的行为。我们认为，这使得群体中的单个细胞能够对冲它们的 赌一个不确定的未来，我们计划直接测试的假设。各种不同的压力引起一个共同的核心压力反应，我们将继续确定负责这些不同的输入信号通路，并测试是否大多数或所有的压力过滤通过一个共同的传感机制。另一方面，不同的压力激活不同的，尽管重叠的，基因的队列，至少部分地通过指导结合Msn 2不同的启动子。我们将测试这是否是通过间接的协同性，其中一个转录因子的结合揭示了第二个因子通过核小体置换，最近提出的模型，但在体内未经测试的结合位点。安静。细胞一生中的绝大部分时间都处于静止、非生长状态，但我们对这种状态的了解却少得可怜。我们计划通过阐明一些静止特性来纠正这一缺点，包括大规模基因组组织和静止细胞的全局染色质结构，并确定这些新结构在多大程度上有助于饥饿条件下细胞的长期存活。我们的研究解决了困难但基本的问题，即细胞在不确定的环境中平衡生长与生存的方法，以及通过信号通路获得的信息如何告知这种平衡行为。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代谢和发育中的作用，以及这些信号网络的扰动如何导致癌症和其他疾病的不利结果。

 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.