Ras and TOR signaling in yeast

描述(由申请人提供)：所有细胞在面对不断变化的环境条件时，通过采用适当的新陈代谢和发育计划来对外部提示做出反应。这些反应在不同的时间尺度上发生，从发生在几分钟内的代谢流量的变化，到在一个小时左右过程中发生的转录模式的重新编程，再到几天后展开的发育程序。然而，所有这些反应都是信号通路输入的结果，这些信号通路将外部事件连接到细胞的内部工作。我们建议继续研究酵母中主要的营养信号通路，Ras/PKA和Tor，在所有三个时间尺度的代谢调节过程中所起的作用。我们最近剖析了变构和信号介导的丙酮酸激酶翻译后调节的作用，丙酮酸激酶是碳分解代谢的关键收缩点，并表明这两个过程协同作用，通过糖酵解途径对通量提供极其敏感的调节。我们计划总结这项研究，并将类似的分析扩展到细胞中的其他关键代谢收缩点，包括脂肪和氮代谢。这些研究应该加深我们对信号通路在调节新陈代谢中的作用的理解，这是评估和解决各种慢性疾病(如癌症和糖尿病)的关键问题。压力反应。我们最近对主要的应激反应调节因子MSN2的研究使我们能够破译细胞用来整合来自多个环境信号的输入的复杂演算。此外，我们的研究已经证明了噪声在这一调节中的关键作用，它赋予了遗传上相当不同的行为 相同的细胞，允许一个群体中的单个细胞对冲他们对不确定未来的押注。我们计划进一步研究MSN2的调节，以确定细胞整合多个通常是竞争的信号的方法，并测试噪音在物种长期生存中的作用。宁静。细胞一生中的绝大多数时间都处于静止、不生长的状态，但我们对这种状态的了解却非常匮乏。我们计划通过阐明一些静止属性来纠正这一缺点，包括定义允许在静止状态下存活的蛋白质谱和代谢格局，并研究信号通路调节进入和退出静止状态的方式。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。 公共卫生相关性：我们的研究旨在了解细胞在应对可用资源、外部压力和环境提示时控制其生长、新陈代谢和发育的方法。我们在这项研究中产生的信息对于理解真核细胞的生长控制非常有价值，特别是在评估细胞如何适应癌症和糖尿病等病理条件下的异常内部和外部信号方面。

DESCRIPTION (provided by applicant): All cells respond to external cues by adopting appropriate metabolic and developmental programs in the face of changing environmental conditions. These responses occur on a variety of time-scales, from changes in metabolic flux that take place in minutes, to reprogramming of transcriptional patterns that happen over the course of an hour or so, to developmental programs that unfurl over days. However, all of these responses occur as a result of input from signaling pathways that connect the external events to the internal workings of the cell. We propose to continue our studies of the role of the major nutrient signaling pathways in yeast, Ras/PKA and Tor, in processes that occur at all three time scales metabolic regulation. We have recently dissected the role of allosteric and signal-mediated posttranslational regulation of pyruvate kinase, the key constriction point in carbon catabolism, and showed that both processes collaborate to provide exquisitely sensitive regulation of flux through the glycolytic pathway. We plan to conclude this study and extend similar analyses to other critical metabolic constriction points in the cell, including lipid and nitrogen metabolism. These studies should refine our understanding the role of signaling pathways in regulating metabolism, a key issue in evaluating and addressing various chronic diseases, such as cancer and diabetes. Stress response. Our recent studies of the major stress response regulator, Msn2, have allowed us to decipher the complex calculus used by cells to integrate input from multiple environmental signals. In addition, our studies have demonstrated the critical role of noise in this regulation, which imparts quite diverse behaviors to genetically identical cells, allowing the individual cells in a population to hedge their bets against an uncertain future. We plan to study further Msn2 regulation to define the means by which cells integrate multiple, often competing, signals and to test the role of noise in the long term surviva of the species. Quiescence. Cells spend the vast majority of their lifetime in a quiescent, non-growing state and yet our understanding of this state is woefully lacking. We plan to rectify this shortcoming by elucidating a number of quiescence properties, including defining the protein spectrum and metabolic landscape that allows survival during quiescence, and to examine the means by which signaling pathways regulate entry into and exit from quiescence. 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. PUBLIC HEALTH RELEVANCE: Our research is directed towards understanding the means by which cells control their growth, metabolism and development in response to available resources, external stresses and environmental cues. The information we generate in this study should be very valuable in understand growth control in eukaryotic cells, with particular impact on evaluating how cells adapt to aberrant internal and external cues in pathological conditions such as cancer and diabetes.