Ras and TOR signaling in yeast

描述（由申请人提供）：面对不断变化的环境条件，所有细胞都通过采取适当的代谢和发育程序来响应外部信号。这些反应发生在不同的时间尺度上，从几分钟内发生的代谢通量的变化，到一小时左右发生的转录模式的重新编程，再到几天内展开的发育程序。然而，所有这些反应都是由连接外部事件和细胞内部工作的信号通路输入的结果。我们建议继续研究酵母、Ras/PKA和Tor中主要营养信号通路在所有三个时间尺度代谢调节过程中的作用。我们最近剖析了丙酮酸激酶的变构和信号介导的翻译后调节的作用，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，通过糖酵解途径提供了非常敏感的通量调节。我们计划完成这项研究，并将类似的分析扩展到细胞中的其他关键代谢收缩点，包括脂质和氮代谢。这些研究将完善我们对信号通路在调节代谢中的作用的理解，这是评估和治疗各种慢性疾病（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于整合来自多种环境信号输入的复杂演演。此外，我们的研究已经证明了噪音在这种调节中的关键作用，它在遗传上赋予了相当多样化的行为

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.