Signal Transduction to p70 S6 Kinase 1

描述（由申请人提供）：许多人类疾病是由于细胞生长（细胞质量和大小的增加）、增殖、迁移、生存和死亡的调节不当造成的。这些过程受到含有哺乳动物雷帕霉素靶蛋白（mTOR）、Lst8和Raptor的复合物（mTORC1复合物）的严格调控。S6蛋白激酶（S6K）是mTORC1的主要效应体。mTORC1/S6K信号系统是细胞多个稳态输入的中心整合点，可感知生长因子可用性、能量水平和氨基酸充足性。mTORC1/S6K信号的过度激活是几乎所有人类癌症的共同特征。mTORC1抑制剂，如雷帕霉素及其类似物，目前正在临床评估用于治疗癌症。虽然这些抑制剂显示出一些希望，但雷帕霉素不敏感的mTOR信号也会影响肿瘤的发生，并且存在反馈回路，在雷帕霉素治疗后上调生存途径。因此，需要针对该途径的其他成分的额外治疗剂。通过采用全系统的方法来定义mTORC1/S6K通路调控以及该信号系统调节各种生物过程的机制，我们希望提供见解，从而确定治疗mTORC1/S6K依赖性癌症和其他代谢紊乱的新治疗策略。

DESCRIPTION (provided by applicant): Many human diseases result from improper regulation of cell growth (an increase in cell mass and size), proliferation, migration, survival and death. These processes are critically regulated by a complex containing the mammalian target of rapamycin (mTOR), Lst8 and Raptor, called the mTORC1 complex. The S6 protein kinases (S6K) are major effectors of mTORC1. The mTORC1/S6K signaling system is the cell's central integration point for multiple homeostatic inputs, sensing growth factor availability, energy levels, and amino acid sufficiency. Hyperactivation of mTORC1/S6K signaling is a common feature of nearly all human cancers. mTORC1 inhibitors, such as rapamycin and its analogs, are currently being clinically evaluated for the treatment of cancer. While the inhibitors have exhibited some promise, rapamycin- insensitive mTOR signaling also influences tumorigenesis, and feedback loops exist that up- regulate survival pathways following rapamycin treatment. Thus, additional therapeutic agents targeting other components of this pathway are needed. By taking a systems-wide approach towards defining mTORC1/S6K pathway regulation and the mechanisms by which this signaling system modulates various biological processes, we hope to provide insights that will lead to the identification of novel therapeutic strategies for the treatment of mTORC1/S6K- dependent cancers and other metabolic disorders. Aim 1 will focus on the connection between S6K1 signaling, gene expression and cell growth control through an S6K1-specific interacting protein SKAR. Approaches are described that investigate the role of SKAR and S6K1 in the regulation of mRNA biogenesis and protein translation. This aim also sets the foundation for how we will approach all mRNA binding proteins linked to the mTORC1/S6K signaling system identified in Aim 2. The approach outlined in Aim 2 combines a variety of biochemical purification approaches with mass spectrometry analysis to identify and validate a common set of proximal upstream regulators and downstream effectors of the S6K signaling system. The use of multiple converging lines of investigation will focus our efforts on the most critical components of the pathway, allowing us to dissect how S6K regulates so many disparate cellular processes. Aim 3 utilizes RNAi-based genetic approaches to elucidate the mechanism of homeostatic regulation of the mTORC1/S6K pathway. To this end, we have developed a sensitive, high- throughput, image-based screening strategy for monitoring S6K activity in vivo. We propose to utilize this unique assay to broadly interrogate mitogen- and nutrient-regulated inputs into the mTORC1/S6K pathway. PUBLIC HEALTH RELEVANCE: We hope that the studies outlined in this proposal will deepen our understanding of the defects in mTORC1/S6K signaling that are responsible for cancer progression and cell growth-associated diseases, such as the childhood cancer predisposition syndrome Tuberous Sclerosis. These studies will also impact our understanding of other metabolic diseases linked to S6K, such as diabetes and obesity. We believe such mechanistic insight will open the door to the identification of novel therapeutic strategies for inhibiting the growth factor and/or amino acid sensing arms of the mTORC1/S6K signaling network.