Regulation of the mTOR growth pathway by nutrients

描述(由申请人提供)： 生长(质量积累)是细胞、器官和身体大小的关键决定因素，在癌症和糖尿病等疾病中经常被解除管制。我们的长期研究目标是识别和表征控制生长的分子机制，并阐明它们在哺乳动物正常和疾病生理中的作用。我们正在研究哺乳动物的TOR(MTOR)途径，这是一个保守的信号系统，正在成为真核生物生长的关键规则，也是FDA批准的免疫抑制剂雷帕霉素的靶标。最近的临床试验表明，雷帕霉素也可能用于治疗某些癌症和自身免疫性疾病，以及防止球囊血管成形术开放的血管再狭窄。我们最近从人类细胞中纯化了一个含有mTOR的蛋白质复合体，并鉴定了几个新的蛋白质，这些蛋白质对于细胞内mTOR途径的功能是必不可少的。其中一种蛋白质，我们称之为Raptor，通过以营养调节的方式与mTOR结合来控制mTOR激酶的活性。我们的初步证据表明，mTOR-Raptor复合体不直接感受营养物质，但通过一种未知的机制(S)对线粒体通过营养物质代谢产生的信号(S)做出反应。此外，在某些人类癌细胞中，mTOR途径的调节是错乱的，以至于mTOR-Raptor关联和mTOR下游效应的活性，如S6K1，都不对营养物质或线粒体功能做出反应。为了了解营养物质如何调控mTOR生长途径，我们建议：(1)确定并表征控制mTOR-Raptor关联和途径的营养调控的翻译后机制；(2)确定我们在初步研究中发现的一种新的36 kDa mTOR结合蛋白GbetaL对营养物质调节猛禽-mTOR关联至关重要的原因；以及(3)确定在某些人类癌细胞中导致mTOR-Raptor关联和途径变得对营养不敏感的机制，并了解这种类型的解除调控在体内肿瘤形成和生长中的作用。我们的工作不仅将从根本上促进我们对哺乳动物生长调节机制的理解，还将发现可能作为药物开发靶点的新的信号机制。

DESCRIPTION (provided by applicant): Growth (mass accumulation) is a critical determinant of cell, organ, and body size and is often deregulated in diseases such as cancer and diabetes. Our long-term research goal is to identify and characterize the molecular mechanisms that control growth and to elucidate their roles in the normal and diseased physiology of mammals. We are studying the mammalian TOR (mTOR) pathway, a conserved signaling system that is emerging as a critical regular of growth in eukaryotes and is the target of the FDA-approved immunosuppressant rapamycin. Recent clinical trials indicate that rapamycin may also be useful for treating certain cancers and autoimmune diseases and for preventing the restenosis of vessels opened with balloon angioplasty. From human cells we recently purified an mTOR-containing protein complex and identified several novel proteins essential for the function of the mTOR pathway within cells. One of these proteins, which we termed raptor, controls the mTOR kinase activity by binding to mTOR in a nutrient-regulated fashion. Our preliminary evidence indicates that the mTOR-raptor complex does not sense nutrients directly but responds, through an unknown mechanism(s), to a signal(s) generated by mitochondria through the metabolism of nutrients. In addition, in certain human cancer cells the regulation of the mTOR pathway is deranged so that neither the mTOR-raptor association nor the activity of downstream effects of mTOR, such as S6K1, responds to nutrients or mitochondrial function. To understand how nutrients regulate the mTOR growth pathway we propose to: (1) identify and characterize the nutrient-regulated post-translational mechanisms that control the mTOR-raptor association and pathway; (2) determine why GbetaL, a novel 36 kDa mTOR-binding protein we discovered in our preliminary studies, is essential for nutrients to regulate the raptor-mTOR association; and (3) determine the mechanisms that cause the mTOR-raptor association and pathway to become nutrient-insensitive in certain human cancer cells and to understand the role of this type of deregulation in the formation and growth of tumors in vivo. Our work will not only lead to a fundamental advance in our understanding of the mechanisms that regulate growth in mammals, but also to the discovery of novel signaling mechanisms that are likely of value as targets for drug development.