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TOR Complex 2 and sphingolipid biosynthesis.

TOR 复合物 2 和鞘脂生物合成。

基本信息

批准号：
8293157
负责人：
TED POWERS
金额：
$ 30.5万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8293157
关键词：
Address Affect Aging Anabolism Apoptosis Area Biochemical Biological Models Biomedical Research Catabolism Cell Culture Techniques Cell Proliferation Cells Ceramides Complex Disease Drug effect disorder Enzymes Equilibrium Eukaryota Eukaryotic Cell Family Genetic Goals Health Human Investigation Laboratories Link Lipids Malignant Neoplasms Mammalian Cell Mediating Metabolism Molecular Mutation Orthologous Gene Pathway interactions Pharmaceutical Preparations Phosphotransferases Physiological Play Process Production Proliferating Property Protein Isoforms Protein-Serine-Threonine Kinases Regulation Relative (related person)Role Saccharomycetales Set protein Signal Pathway Signal Transduction Sirolimus Sphingolipids Stress System Therapeutic Time Work Yeasts base cancer cell cancer therapy cell growth cell killing cell transformation dihydroceramide desaturase enzyme activity in vitro activity in vivo insight interest long chain fatty acid member neoplastic cell novel protein complex research study response tumorigenesis

项目摘要

Our long-term goal is to understand the molecular mechanisms by which cell growth is controlled in eukaryotic cells, in particular by the rapamycin-sensitive TOR kinase. Recent studies in several laboratories, including my own, have demonstrated that TOR functions as part of two distinct protein complexes, TORC1 and TORC2, where TORC1 is uniquely inhibited by rapamycin. Rapamycin is proving to have many beneficial therapeutic applications, including as a potential anti-cancer treatment, and so there is great interest in understanding more about the cellular role of TOR. Because it is not a direct target for rapamycin, however, the cellular role of TORC2 has remained much less well characterized than TORC1. Accordingly, alternative approaches are needed to study TORC2. To this end, we have discovered recently that a mutation within a TORC2-specific component affects dramatically the earliest steps of the sphingolipid pathway, in particular the de novo formation of ceramides, in budding yeast. More recently, we have extended this observation to mammalian cells, where we have shown that inhibiting mTORC2 function in HEK393T cells also leads to a reduction in the activity of the enzyme ceramide synthase. Ceramides, as well as their immediate precursors, the fatty acid long chain bases (LCBs), represent classes of lipids that are increasingly recognized as playing crucial roles in malignant cell growth, tumorigenesis, as well as aging. Thus, both TOR and ceramide biosynthesis represent important areas important for biomedical research, and our findings indicate for the first time that they are intimately linked. In the experiments proposed here, we will identify the mechanism by which ceramide synthesis is regulated by TORC2, including a detailed analysis of the ceramide synthase, and will begin to delineate the signaling pathway involved in this regulation. For this purpose, we will use both yeast and mammalian cells as complementary experimental systems. We will also address the role that mTORC2 signaling plays in the response of certain cancer cells to chemotherapeutic drugs, which are known to increase the de novo synthesis of ceramides and contribute to the cell killing action of these drugs by inducing ceramide-mediated apoptosis.

我们的长期目标是了解细胞在真核细胞中，生长受到雷帕霉素敏感的 TOR激酶。包括我自己在内的几个实验室最近的研究表明，证明TOR作为两种不同蛋白质复合物的一部分发挥作用， TORC1和TORC2，其中TORC1被雷帕霉素唯一抑制。事实证明，雷帕霉素具有许多有益的治疗应用，包括作为一种潜在的抗癌治疗方法，了解更多关于TOR的细胞作用。因为它不是一个直接的然而，作为雷帕霉素的靶点，TORC 2的细胞作用仍然很大不像TORC1那么好描述。因此，替代方法是需要研究TORC2。为此，我们最近发现， TORC2特异性组分内的突变显著影响最早的鞘脂途径的步骤，特别是从头形成神经酰胺，在芽殖酵母中。最近，我们扩展了这一观察，在哺乳动物细胞中，我们已经证明，抑制mTORC 2功能， HEK393T细胞也导致神经酰胺酶活性降低合成酶神经酰胺，以及它们的直接前体，脂肪酸长链碱基（LCB）代表越来越多地被认识到的脂质类在恶性细胞生长、肿瘤发生以及衰老中起着关键作用。因此，TOR和神经酰胺生物合成都代表了重要的领域，生物医学研究，我们的研究结果首次表明，他们是紧密相连在这里提出的实验中，我们将确定神经酰胺合成受TORC 2调节，包括对神经酰胺合成的详细分析。神经酰胺合酶，并将开始描绘参与的信号通路，这个规定。为此，我们将使用酵母和哺乳动物细胞作为补充实验系统。我们还将讨论 mTORC2信号传导在某些癌细胞对肿瘤的反应中起作用。化学治疗药物，已知其增加肿瘤的从头合成。神经酰胺，并有助于这些药物的细胞杀伤作用，神经酰胺介导的凋亡。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Redesigning TOR Kinase to Explore the Structural Basis for TORC1 and TORC2 Assembly.

DOI：
10.3390/biom8020036
发表时间：
2018-06-01
期刊：
Biomolecules
影响因子：
5.5
作者：
Hill A;Niles B;Cuyegkeng A;Powers T
通讯作者：
Powers T

Selective ATP-competitive inhibitors of TOR suppress rapamycin-insensitive function of TORC2 in Saccharomyces cerevisiae.

TOR 的选择性 ATP 竞争性抑制剂可抑制酿酒酵母中 TORC2 的雷帕霉素不敏感功能。

DOI：
10.1021/cb300058v
发表时间：
2012
期刊：
ACS chemical biology
影响因子：
4
作者：
Liu,Qingsong;Ren,Tao;Fresques,Tara;Oppliger,Wolfgang;Niles,BradJ;Hur,Wooyoung;Sabatini,DavidM;Hall,MichaelN;Powers,Ted;Gray,NathanaelS
通讯作者：
Gray,NathanaelS

TOR complex 2-Ypk1 signaling maintains sphingolipid homeostasis by sensing and regulating ROS accumulation.

TOR复合物2-ippK1信号传导通过传感和调节ROS积累来保持鞘脂稳态。