ROLE AND FUNCTION OF MAMMALIAN SPHINGOMYELIN SYNTHASES

哺乳动物鞘磷脂合成酶的作用和功能

• 批准号: 7610446
• 负责人: CHIARA LUBERTO
• 金额: $ 20.61万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7610446
• 关键词: 1,2-diacylglycerol; Anabolism; Biochemical; Biochemical Reaction; Cell Proliferation; Cell Survival; Cell physiology; Cells; Cellular Membrane; Ceramides; Class; Cloning; Computer Retrieval of Information on Scientific Projects Database; Cytokine Signaling; Diglycerides; Enzymes; Funding; Genes; Grant; Human; Inflammatory Response; Institution; Interleukin-2; Lecithin; Lipids; Mammalian Cell; NF-kappa B; Phospholipids; Phosphorylcholine; Physiological; Proteins; Regulation; Research; Research Personnel; Resources; Role; Source; Sphingomyelins; Testing; United States National Institutes of Health; Yeasts; base; knock-down; response; sphingomyelin synthase; transcription factor

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The specific aims have been slightly modified from those proposed in the original application. Sphingomyelin synthase (SMS) represents an important class of enzymes responsible for sphingomyelin (SM) biosynthesis. In particular, SMS transfers a phosphorylcholine moiety from phosphatidylcholine (PC) to ceramide to form SM and diacylglycerol (DAG). Therefore SMS not only produces SM, a crucial phospholipid for the integrity of cellular membranes but also regulates in opposing directions the levels of two bioactive lipids with opposing functions such as DAG and ceramide. Ceramide is an established negative regulator of cell proliferation whereas DAG is a well-accepted mitogenic factor. Previous studies conducted by the PI showed that activation of SM synthesis resulted in activation of NF-kB, a pivotal transcription factor, involved in the regulation of important cellular functions, including cell survival and inflammatory responses. Recently, the cloning of candidate SMSs led to the identification of two mammalian genes (SMS1 and SMS2) that, when expressed in yeast cells, encoded for proteins with SMS activity. Our preliminary results confirmed the different localization of the two putative SMSs. They also pointed to a physiologic role for both SMS1 and SMS2 as bona fide SMSs in mammalian cells. Interestingly, we found that knock-down of SMS1 impaired activation of NF-kB. Based on the potential role of SMS1 in promoting NF-kB activation and because NF-kB activation is a key component of the cellular response to cytokine signaling, we hypothesize that SMS1 regulates activation of NF-kB through modulation of the bioactive lipids controlled by its biochemical reaction, and that SMS1, through activation of NF-kB, is a determinant for cytokine signaling. In order to test our hypothesis, we will determine the biochemical function of human SMS1 and SMS2 in mammalian cells and establish the role and function of SMS1 in the regulation of NF-kB.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 中心，不一定是研究者的机构。 具体目标与原始申请中提出的目标相比略有修改。 鞘磷脂合酶 (SMS) 是负责鞘磷脂 (SM) 生物合成的一类重要酶。具体而言，SMS 将磷脂酰胆碱 (PC) 中的磷酰胆碱部分转移至神经酰胺，形成 SM 和二酰甘油 (DAG)。因此，SMS 不仅产生 SM（一种对细胞膜完整性至关重要的磷脂），而且还以相反的方向调节两种具有相反功能的生物活性脂质（例如 DAG 和神经酰胺）的水平。神经酰胺是一种公认​​的细胞增殖负调节剂，而 DAG 是一种公认​​的促有丝分裂因子。 PI 之前进行的研究表明，SM 合成的激活会导致 NF-kB 的激活，NF-kB 是一种关键转录因子，参与重要细胞功能的调节，包括细胞存活和炎症反应。 最近，候选 SMS 的克隆导致了两个哺乳动物基因（SMS1 和 SMS2）的鉴定，当它们在酵母细胞中表达时，编码具有 SMS 活性的蛋白质。 我们的初步结果证实了两个假定短信的不同本地化。他们还指出 SMS1 和 SMS2 作为真正的 SMS 在哺乳动物细胞中的生理作用。有趣的是，我们发现 SMS1 的敲低会损害 NF-kB 的激活。 基于 SMS1 在促进 NF-kB 激活中的潜在作用，并且由于 NF-kB 激活是细胞对细胞因子信号传导反应的关键组成部分，我们假设 SMS1 通过调节由其控制的生物活性脂质来调节 NF-kB 的激活。 SMS1 通过激活 NF-kB 是细胞因子信号转导的决定因素。为了检验我们的假设，我们将确定人类 SMS1 和 SMS2 在哺乳动物细胞中的生化功能，并确定 SMS1 在 NF-kB 调节中的作用和功能。