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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 特定目标已从原始应用中提出的目标进行了稍微修改。 鞘磷脂合酶（SMS）代表了负责鞘磷脂（SM）生物合成的重要酶。特别是，SMS将磷酸胆碱部分从磷脂酰胆碱（PC）转移到神经酰胺，形成SM和二酰基甘油（DAG）。因此，SMS不仅会产生SM，这是细胞膜完整性的关键磷脂，而且还会在相反方向上调节两个具有相反功能（例如DAG和Ceramide）的生物活性脂质的水平。神经酰胺是细胞增殖的既定负调节剂，而DAG是一个良好认可的有丝分裂因子。 PI先前进行的研究表明，SM合成的激活导致NF-KB激活（一种关键转录因子，参与了重要的细胞功能的调节，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，这些基因在酵母细胞中表达时，编码为具有SMS活性的蛋白质。 我们的初步结果证实了两个推定的SMS的不同定位。他们还指出了SMS1和SMS2的生理作用，因为哺乳动物细胞中的真正SMSS。有趣的是，我们发现SMS1的敲除损害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NF-KB的激活，通过调节生物活性脂质通过其生物活性脂质通过其生物学反应和NF的smss Action Activation cys Activation cys Activation cys Activation cybb-nf-kb。信号。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。