Sphingosine kinases in cancer cell signaling

癌细胞信号传导中的鞘氨醇激酶

基本信息

批准号：
8212071
负责人：
SARAH SPIEGEL
金额：
$ 27.11万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1994
资助国家：
美国
起止时间：
1994-06-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8212071
关键词：
Acetylation Acute Address Affect Anti-Inflammatory Agents Anti-inflammatory Apoptotic Area Binding Binding Sites Biological Process Biology Bone Marrow Cell Nucleus Cell Survival Cell physiology Cell surface Cells Cellular biology Chronic Colitis Colon Carcinoma Data Development Disease Enzyme Inhibitor Drugs Enzyme Inhibitors Enzymes Epigenetic Process Epithelial Cells Event Family Gene Expression Gene Expression Regulation Genes Genetic Genetic Transcription HDAC1 gene Health Histone Deacetylase Histones In Vitro Inflammation Inflammatory Inflammatory Bowel Diseases Interleukin-6 Intestines Ligands Link Location Lymphocyte Lysine Malignant Neoplasms Mediating Mediator of activation protein Molecular Molecular Target Myeloid Cells NF-kappa B Nature Nuclear Pathologic Processes Pathway interactions Phosphotransferases Physiological Processes Polyubiquitination Premalignant Process Production Proteins Recruitment Activity Regulation Research Role Signal Transduction Sphingolipids Sphingosine-1-Phosphate Receptor TNF gene TNF receptor-associated factor 2 Tumor Promotion Work angiogenesis base cancer cell cell growth clinical application cofactor colitis associated cancer cytokine in vivo member mouse model novel pharmacophore programs receptor reconstitution small molecule sphingosine 1-phosphate sphingosine kinase trafficking transcription factor tumor tumor progression ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): Sphingosine-1-phosphate (S1P) is a potent sphingolipid mediator that regulates diverse cellular processes important for cancer progression including cell growth and survival, invasion, angiogenesis, lymphocyte trafficking, and inflammation, among others. Although S1P is produced inside cells by two closely related sphingosine kinases, SphK1 and SphK2, most of the research to date in the S1P field has been concentrated on its actions as a ligand for the five S1P receptors, and prior to our work, no intracellular targets had been recognized. We recently identified HDAC1/2 as the first direct intracellular targets of S1P, and demonstrated that S1P, produced by nuclear SphK2, is an endogenous small molecule inhibitor of these enzymes, linking nuclear S1P to epigenetic regulation of gene expression. In preliminary studies, we have discovered that TNF receptor-associated factor 2 (TRAF2), a key component in activation of NF-kB, is another novel intracellular target of S1P. Our data indicates that S1P may be the missing cofactor for the E3 ubiquitin ligase activity of TRAF2, suggesting a new paradigm for regulation of NF-kB, a transcription factor important for cancer and inflammation. In this proposal, we will examine the hypothesis that the location of S1P production dictates its functions and that S1P is not only a ligand for the S1PRs but also serves as an intracellular molecular switch that regulates the activity of its targets, HDAC1/2 and TRAF2, important for cancer and inflammation. In the first aim, we will determine the role of S1P produced by SphK2 in the nucleus as an endogenous regulator of HDACs. In the second, we will determine the role of S1P produced by SphK1 as a direct regulator of the E3 ligase activity of TRAFs, lysine 63-linked polyubiquitination, and NF-kB signaling. The third aim will address the importance of S1P and its regulation of HDAC1/2 and TRAF2 in a mouse model of chronic inflammation leading to cancer. These three aims represent a novel and unique approach to understanding S1P biology and its multi-faceted actions and will open new areas of research. This proposal provides a paradigm shift from "inside-out" signaling by S1P to include important signaling inside cells and will provide evidence that S1P is one of the critical factors that bridges chronic inflammation to tumor promotion and progression. PUBLIC HEALTH RELEVANCE: The bioactive sphingolipid metabolite S1P and the kinases that produce it, SphK1 and SphK2, have emerged as critical regulators of numerous fundamental biological processes important for health and disease, particularly cancer and inflammation. It is difficult to find an area of cell biology and physiology in which S1P does not have important if not key roles. This proposal will be a major contribution towards understanding the enigmatic nature of the pleiotropic actions of S1P, modifying the focus of research on S1P signaling at the cell surface to include signaling inside cells, and will have important clinical applications for inflammation and cancer.

描述（由申请人提供）：1-磷酸盐（S1P）是一种有效的鞘脂介质，它调节对癌症进展至关重要的多种细胞过程，包括细胞生长和存活，侵袭，血管生成，血管生成，淋巴细胞运输和炎症等。尽管S1P是通过两个密切相关的鞘氨酸激酶SPHK1和SPHK2在细胞内部产生的，但迄今为止，S1P领域中的大多数研究都集中在其作为五个S1P受体的配体的作用上，并且在我们工作之前，未识别细胞内靶标。我们最近将HDAC1/2确定为S1P的第一个直接细胞内靶标，并证明由核SPHK2产生的S1P是这些酶的内源性小分子抑制剂，将核S1P与基因表达的表观遗传调节联系起来。在初步研究中，我们发现TNF受体相关因子2（TRAF2）是NF-KB激活的关键成分，是S1P的另一个新型细胞内靶标。我们的数据表明，S1P可能是TRAF2的E3泛素连接酶活性的缺失辅助因子，这表明新的NF-KB调节范式是NF-KB的新范式，NF-KB是对癌症和炎症重要的转录因子。在该提案中，我们将研究以下假设：S1P产生的位置决定了其功能，S1P不仅是S1PR的配体，而且还可以用作细胞内分子开关，可调节其靶标的HDAC1/2和TRAF2的活性，对癌症和炎症很重要。在第一个目标中，我们将确定SPHK2在核中作为HDAC的内源性调节剂产生的S1P的作用。在第二个中，我们将确定SPHK1作为TRAFS E3连接酶活性的直接调节剂，赖氨酸63连接的多泛素化和NF-KB信号传导的直接调节剂的作用。第三个目标将解决S1P的重要性及其对HDAC1/2和TRAF2的调节，这会导致癌症的慢性炎症模型。这三个目标代表了一种新颖而独特的方法，用于理解S1P生物学及其多方面的行动，并将开放新的研究领域。该提案提供了从S1P的“内外”信号传导，包括在细胞内部包含重要信号传导，并将提供证据表明S1P是将慢性炎症促进肿瘤促进和进展的关键因素之一。公共卫生相关性：生物活性鞘脂代谢物S1P以及产生它的激酶SPHK1和SPHK2已成为许多对健康和疾病，尤其是癌症和炎症重要的基本生物学过程的关键调节剂。很难找到一个细胞生物学和生理学领域，其中S1P如果不是关键角色，那么S1P并不重要。该提案将是理解S1P多效应作用的神秘性的主要贡献，从而改变了细胞表面的S1P信号的研究重点，以包括细胞内部的信号传导，并在炎症和癌症中具有重要的临床应用。