Sphingolipid Signaling

鞘脂信号转导

• 批准号: 7969270
• 负责人: SHELDON MILSTIEN
• 金额: $ 8.31万
• 依托单位: NATIONAL INSTITUTE OF MENTAL HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7969270
• 关键词: Accounting; Affect; Agonist; Anaphylaxis; Animal Model; Animals; Apoptosis; Asthma; Astrocytes; Autophagocytosis; Binding; Biological Process; Brain; Cardiovascular Diseases; Cardiovascular system; Cell Death; Cell Death Process; Cell Line; Cell Nucleus; Cell Proliferation; Cell physiology; Cells; Ceramides; Cessation of life; Chromatin Structure; Chronic; Collaborations; Data; Development; Differentiation and Growth; Disease; Enzymes; Epigenetic Process; Equilibrium; Extrinsic asthma; G-Protein-Coupled Receptors; Gene Expression; Gene Targeting; Genetic Transcription; Glioblastoma; Goals; Growth; Health; Hearing; Heart; Histone Acetylation; Histones; Homeostasis; Human; Implant; In Vitro; Inflammation; Inflammatory; Interleukin-1; Knowledge; Lead; Ligands; Link; Lipids; Location; Malignant - descriptor; Malignant Neoplasms; Mediating; Membrane; Messenger RNA; Metabolism; Multiple Sclerosis; Mus; Names; Nervous system structure; Neuroglia; Neurons; Nuclear; Paper; Pathway interactions; Patients; Phosphotransferases; Physiological Processes; Physiology; Play; Production; Publishing; Regulation; Regulator Genes; Reporting; Role; Science; Signal Transduction; Signaling Molecule; Sphingolipids; Sphingosine; Sphingosine-1-Phosphate Receptor; Therapeutic Agents; Translating; Universities; Virginia; autocrine; cancer type; cell growth; cell motility; cytokine; human disease; inhibiting antibody; inhibitor/antagonist; leukemia; lipid mediator; medical schools; neuronal survival; new therapeutic target; outcome forecast; paracrine; protein expression; receptor; response; sphingosine 1-phosphate; sphingosine kinase; therapeutic target; tumor growth; tumor xenograft

Sphingosine-1-phosphate (S1P) is a potent lipid mediator that regulates many vital biological processes, including cell growth, death, and differentiation. S1P has been shown to play important roles in normal and patho-physiological processes, including cancer, asthma, allergic responses, hearing, and development of the cardiovascular and nervous systems. In a continuing and highly successful collaboration with Dr. Sarah Spiegel at Virginia Commonwealth University School of Medicine, we are elucidating the mechanisms by which S1P is produced by two sphingosine kinases (SphK1 and SphK2), how its levels are regulated, and how it mediates such diverse actions. S1P is a ligand for five specific G protein-coupled receptors (named S1Psub(1-5)) that regulate many vital cellular processes and account for the pleiotropic effects of S1P. In fact, no cell in the body has been found that does not express as least one S1P receptor. Although they were long considered to be merely structural components of membranes, in the recent decades it has become apparent that sphingolipids have other important functions. More recently, S1P and its precursors, sphingosine and ceramide, have been implicated in the regulation of many aspects of neuronal proliferation, differentiation, survival and apoptosis. We have been developing specific SphK1 inhibitors as potential therapeutic agents. We previously reported that a specific isotype inhibitor of SphK1 that we called SK1-I decreased growth and survival of human leukemia cell lines and primary leukemia cells from patients, and markedly reduced growth of xenograft tumors grown from human leukemia cells implanted in mice. Elevated levels of SphK1, but not SphK2, were correlated with a shorter survival prognosis for patients with glioblastoma multiforme. Chronic inflammation and inflammatory cytokines have recently been implicated in the development and progression of various types of cancer. In the brain, neuroinflammatory cytokines affect the growth and differentiation of both normal and malignant glial cells, with interleukin 1 (IL-1) shown to be secreted by the majority of glioblastoma cells. S1P induces invasion of glioblastoma cells. In this study, we showed that the expression of IL-1 correlates with the expression of SphK1 in glioblastoma cells, and neutralizing anti-IL-1 antibodies inhibit both the growth and invasion of glioblastoma cells. Furthermore, IL-1 up-regulates SphK1 mRNA levels, protein expression, and activity in both primary human astrocytes and various glioblastoma cell lines; however, it does not affect SphK2 expression. In summary, our results suggest that SphK1 expression is transcriptionally regulated by IL-1 in glioblastoma cells, and this pathway may be important in regulating survival and invasiveness of glioblastoma cells. In preliminary studies, we have also found that treating mice with the SphK1 inhibitor SK1-I inhibited glioblastoma tumor growth and enhanced survival. In an invited review, we summarized the data to date on the roles of S1P and the kinases that produce it as critical regulators of numerous fundamental biological processes important for health and disease. Activation of SphKs by a variety of agonists increases intracellular S1P, which in turn can be secreted out of the cell and bind to and signal through S1P receptors (S1PRs) in an autocrine and/or paracrine manner. We suggest that this "inside-out" signaling by S1P may play a role in many human diseases. We focussed this review mainly on recent reports showing how SphKs are activated and how S1P reaches its receptors, the role of SphKs and S1P in regulating sphingolipid homeostasis, and the potential importance of the SphK/S1P axis as a therapeutic target in human diseases. We previously found that SphK1 was important for cell growth and survival and SphK2 seemed to inhibit proliferation and promote cell death. SphK1 and SphK2 have different cellular localizations and have opposing roles in the regulation of sphingolipid metabolism suggesting that the location of S1P production in the cell dictates its functions. In a paper that will be published September 4, 2009 in Science, we report the important discovery that cell nuclei contain S1P that is produced there by nuclear localized SphK2 and that SphK2 and S1P are important endogenous regulators of gene transcription. We found that S1P was an endogenous inhibitor of histone deacetylases (HDACs), enzymes that regulate chromatin structure and gene expression and thus HDACs are the first identified intracellular targets of S1P. Our data reveal a new paradigm of S1P signaling produced by nuclear sphingolipid metabolism, suggesting an important function for SphK2 in the nucleus. HDACs have emerged as key targets to reverse aberrant epigenetic changes associated with human diseases, such as cancer. S1P may therefore influence the delicate balance and dynamic turnover of histone acetylation and the transcription of target genes, linking them to epigenetic regulation in response to environmental signals.

鞘氨醇1-磷酸盐（S1P）是一种有效的脂质介质，可调节许多重要的生物学过程，包括细胞生长，死亡和分化。 S1P已被证明在正常和病态生理过程中起着重要作用，包括癌症，哮喘，过敏反应，听力和心血管和神经系统的发展。在与弗吉尼亚联邦大学医学院的莎拉·斯皮格尔（Sarah Spiegel）博士进行的持续和非常成功的合作中，我们正在阐明由两个鞘氨醇激酶（SPHK1和SPHK2）生产的S1P的机制，如何调节其水平以及如何调节这种不同的行动。 S1P是一种适用于五个特定G蛋白偶联受体（称为S1PSUB（1-5））的配体，可调节许多重要的细胞过程，并解释了S1P的多效效应。实际上，没有发现体内至少一个S1P受体的细胞。尽管它们长期以来被认为仅仅是膜的结构成分，但在近几十年中，鞘脂具有其他重要功能已变得很明显。最近，S1P及其前体，鞘氨酸和神经酰胺，与神经元增殖，分化，生存和凋亡的许多方面有关。 我们一直在开发特定的SPHK1抑制剂作为潜在的治疗剂。我们先前曾报道过，我们称SK1-I的特异性同种型抑制剂降低了患者的人白血病细胞系和原发性白血病细胞的生长和存活，并显着降低了植入小鼠中人类白血病细胞的异种移植肿瘤的生长。 SPHK1的水平升高，而不是SPHK2，与多形胶质母细胞瘤患者的生存预后相关。慢性炎症和炎症细胞因子最近与各种类型癌症的发展和进展有关。在大脑中，神经炎性细胞因子会影响正常和恶性神经胶质细胞的生长和分化，白介素1（IL-1）被大多数被大多数胶质母细胞瘤细胞分泌。 S1P诱导胶质母细胞瘤细胞的侵袭。在这项研究中，我们表明IL-1的表达与胶质母细胞瘤细胞中SPHK1的表达相关，并且中和抗IL-1抗体抑制了胶质母细胞瘤细胞的生长和侵袭。此外，IL-1上调了原代人星形胶质细胞和各种胶质母细胞瘤细胞系中的SPHK1 mRNA水平，蛋白质表达和活性。但是，它不会影响SPHK2表达。总而言之，我们的结果表明，SPHK1表达在胶质母细胞瘤细胞中受IL-1的转录调节，并且该途径对于调节胶质母细胞瘤细胞的存活和侵入性可能很重要。在初步研究中，我们还发现用SPHK1抑制剂SK1-I治疗小鼠抑制了胶质母细胞瘤肿瘤的生长并增强生存率。 在邀请的综述中，我们总结了迄今为止S1P和激酶的数据，这些数据是对健康和疾病重要的许多基本生物学过程的关键调节剂。各种激动剂对SPHK的激活增加了细胞内S1P，而细胞内S1P可以从细胞中分泌出来，并以自分泌和/或旁分泌方式与S1P受体（S1PR）结合并通过S1P受体（S1PRS）结合。我们建议S1P的这种“内部”信号传导可能在许多人类疾病中起作用。我们将本综述重点放在最近的报告上，显示了SPHK是如何激活的以及S1P如何达到其受体，SPHK和S1P在调节鞘脂稳态中的作用，以及SPHK/S1P轴作为治疗靶标在人类疾病中的潜在重要性。 我们先前发现SPHK1对于细胞生长和生存很重要，而SPHK2似乎抑制了增殖并促进细胞死亡。 SPHK1和SPHK2具有不同的细胞定位，并且在调节鞘脂代谢的调节中具有相反的作用，这表明S1P产生在细胞中的位置决定了其功能。在将于2009年9月4日发表的一篇论文中，我们报告了一个重要发现，即细胞核中包含由核局部sphk2产生的S1P，而SPHK2和S1P是基因转录的重要内源性调节剂。我们发现S1P是组蛋白脱乙酰基酶（HDACS）的内源性抑制剂，调节染色质结构和基因表达的酶，因此HDACS是S1P的第一个鉴定出的细胞内靶标。 我们的数据揭示了由核鞘脂代谢产生的S1P信号传导的新范式，这表明SPHK2在核中具有重要功能。 HDAC已成为逆转与人类疾病（例如癌症）相关的异常表观遗传变化的关键目标。因此，S1P可能会影响组蛋白乙酰化和靶基因的转录的微妙平衡和动态周转率，从而将其与响应环境信号的表观遗传调节联系起来。