Sphingosine Kinases in Cancer Cell Signaling

癌细胞信号转导中的鞘氨醇激酶

• 批准号: 7405469
• 负责人: SARAH SPIEGEL
• 金额: $ 27.02万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-06-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7405469
• 关键词: Affect; Agar; Agonist; Amino Acid Sequence; Anabolism; Antibodies; Apoptosis; Apoptotic; BAK1 gene; BAX gene; BH3 Domain; Back; Bax protein; Biochemical Genetics; Blood Vessels; Calcium; Cell Proliferation; Cell Surface Receptors; Cell Survival; Cell physiology; Cells; Ceramides; DNA Sequence Rearrangement; DNA biosynthesis; DNA chemical synthesis; Development; Dimensions; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Ethanolamines; Family; Figs - dietary; G-Protein-Coupled Receptors; Genetic; Goals; Growth; Homeostasis; Immunity; Isoenzymes; Kinetics; Knockout Mice; Label; Ligands; Lipids; Localized; Lymphocyte; Malignant Neoplasms; Mammals; Mediating; Mediator of activation protein; Membrane; Metabolism; Mitochondria; Mus; Organism; Pathway interactions; Phenotype; Phosphorylation; Phosphotransferases; Physiological; Plants; Play; Process; Production; Property; Protein Isoforms; Proteins; Regulation; Research Personnel; Role; Scaffolding Protein; Signal Transduction; Small Interfering RNA; Sphingolipids; Sphingosine; Sphingosine-1-Phosphate Receptor; Stimulus; TNF gene; Tissues; Uncertainty; Vascular Endothelial Growth Factors; Yeasts; angiogenesis; base; cancer cell; cell growth; cell motility; dihydroceramide desaturase; ethanolamine; extracellular; fly; link protein; lipid mediator; migration; mutant; programs; protein function; response; serine palmitoyltransferase; sphingosine 1-phosphate; sphingosine kinase; sphingosine-1-phosphate phosphatase; tandem mass spectrometry; tool; trafficking; tumor; tumor progression

DESCRIPTION (provided by applicant): Sphingosine kinase (SphK) is a central enzyme regulating the levels of sphingosine-1-phosphate (S1P), a bioactive sphingolipid metabolite and a ligand for a family of 5 S1P receptors. We have previously cloned and characterized 2 distinct isoforms, SphK1 and SphK2. SphK1 is activated by a numerous stimuli to promote cell proliferation, cell survival, migration and tumor formation. SphK1 and intracellularly generated S1P can signal "inside-out" to regulate cytoskeletal rearrangements and cell movement, yet stimulates cell growth and suppresses apoptosis independently of S1P receptors. Remarkably, although highly similar in sequence to SphK1 and possessing the same 5 conserved domains, we recently found that SphK2 rather than promoting growth and survival, suppressed growth and also enhanced apoptosis. The goal of this proposal is to determine how these 2 very closely related and similar isoenzymes that can produce the same product can have such different functions. We will examine the hypothesis that the opposite actions of SphK1 and SphK2 result from their specific regulation and/or translocation to distinct cellular compartments to produce distinct pools of S1P or other phosphorylated sphingoid bases that have unique functions, and thus affect cellular processes that are particularly important for the transformed phenotype. Biochemical and genetic approaches will be utilized to determine whether endogenous SphK1 and SphK2 have redundant, overlapping, complementary, or antagonistic functions in growth, survival and motility of cancer cells. We will also elucidate their unrecognized roles in regulating ceramide biosynthesis and the sphingolipidome and determine whether SphK2 is a dual function BH3-only protein that links the Bcl-2 family, calcium homeostasis, and regulation of apoptosis. Collectively, these studies will add a new dimension to the physiological roles of SphK1 and SphK2 whose activities are central and obligatory in controlling levels of S1P, a potent lipid mediator that regulates many cellular processes important for cancer.

描述（由申请人提供）：鞘氨醇激酶（SphK）是一种调节鞘氨醇-1-磷酸（S1 P）水平的中心酶，S1 P是一种生物活性鞘脂代谢物，是5种S1 P受体家族的配体。我们以前克隆和表征2个不同的亚型，SphK 1和SphK 2。SphK 1被许多刺激物激活，以促进细胞增殖、细胞存活、迁移和肿瘤形成。SphK 1和胞内产生的S1 P可以通过“由内而外”的信号传导来调节细胞骨架重排和细胞运动，但不依赖于S1 P受体而刺激细胞生长和抑制细胞凋亡。值得注意的是，尽管SphK 1在序列上高度相似，并且具有相同的5个保守结构域，但我们最近发现SphK 2不是促进生长和存活，而是抑制生长并增强凋亡。本提案的目的是确定这两种非常密切相关和相似的同工酶如何产生相同的产物，并具有如此不同的功能。我们将研究的假设，SphK 1和SphK 2的相反的行动，从他们的特定的调节和/或易位到不同的细胞隔室，产生不同的池S1 P或其他磷酸化鞘氨醇碱，具有独特的功能，从而影响细胞的过程，是特别重要的转化表型。将利用生物化学和遗传学方法来确定内源性SphK 1和SphK 2在癌细胞的生长、存活和运动中是否具有冗余、重叠、互补或拮抗功能。我们还将阐明其在调节神经酰胺生物合成和鞘脂组中未被认识的作用，并确定SphK 2是否是一种双功能BH 3-only蛋白，其连接Bcl-2家族，钙稳态和凋亡调节。总的来说，这些研究将为SphK 1和SphK 2的生理作用增加一个新的维度，SphK 1和SphK 2的活动在控制S1 P水平方面是中心和强制性的，S1 P是一种有效的脂质介质，调节许多对癌症重要的细胞过程。