Roles of Glycoconjugates and Redox Signaling in Tumor Biology

糖缀合物和氧化还原信号在肿瘤生物学中的作用

基本信息

批准号：
8763693
负责人：
david d roberts
金额：
$ 47.29万
依托单位：
DIVISION OF CLINICAL SCIENCES - NCI
依托单位国家：
美国
项目类别：
财政年份：
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/8763693
关键词：
Adverse effects Affinity Anabolism Angiogenesis Inhibitors Animal Model Binding Biological Process CD44 Antigens CD44 gene CD47 gene Cancer Patient Cancer cell line Carbon Monoxide Cardiovascular Physiology Cardiovascular system Cell Adhesion Molecules Cell surface Cells Cystathionine beta-Synthase Cysteine Desulfhydrase Development Diagnostic Enzymes Etiology Exhibits Extracellular Matrix FDA approved Family Fibronectins Glycoconjugates Glycolipids Glycoproteins Glycosaminoglycans Hemostatic function Heparan Sulfate Proteoglycan Hyaluronan Hydrogen Sulfide Immunologic Surveillance Integrins Interleukin-2 Knockout Mice Ligands MEKs Mediating Mediator of activation protein Messenger RNA Metabolic Pathway Mitogen-Activated Protein Kinases Molecular Mus Mutant Strains Mice Neoplasm Metastasis Oxidation-Reduction Pathologic Neovascularization Pathway interactions Peptides Pharmaceutical Preparations Phosphorylation Play Polysaccharides Property Proteins Proteoglycan Relative (related person)Role Signal Transduction Splenocyte T-Cell Activation T-Cell Receptor T-Lymphocyte T-Lymphocyte Subsets Therapeutic Uses Thrombospondin 1 Thrombospondins Thymus Gland Tumor Angiogenesis Tumor Biology Tumor Tissue Wild Type Mouse angiogenesis autocrine blood pressure regulation glycosylation inhibitor/antagonist neoplastic cell neovascularization novel prevent receptor response small molecule therapeutic angiogenesis therapeutic target thymocyte tissue culture

项目摘要

Thrombospondin-1 is a potent suppressor of T cell activation via its receptor CD47. However, the precise mechanism for this inhibition remains unclear. Because H2S is an endogenous potentiator of T cell activation and is necessary for full T cell activation, we hypothesized that thrombospondin-1 signaling through CD47 inhibits T cell activation by antagonizing H2S signaling. Primary T cells from thrombospondin-1 null mice were more sensitive to H2S-dependent activation assessed by proliferation and induction of interleukin-2 and CD69 mRNAs. Exogenous thrombospondin-1 inhibited H2S responses in wild type and thrombospondin-1 null T cells but enhanced the same responses in CD47 null T cells. Fibronectin, which shares integrin and glycosaminoglycan binding properties with thrombospondin-1 but not CD47 binding, did not inhibit H2S signaling. A CD47-binding peptide derived from thrombospondin-1 inhibited H2S-induced activation, whereas two other functional sequences from thrombospondin-1 enhanced H2S signaling. Therefore, engaging CD47 is necessary and sufficient for thrombospondin-1 to inhibit H2S-dependent T cell activation. H2S stimulated T cell activation by potentiating MEK-dependent ERK phosphorylation, and thrombospondin-1 inhibited this signaling in a CD47-dependent manner. Thrombospondin-1 also limited activation-dependent T cell expression of the H2S biosynthetic enzymes cystathionine beta-synthase and cystathionine gamma-lyase, thereby limiting the autocrine role of H2S in T cell activation. Thus, thrombospondin-1 signaling through CD47 is the first identified endogenous inhibitor of H2S signaling and constitutes a novel mechanism that negatively regulates T cell activation.

血小板传播1是通过其受体CD47激活T细胞激活的有效抑制剂。但是，这种抑制的确切机制尚不清楚。由于H2S是T细胞激活的内源性增强剂，对于全T细胞激活是必要的，因此我们假设通过CD47的血小板传播信号传导通过拮抗H2S信号传导抑制T细胞激活。来自血小板蛋白-1 NULL小鼠的原代T细胞对通过增殖和诱导白介素-2和CD69 mRNA评估的H2S依赖性激活更敏感。外源性血小板素1抑制了野生型和血小板蛋白-1 null T细胞中的H2S反应，但增强了CD47 null T细胞中相同的反应。纤连蛋白共享整合素和糖胺聚糖的结合特性与血小板传播1但不抑制H2S信号传导。源自血小板素-1的CD47结合肽抑制了H2S诱导的激活，而血小板传播1增强的H2S信号传导的其他两个功能序列。因此，参与CD47是必需的，足以使血小板传播1抑制H2S依赖性T细胞激活。 H2S通过增强MEK依赖性ERK磷酸化而刺激T细胞的激活，而血小板传播1则以CD47依赖性方式抑制了该信号传导。血小板传播1还限制了H2S生物合成酶的活化依赖性T细胞表达，Cystathionineβ-合成酶和胱淀粉γ-溶解酶，从而限制了H2S在T细胞活化中的自身分泌作用。因此，通过CD47通过CD47信号传导是H2S信号传导的第一个鉴定的内源性抑制剂，构成了一种负面调节T细胞激活的新机制。