Project 4: Sphingomyelin Synthase in Chronic Myelogenous

项目4：慢性粒细胞性鞘磷脂合成酶

• 批准号: 9130753
• 负责人: CHIARA LUBERTO
• 金额: $ 18.5万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9130753
• 关键词: 5' Untranslated Regions; ABL1 gene; Affect; Apoptosis; Cancer Biology; Cancer Model; Cell Proliferation; Cell Survival; Cell physiology; Cells; Ceramides; Chronic; Chronic Myeloid Leukemia; Combined Modality Therapy; Coupled; Data; Development; Diglycerides; Down-Regulation; Enzymes; Generations; Genes; Genetic Transcription; Goals; Knowledge; Laboratories; Link; Lipids; Malignant Neoplasms; Mammals; Mediating; Messenger RNA; Modeling; Myelogenous; Neoplasms; Oncogenes; Pathogenesis; Pathology; Pathway interactions; Protein Kinase; Protein Tyrosine Kinase; Protein phosphatase; Reaction; Regulation; Role; STAT protein; Signal Pathway; Signal Transduction; Sphingolipids; Sphingomyelins; Stream; Testing; Therapeutic; Therapeutic Intervention; Time; Translational Regulation; Translations; Tumor Suppressor Proteins; abl Oncogene; base; bcr-abl Fusion Proteins; cancer therapy; cancer type; in vivo; lipid metabolism; malignant breast neoplasm; novel; promoter; sphingomyelin synthase; transcription factor; tumorigenic

ABSTRACT The long-term goal of this project is to elucidate the role, regulation and therapeutic relevance of sphingomyelin synthase (SMS) in cancer. The current proposal focuses on Chronic Myelogenous Leukemia (CML) but our observations suggest that SMS may be relevant in other neoplasms, such as breast cancer. SMS contributes to lipid metabolism by synthesizing the sphingolipid sphingomyelin (SM). Importantly, in the course of its reaction, SMS consumes ceramide and produces diacylglycerol (DAG), two critical bioactive lipids with opposing functions in the control of key cellular processes that include proliferation, apoptosis, and differentiation. Because of the regulation of ceramide and DAG, SMS is poised to be linked to cancer, but current knowledge about this potential link is very limited. In mammals, there are two SMS enzymes (SMS1 and SMS2) encoded by two distinct genes (SMS1 and SMS2). At this time, nothing is known about SMS1 or SMS2 upstream regulation and their potential downstream signaling functions in cancer biology. Preliminary data from the PI's laboratory establish a novel connection between SMS1 and the BCR- ABL oncogene, responsible for the onset of CML. Importantly, preliminary results from the PI's laboratory support the hypothesis that BCR-ABL1 enhances expression of SMS1 through a novel concerted mechanism of transcriptional/translational regulation and that elevated SMS1 activity sustains the tumorigenic potential of CML cells. To test this hypothesis we will: 1. Determine the role of SMS1 in CML pathobiology and its mechanism of action and 2. Elucidate the mechanism of SMS1 regulation by BCR- ABL1. The discovery of the BCR-ABL1/SMS1 connection provides the first molecularly defined model for a better understanding of potential modes of regulation and down-stream functions of the elusive SMS1 in a cancer model and establishes novel connections in the bcr-abl signaling network potentially uncovering novel pharmacological targets for CML. Moreover the identification of the direct upstream regulators of SMS1 might uncover the association of SMS1 with other pathologies (including other types of cancers) in which the newly characterized upstream regulator is a critical determinant.

抽象的 该项目的长期目标是阐明鞘磷脂的作用，调节和治疗相关性 癌症中的合酶（SMS）。当前的提案重点是慢性髓质白血病（CML），但我们 观察结果表明，SMS可能与其他肿瘤（例如乳腺癌）相关。 SMS通过合成鞘脂鞘脂素（SM）来促进脂质代谢。重要的是，在 反应的过程，SMS消耗神经酰胺并产生二酰基甘油（DAG），两个关键的生物活性 在控制关键细胞过程中具有相反功能的脂质，包括增殖，凋亡和 分化。由于神经酰胺和DAG的调节，SMS有望与癌症有关，但是 当前关于此潜在链接的知识非常有限。在哺乳动物中，有两个SMS酶（SMS1 和SMS2）由两个不同的基因（SMS1和SMS2）编码。目前，关于SMS1或 SMS2上游调节及其在癌症生物学中的潜在下游信号传导功能。 PI实验室的初步数据建立了SMS1与BCR-之间的新联系 ABL Oncogene，负责CML的发作。重要的是，PI实验室的初步结果 支持以下假设，即BCR-ABL1通过新颖的协调来增强SMS1的表达 转录/翻译调节的机制和升高SMS1活性的机制维持 CML细胞的致瘤潜力。为了检验该假设，我们将：1。确定SMS1在CML中的作用 病理生物学及其作用机理及其2。 ABL1。 BCR-ABL1/SMS1连接的发现提供了第一个分子定义的模型 更好地理解一个监管的潜在模式和难以捉摸的SMS1的下游功能 癌症模型并在BCR-ABL信号网络中建立新的联系可能会发现新颖 CML的药理靶标。此外，SMS1的直接上游调节器的识别可能 揭示SMS1与其他病理的关联（包括其他类型的癌症） 上游调节剂的特征是关键决定因素。