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: 8742662
• 负责人: CHIARA LUBERTO
• 金额: $ 18.39万
• 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 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8742662
• 关键词: 1,2-diacylglycerol; 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）。目前的提案重点关注慢性粒细胞白血病 (CML)，但我们的 观察结果表明短信可能与其他肿瘤有关，例如乳腺癌。 SMS 通过合成鞘脂鞘磷脂 (SM) 促进脂质代谢。重要的是，在 在反应过程中，SMS 消耗神经酰胺并产生二酰基甘油 (DAG)，这是两种关键的生物活性物质 脂质在控制关键细胞过程中具有相反的功能，包括增殖、凋亡和 差异化。由于神经酰胺和 DAG 的调节，短信可能与癌症有关，但是 目前对这种潜在联系的了解非常有限。在哺乳动物中，有两种 SMS 酶（SMS1 和 SMS2）由两个不同的基因（SMS1 和 SMS2）编码。此时，对 SMS1 或 SMS1 还一无所知 SMS2 上游调控及其在癌症生物学中潜在的下游信号传导功能。 来自 PI 实验室的初步数据在 SMS1 和 BCR- 之间建立了一种新颖的连接 ABL 癌基因，负责 CML 的发生。重要的是，PI 实验室的初步结果 支持以下假设：BCR-ABL1 通过一种新颖的协同作用增强 SMS1 的表达 转录/翻译调节机制以及 SMS1 活性的升高维持 CML 细胞的致瘤潜力。为了检验这一假设，我们将： 1. 确定 SMS1 在 CML 中的作用 病理生物学及其作用机制2.阐明BCR-调节SMS1的机制 ABL1。 BCR-ABL1/SMS1 连接的发现提供了第一个分子定义的模型 更好地了解难以捉摸的 SMS1 的潜在调节模式和下游功能 癌症模型并在 bcr-abl 信号网络中建立新的连接，有可能揭示新的 CML 的药理学靶点。此外，SMS1 直接上游监管机构的识别可能会 揭示 SMS1 与其他病理学（包括其他类型的癌症）的关联，其中新发现的 上游调节器的特征是一个关键的决定因素。