Sphingosine Kinase Compartmentalization in Tumorogenesis

肿瘤发生中的鞘氨醇激酶区室化

• 批准号: 7095132
• 负责人: BRIAN W. WATTENBERG
• 金额: $ 25.31万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-15 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7095132
• 关键词: 3T3 cells; active sites; biological signal transduction; carcinogenesis; cell membrane; cell proliferation; cell transformation; chloride channels; confocal scanning microscopy; density gradient ultracentrifugation; enzyme activity; immunofluorescence technique; molecular oncology; neoplasm /cancer therapy; phosphorylation; protein kinase; protein localization; second messengers; sphingosine; tumor suppressor proteins; western blottings

DESCRIPTION (provided by applicant): The long-range goal of the proposed research is to identify molecular targets in sphingolipid signaling pathways for the development of therapeutics to treat cancer. The focus of the present proposal is the signaling enzyme sphingosine kinase-1, which produces the potent second messenger, sphingosine-1-phosphate. Sphingosine kinase represents a candidate target for cancer therapy. This concept is based on the observations that sphingosine kinase is overexpressed in many tumors and that experimental overproduction of sphingosine kinase transforms cells from a growth-controlled state to a tumorigenic state. The localization of sphingosine kinase to distinct intracellular sites is key to its ability to transform cells. The proposed experimental plan will determine why localization is important for transformation. This will form the basis for a discovery of novel molecular targets involved in the transforming ability of sphingosine kinase. To accomplish this goal, three specific aims are proposed. Specific Aim 1. Determine the activation-dependent subcellular localization of sphingosine kinase and sphingolipid metabolites affected by SK activity. Specific Aim 2. Determine the role of SK localization in cellular transformation and protumorigenic pathways. Specific Aim 3. The plasma membrane sphingosine-1-phosphate transport mechanism. Determine the mechanism and functional effects of enhanced sphingosine-1-phosphate secretion by activation of hSK-1.

描述（由申请人提供）：拟议研究的远程目标是确定鞘脂信号传导途径中的分子靶标，以开发治疗癌症的治疗疗法。本提案的重点是信号酶鞘氨醇激酶1，它产生有效的第二信使鞘氨氨酸1-磷酸。鞘氨醇激酶代表了癌症治疗的候选靶标。这个概念是基于观察到的，即鞘氨醇激酶在许多肿瘤中过表达，而实验性过量产生了鞘氨酸激酶会使细胞从生长控制状态转化为肿瘤态。鞘氨醇激酶在不同的细胞内部位的定位是其转化细胞能力的关键。提出的实验计划将确定为什么定位对于转化很重要。这将构成发现与鞘氨醇激酶转化能力有关的新分子靶标的基础。为了实现这一目标，提出了三个具体目标。具体目标1。确定鞘氨醇激酶和受SK活性影响的鞘脂代谢产物的激活依赖性亚细胞定位。具体目标2。确定SK定位在细胞转化和原始途径中的作用。特定目标3。质膜1-磷酸转运机制。通过激活HSK-1来确定增强的链球菌1-磷酸分泌的机理和功能效应。