Sphingosine Kinase Compartmentalization in Tumorogenesis

描述(申请人提供)：这项拟议研究的长期目标是确定鞘脂信号通路中的分子靶点，以开发治疗癌症的药物。本提案的重点是信号转导酶鞘氨醇激酶-1，它产生强大的第二信使-鞘氨醇-1-磷酸。鞘氨醇激酶是癌症治疗的候选靶点。这一概念是基于以下观察结果：鞘氨醇激酶在许多肿瘤中过表达，实验中过量生产的鞘氨醇激酶将细胞从生长控制状态转变为肿瘤状态。鞘氨醇激酶定位于不同的细胞内位置是其转化细胞能力的关键。拟议的实验计划将确定为什么本地化对转型很重要。这将为发现与鞘氨醇激酶转化能力有关的新的分子靶点奠定基础。为了实现这一目标，提出了三个具体目标。具体目的1.确定受SK活性影响的鞘氨醇激酶和鞘磷脂代谢产物的激活依赖的亚细胞定位。具体目的2.确定SK定位在细胞转化和致癌途径中的作用。具体目的3.质膜鞘氨醇-1-磷酸转运机制。确定HSK-1激活促进鞘氨醇-1-磷酸分泌的机制和功能效应。

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.