Sphingosine Kinase Compartmentalization in Tumorogenesis

描述（由申请人提供）：拟议研究的长期目标是确定鞘脂信号通路中的分子靶点，用于开发治疗癌症的疗法。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。这一概念是基于观察到鞘氨醇激酶在许多肿瘤中过度表达，并且实验中鞘氨醇激酶的过量产生将细胞从生长控制状态转变为致瘤状态。鞘氨醇激酶在细胞内不同位置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本地化对转型很重要。这将形成一个新的分子靶标参与鞘氨醇激酶的转化能力的发现的基础。为实现这一目标，提出了三个具体目标。具体目标确定受SK活性影响的鞘苷激酶和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定位在细胞转化和蛋白形成途径中的作用。具体目标3。鞘氨醇-1-磷酸的质膜转运机制。通过激活hSK-1来确定鞘氨醇-1-磷酸分泌增强的机制和功能作用。

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.