Project 3: Role of Sphingosine Kinase in P53 Cancer Biology

项目总结 这个项目的长期目标是定义鞘氨醇激酶1(SK1)作为一种新的和关键的 P53抑制肿瘤作用的下游靶点，并建立SK1作为潜在的靶点 癌症治疗，尤其是在p53缺失或突变的肿瘤中。P53及其途径的组成成分 作为关键的肿瘤抑制因子，它们在大多数癌症中是不受调控的。瞄准这条路 由于所涉及的蛋白质的性质和功能，一直是困难的。在过去的几年里，我们有 开始揭示P53和SK1之间深刻而新颖的联系。SK1是一种高度受调控的酶 这在调节生物活性鞘氨醇-1-磷酸(S1P)的水平方面起着关键作用， 在神经酰胺的清除中。S1P是一种促进肿瘤的鞘磷脂，作用于细胞 生长、血管生成和抗炎，而神经酰胺已成为一种肿瘤抑制脂质 参与调节细胞衰老、细胞凋亡和生长停滞。因此，SK1通过调节 这两种关键的生物活性脂质的相互转化，在肿瘤生物学中起着核心作用。在上一次 我们发现P53的诱导会导致SK1的丢失。此外，在我们最近出版的 研究表明，这种P53诱导的SK1的丢失是允许P53诱导的抑制SK1的关键 胸腺淋巴瘤、骨肉瘤和其他癌症--结合使用P53/SK1的研究证明 基因敲除的老鼠。这些正在进行的研究提供了以前未被认识到的、新颖的和坚实的联系 在P53、SK1和生物活性鞘脂之间，后者介导了P53在肿瘤抑制中的关键作用。 反过来，这些研究提出了一些关于p53对SK1和On的具体影响的基本问题。 生物活性鞘脂网络：什么生物活性脂类介导什么特定的P53反应，以及什么 这其中涉及到机制吗？这些发现使我们得出这样的假设，即SK1的丢失是 介导P53的抑瘤作用。P53的丢失或其突变导致SK1的持久性 然后允许肿瘤的发展和/或进展。这一假设将通过追求 具体目的如下：1)明确P53诱导SK1缺失的机制。2)定义 生物活性鞘脂在介导p53抑瘤作用中的作用。3)建立 SK1作为p53突变癌症的治疗靶点。确定P53调控的机制 SK1不仅将阐明这两个组件之间令人兴奋的新联系，而且还将导致 在确定新的治疗靶点方面。

PROJECT SUMMARY The long-term goals of this project are to define the role of sphingosine kinase 1 (SK1) as a novel and critical downstream target for the tumor suppressive action of p53, and to establish SK1 as a potential target for cancer therapy, especially in tumors with loss of or mutant p53. p53 and components its pathway have emerged as key tumor suppressors, which are disregulated in the majority of cancers. Targeting this pathway has been difficult due to the nature and function of the involved proteins. Over the last few years, we have begun to uncover a profound and novel connection between p53 and SK1. SK1 is a highly regulated enzyme that plays a critical role in regulating the levels of the bioactive sphingolipid sphingosine-1-phosphate (S1P), and in the clearance of ceramide. S1P has emerged as a tumor-promoting sphingolipid with actions on cell growth, angiogenesis and anti-inflammation whereas ceramide has emerged as a tumor suppressor lipid involved in regulation of cell senescence, apoptosis and growth arrest. Thus, SK1, by regulating the interconversion of these two critical bioactive lipids, assumes a central role in tumor biology. In the previous funding period we showed that induction of p53 results in loss of SK1. Moreover in our recently published studies, we demonstrated that this p53-induced loss of SK1 is critical for allowing p53-induced suppression of thymic lymphoma, osteosarcoma, and other cancers as evidenced in studies using the combined p53/SK1 knock-out mice. These ongoing studies provide previously unappreciated, novel and solid connections between p53, SK1, and bioactive sphingolipids, the latter mediating key effects of p53 on tumor suppression. In turn, these studies raise a number of fundamental questions as to the specific effects of p53 on SK1 and on the networks of bioactive sphingolipids: what bioactive lipid mediates what specific p53 responses, and what are the mechanisms involved? These findings have led us to the hypothesis that loss of SK1 is a key event in mediating the tumor suppressor effects of p53. Loss of p53 or its mutation results in persistence of SK1 which then allows tumor development and/or progression. This hypothesis will be investigated by pursuing the following specific aims: 1) To define the mechanisms by which p53 induces loss of SK1. 2) To define the role of bioactive sphingolipids in mediating the effects of p53 on tumor suppression. 3) To establish SK1 as a therapeutic target in p53-mutant cancers. Identifying the mechanisms by which p53 regulates SK1 will not only shed light on this exciting novel connection between the two components, but will also result in the identification of novel therapeutic targets.