Regulation of RNA metabolism and cell growth control by SR protein kinases

项目摘要 该提案寻求资助GM052872的竞争性更新，该资助一直支持我们的基本 综述了近二十年来SR蛋白特异激酶的研究进展。根据我们最近的发现， 在哺乳动物中主要负责转导生长因子信号以调节可变剪接 SRPK1能够作为癌基因或肿瘤抑制基因，通过调节细胞的募集， 关键的Akt特异性磷酸酶PHLPP1，我们处于独特的位置，攻击新的致瘤机制 与SRPK1功能改变有关。由于SRPK1是大多数组织中SR蛋白的主要激酶， （SRPK2仅限于神经系统），我们建议将重点放在具体目标1上，研究其在神经系统中的作用。 从初始细胞衰老到转化的过渡。拟议的研究将确定其监管 最近阐明的由SRSF1（SR蛋白）、MDM2（E3连接酶）组成的三元复合物的功能 用于p53）和RPL 5（一种60S核糖体蛋白）来检验SRPK 1调节细胞膜形成的假设。 三元复合物，以控制MDM2从复合物中的释放，从而诱导p53去稳定化。鉴于 在细胞模型上观察到剪接激酶与其他致癌信号的协同作用，我们建议 通过在具体目标2中开发动物模型来确定这种体内协同作用。我们亦建议探讨 TCGA鉴定的Akt诱导磷酸化位点SRPK1突变的生物学意义 项目在第三个具体目标中，我们建议寻求一种新的化学策略来阻断SRPK1，因为 新的证据表明SRPK1可能是一个关键的癌症靶点，新的SRPK1抑制剂的特征已经 产生了一系列令人兴奋的结果，表明开发这种抑制剂作为一种有效的 抗癌剂。在这个目标中，拟议的实验将使用化学工具来探索 在前两个目标中开发的细胞和动物模型上的癌症信号传导。

Project Summary This proposal seeks competitive renewal of the grant GM052872, which has been supporting our basic research on SR protein-specific kinases in the past two decades. In light of our recent discoveries that SRPKs are largely responsible for transducing growth factor signaling to regulate alternative splicing in mammalian cells, and SRPK1 is able to act either as an oncogene or tumor suppressor by regulating the recruitment of a critical Akt-specific phosphatase PHLPP1, we are in a unique position to attack novel tumorigenic mechanisms associated with altered SRPK1 function. As SRPK1 is the major kinase for SR proteins in most tissues (SRPK2 is restricted to the nerve system), we propose to focus in specific aim 1 on investigating its role in the transition from initial cell senescence to transformation. The proposed studies will determine its regulatory function on a recently elucidated ternary complex consisting of SRSF1 (an SR protein), MDM2 (an E3 ligase for p53), and RPL5 (a 60S ribosomal protein) to test the hypothesis that SRPK1 regulates the formation of the ternary complex to control the release of MDM2 from the complex to induce p53 destabilization. Given the synergy of the splicing kinase with other oncogenic signals observed on cellular models, we propose to determine such synergy in vivo by developing animal models in specific aim 2. We also propose to explore the biological significance of SRPK1 mutations on Akt-induced phosphorylation sites identified by the TCGA project. In the third specific aim, we propose to pursue a new chemical strategy to block SRPK1 because of new evidence that SRPK1 may be a key cancer target and characterization of a new SRPK1 inhibitor has generated a larger set of exciting results to suggest a great potential in developing the inhibitor as an effective anti-cancer agent. The proposed experiments in this aim will use the chemical tool to probe the mechanism of cancer signaling on the cell and animal models developed in the first two aims.