Regulation of Mdm2 activity by kinase signaling pathways

描述（由申请人提供）：鼠双微体（Mdm 2）在人类恶性肿瘤中频繁过表达，其通过p53依赖性和非依赖性机制促进肿瘤进展。在激酶信号级联调节Mdm 2活性没有很好地定义在响应生长因子。我们已经发现Mdm 2受c-Src调节，c-Src将Mdm 2转化为neddylating酶，从而增加Mdm 2的半衰期。此外，Mdm 2可以结合肿瘤抑制因子von Hippel Lindau（pVHL）。Mdm 2可以将nedd 8缀合至pVHL和p53。Mdm 2在调节pVHL和p53中的作用阻止了肿瘤抑制因子Maspin的诱导。因此，我们的中心假设是细胞表面信号传导途径将Mdm 2改变为neddylating酶，其然后阻断p53-pVHL复合物的形成和下游效应物的诱导。Aim 1中的实验将确定Src磷酸化是否将Mdm 2改变为neddylating酶。Aim 2中的实验将建立p53/pVHL/Maspin肿瘤抑制网络，并显示Mdm 2是否可以调节p53和/或pVHL以阻止Maspin诱导。总之，我们的研究将显示几种新的途径：Mdm 2的激酶介导的neddylating活性;抗血管生成p53/pVHL/Maspin网络;以及Mdm 2阻止pVHL整合到p53/pVHL/Maspin途径中以促进肿瘤进展。这些研究的结果将揭示几个未被发现的途径，最终将导致改进的疗法，以针对这些途径，以改善患者的预后。

DESCRIPTION (provided by applicant): The murine double minute (Mdm2) is overexpressed frequently in human malignancies, which contributes to tumor progression through p53-dependent and -independent mechanisms. In the kinase signaling cascades that regulate Mdm2 activity are not well defined in response to growth factors. We have found that Mdm2 is regulated by c-Src, which converts Mdm2 to a neddylating enzyme, which increases the half-life of Mdm2. Moreover, Mdm2 can bind to the tumor suppressor von Hippel Lindau (pVHL). Mdm2 can conjugate nedd8 to pVHL and p53. The role of Mdm2 in regulating pVHL and p53 prevents the induction of the tumor suppressor Maspin. Thus, our central hypothesis is cell surface signaling pathways change Mdm2 to a neddylating enzyme, which then blocks the formation of the p53-pVHL complex and induction of downstream effectors Experiments in Aim1 will determine whether Src phosphorylation changes Mdm2 to a neddylating enzyme. Experiments in Aim2 will establish a p53/pVHL/Maspin tumor suppressor network and show whether Mdm2 can regulate p53 and/or pVHL to prevent Maspin induction. Together our studies will show several novel pathways: kinase mediated-neddylating activity of Mdm2; anti-angiogenic p53/pVHL/Maspin network; and Mdm2 preventing pVHL from integrating into the p53/pVHL/Maspin pathway for tumor progression. Results from these studies will reveal several undiscovered pathways that will ultimately lead to improved therapies to target these pathways to improve patient outcomes.