Regulation of Mdm2 activity by kinase signaling pathways

描述（由申请人提供）：小鼠双分钟（Mdm2）在人类恶性肿瘤中频繁过表达，通过p53依赖和不依赖机制促进肿瘤进展。在激酶信号中，调节Mdm2活性的级联反应在对生长因子的反应中没有很好的定义。我们发现Mdm2受c-Src调控，c-Src将Mdm2转化为一种类木化酶，从而延长Mdm2的半衰期。此外，Mdm2还能与肿瘤抑制因子pVHL结合。Mdm2可将nedd8与pVHL和p53结合。Mdm2在调节pVHL和p53中的作用阻止肿瘤抑制因子Maspin的诱导。因此，我们的中心假设是细胞表面信号通路将Mdm2改变为类木化酶，然后阻断p53-pVHL复合物的形成并诱导下游效应物。Aim1实验将确定Src磷酸化是否将Mdm2改变为类木化酶。Aim2实验将建立p53/pVHL/Maspin肿瘤抑制网络，并验证Mdm2是否可以调节p53和/或pVHL来阻止Maspin的诱导。我们的研究将共同揭示几种新的途径：激酶介导Mdm2的类化活性；抗血管生成p53/pVHL/Maspin网络；Mdm2阻止pVHL整合到p53/pVHL/Maspin通路中，从而导致肿瘤进展。这些研究的结果将揭示一些未被发现的途径，最终将导致针对这些途径的改进治疗，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.