Regulation of Mdm2 activity by kinase signaling pathways

描述（由申请人提供）：鼠双微体（Mdm2）在人类恶性肿瘤中频繁过度表达，其通过p53依赖性和非依赖性机制促进肿瘤进展。在调节 Mdm2 活性的激酶信号级联中，对于生长因子的反应尚未明确定义。我们发现Mdm2受到c-Src的调节，c-Src将Mdm2转化为neddylated酶，从而增加Mdm2的半衰期。此外，Mdm2 可以与肿瘤抑制因子 von Hippel Lindau (pVHL) 结合。 Mdm2 可以将 nedd8 与 pVHL 和 p53 结合。 Mdm2 在调节 pVHL 和 p53 中的作用可阻止肿瘤抑制因子 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 neddylating 酶，然后阻止 p53-pVHL 复合物的形成和下游效应子的诱导。Aim1 中的实验将确定 Src 磷酸化是否将 Mdm2 改变为 neddylating 酶。 Aim2 中的实验将建立 p53/pVHL/Maspin 肿瘤抑制网络，并显示 Mdm2 是否可以调节 p53 和/或 pVHL 以阻止 Maspin 诱导。我们的研究将共同​​展示几种新的途径：Mdm2 激酶介导的 neddylation 活性；抗血管生成 p53/pVHL/Maspin 网络； Mdm2 阻止 pVHL 整合到 p53/pVHL/Maspin 通路中以促进肿瘤进展。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改进治疗方法，从而改善患者的治疗结果。

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.