Regulation of Mdm2 activity by kinase signaling pathways

描述(申请人提供)：小鼠双分钟(MDM2)在人类恶性肿瘤中经常过度表达，它通过p53依赖和独立的机制促进肿瘤进展。在激酶中，调节MDM2活性的信号级联并不是很好地定义为对生长因子的响应。我们发现MDM2受c-Src的调节，c-Src将MDM2转化为一种半衰酶，从而延长了MDM2的半衰期。此外，MDM2还能与肿瘤抑制因子von Hippel Lindau(PVHL)结合。MDM2能将NEDD8与pVHL和P53结合。MDM2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，细胞表面的信号通路将MDM2改变为脱氧核酸酶，然后阻止p53-pVHL复合体的形成，Aim1中下游效应的诱导实验将确定Src磷酸化是否将MDM2转变为脱氧核酸酶。在AIM2中的实验将建立一个p53/pVHL/Maspin肿瘤抑制网络，并表明MDM2是否可以调节p53和/或pVHL来阻止Maspin的诱导。我们的研究将揭示几条新的通路：蛋白激酶介导的MDM2通路；抗血管生成的p53/pVHL/Maspin网络；以及MDM2阻止pVHL整合到p53/pVHL/Maspin通路以促进肿瘤进展。这些研究的结果将揭示几条未被发现的途径，这些途径最终将导致改进的治疗方法，以针对这些途径来改善患者的结果。

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.