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.
Show how Src-phosphorylation of Mdm2 converts it to a neddylating enzyme, and inactivates p53's the ability to induce the tumor suppressor Maspin. Demonstrate that there is a p53/pVHL complex that induces Maspin in response to hypoxia and how Mdm2 can disrupt this tumor suppressor axis.
|Batuello, Christopher N; Hauck, Paula M; Gendron, Jaimie M et al. (2015) Src phosphorylation converts Mdm2 from a ubiquitinating to a neddylating E3 ligase. Proc Natl Acad Sci U S A 112:1749-54|