Inactivation of p53 in almost half of human cancer is caused by aberrations in regulation rather than gene mutation. A better understanding of the mechanisms underlying such p53 inactivation will not only offer new insight into tumorigenesis but also enable the development of strategies to restore p53 function for cancer therapeutics. Recognizing the prevalence of deregulated tyrosine kinase (TK) signaling in tumorigenesis and cancer therapy resistance, we searched for potential TKs able to interfere with the p53 pathway by focusing on the MDM2/MDMX complex because our recent genetic study demonstrated that these two essential p53 inhibitors function together in p53 control. By screening a TK library, a number of candidates were identified and their effect on the MDM2/MDMX complex and p53 activity was confirmed. We hypothesize that oncogenic TKs inactivate p53 at least in part by impinging on the MDM2/MDMX complex, leading to promotion of tumorigenesis and therapeutic resistance (Fig. 1). The proposed work will use both in vitro and in vivo models to functionally characterize TK-mediated modulation of the MDM2/MDMX complex in the context of p53 regulation. We will also explore the use of TK inhibitors (TKIs) to restore p53 function for improving cancer therapeutics efficacy. Three specific aims are proposed: 1) To characterize TKs-mediated modulation of the MDM2/MDMX complex. 2) To determine in vivo biological relevance of TKs-induced alteration of the MDM2/MDMX complex. 3) To explore the therapeutic implications of restoring p53 function via inhibition of TKs.