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.
With our preliminary data indicating the MDM complex as a target of a number of TKs, the application aims at functional characterization of TK signaling network-induced modifications of this complex, which is expected to uncover novel mechanisms of p53 inactivation. Even though it is widely observed that deregulated TKs contribute to carcinogenesis and resistance to cancer therapeutics, the underlying mechanisms are not yet fully elucidated. Impediment of p53 activation by the TKs via affecting the MDM complex would represent a novel mechanism of tumorigenesis and therapy resistance. Our study is significant as it would not only offer insight into deregulated TK-induced carcinogenesis but also provide a basis for a combined use of radio- or chemotherapy with TKIs, which would restore the responsiveness of p53 to chemo or radiotherapy, resulting in improved therapeutic efficacy.
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