TGFbeta is a functional cytokine that has been implicated in tumor suppression. The growth of normal cells and early stage tumor cells is inhibited by TGFbeta. However, late stage tumors often become refractory to TGFbeta, as an adaptation to metastasis. The mechanisms for TGFbeta resistance in humor tumors has not been completely understood. Our results indicate that an oncogene, mdm2, is a likely cause of TGFbeta resistance through a p53-independent mechanism, most likely by interference with the Rb/3E2F functions. While the interaction between MDM2 and p53 has been well characterized, little is known about the p53-independent oncogenic activity of MDM2. The goal of this application is to further explore the p53-independent roles of MDM2 in TGFbeta resistance and tumorigenesis during human tumor development. First, mutational analysis will be performed to determine which regions and activities of MDM2 are essential for it ability to confer TGFbeta resistance. Second, the requirement for the p53- independent activity of MDM2 in TGFbeta resistance and tumorigenesis will e analyzed in human tumor cell lines created with defined genetic alterations involving MDM2 over-expression. Finally, anti-sense MDM2 inhibitors will be used to examine the independence of TGFbeta resistance on MDM2 expression in human breast carcinomas. These studies will not only offer insights into the diverse pathways leading to the loss of TGFbeta sensitivity in tumors, but also reveal novel roles of MDM2 in tumorigenesis.
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