Characterization of thep53 tumor suppressor andmdm2 oncoprotein in human tumors
Proteins encoded by the mdm2 gene, which has potential transforming activity that can be activated by overexpression, can bind to, and inhibit the function of, the protein product of the p53 tumor suppressor gene. As reported here, we have identified two human choriocarcinoma cell lines that express high levels of both p53 and mdm2 proteins. Although mutations in the p53 gene are frequently associated with p53 protein overexpression, several lines of evidence demonstrate that the p53 in these tumor cells has a wild-type nucleotide sequence. Furthermore, the degree of mdm2 protein overexpression in these cells does not result from gene amplification, elevated RNA expression, or altered protein stability; rather our data indicates that the elevated levels of mdm2 protein in these cell lines results from enhanced translation, a mechanism not previously implicated in the regulation of mdm2 gene expression. From this initial study, we decided to investigate several questions. First, is the coupling of the overexpressed wild-type p53 and enhanced translation of mdm2 RNA unique to choriocarcinomas or does this occur in any other tumor type? Second, what is the exact mechanism by which enhanced translation of mdm2 RNA occur in these cells? Third, is there a link between the overexpression of wild-type p53 and the enhanced translation of mdm2 RNA? Lastly, does the overexpression of wild-type p53 and mdm2 proteins contribute to the process of transformation within these tumors? Through our research, we have discovered that the overexpression of wild-type p53 and enhanced translation of mdm2 RNA occurs in a significant percentage and wide variety of human tumors. Furthermore we show that the high levels of wild-type p53 present within these tumors upregulates the expression of a previously unidentified form of mdm2 RNA containing a novel 5$\sp\prime$ untranslated region that is associated with increased translational efficiency, contributing to the high level of mdm2 protein observed. Finally, our results suggest that these tumor cells containing high levels of both wild-type p53 protein and mdm2 proteins may well represent a new scenario of transformation involving these two genes.
Landers, John Edward, "Characterization of thep53 tumor suppressor andmdm2 oncoprotein in human tumors" (1996). Dissertations available from ProQuest. AAI9627952.