Oncogenes induce and activate endogenous p73 protein

The identification of upstream pathways that signal to TP73 is crucial for understanding the biological role of this gene. Since some evidence suggest s that TP73 might play a role in tumorigenesis, we asked whether oncogenes can induce and activate endogenous TP73. Here, we show that endogenous p73 alpha and beta proteins are up-regulated in p53-deficient tumor cells in re sponse to overexpressed E2F1, c-Myc, and Elk E2F1, c-Myc, and E1A-mediated p73 up-regulation leads to activation of the p73 transcription function, as shown by p73-responsive reporter activity and by induction of known endoge nous p73 target gene products such as p21 and HDM2. Importantly, E2F1-, c-M yc-, and E1A-mediated activation of endogenous p73 induces apoptosis in SaO s-2 cells. Conversely, inactivation of p73 by a dominant negative p73 inhib itor (p73DD), but not by a mutant p73DD, inhibits oncogene-induced apoptosi s. These data show that oncogenes can signal to TP73 in vivo. Moreover, in the absence of p53, oncogenes may enlist p73 to induce apoptosis in tumor c ells.