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.