A link between p73 transcriptional activity and p73 degradation.

The p53 family of proteins includes three members, p53, p63, and p73. The levels and stability of p53 are controlled in large part by MDM2, which can bind the p53 N-terminus and promote its degradation. Because the MDM2 gene is transcriptionally activated by p53, it forms part of an autoregulatory feedback loop that directly links the transcriptional activity of p53 with its degradation. In contrast, little is known about the mechanisms that control p63 or p73 stability. In the current study, p73 deletion or point mutants that lacked transactivation activity were stable compared to wild-type p73. A naturally occurring p73 variant (DeltaNp73) was also stable compared to wild-type p73. Finally, fusion of the VP16-transactivation domain to an inactive, stable p73 mutant restored transactivation function and rendered the mutant protein unstable. These results demonstrate that p73 transactivation activity is necessary for rapid p73 turnover, and suggest that one or more transcriptional targets of p73 may promote its degradation.