Mutations in p73 are rare in cancer. Emerging evidence suggests that the 
relative expression of various p73 isoforms may contribute to tumorigenesis. 
Alternative promoters and N-terminal splicing result in the transcription and 
processing of either full-length (TA) or N-terminally truncated (deltaN) p73 
isoforms. TAp73 possesses pro-apoptotic functions, while deltaNp73 has 
anti-apoptotic properties via functional inhibition of TAp73 and p53. Here, we 
report that TAp73, but not deltaNp73, is covalently modified by NEDD8 under 
physiologic conditions in an Mdm2-dependent manner. Co-expression of NEDP1, a 
cysteine protease that specifically cleaves NEDD8 conjugates, was shown to 
deneddylate TAp73. In addition, blockage of the endogenous NEDD8 pathway 
increased TAp73-mediated transactivation of p53- and p73-responsive 
promoter-driven reporter activity, and in conjunction, neddylated TAp73 species 
were found preferentially in the cytoplasm. These results suggest that Mdm2 
attenuates TAp73 transactivation function, at least in part, by promoting 
NEDD8-dependent TAp73 cytoplasmic localization and provide the first evidence of 
a covalent post-translational modification exclusively targeting the TA isoforms 
of p73.