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MDM2, one of the transcriptional targets of p53, can target p53 for degradation in a negative feedback loop. The p53-related protein p73, however, can bind to MDM2 but is not consequently down-regulated. Here we demonstrate that p73 could transactivate the MDM2 promoter in p53-null cell lines. In p53-null cell lines, the level of MDM2 was increased by p73 due to increases in transcription and protein stability of MDM2. In transient transfection assays, inhibition of the transcriptional activity of p73 required a higher amount of MDM2 than that of p53. This is probably due to the fact that MDM2 can target p53, but not p73, for degradation. We demonstrated further that the level of p53 could be altered by a cooperation between MDM2 and p73, but not by transcriptional inactive mutants of p73. Expression of p73 resulted in a reduction of the ectopically expressed p53 in transient transfections or of the endogenous p53 induced by Adriamycin- or UV-mediated damage. These reductions of p53 were likely to be due to an increase in MDM2-mediated proteolysis. These results suggest the possibility that different levels of p73 in the cell may act as a mechanism to modulate p53 responses after DNA damage and other stresses and that an increase rather than a decrease in p73 may play a role in tumorigenesis.