Mdm2, a protein that regulates p53 stability by targeting it for proteasomal degradation, has been shown to be an E3 ubiquitin protein ligase (E3) for both itself and p53. The activity of Mdm2 as an E3 is dependent on its RING finger domain, which coordinates zinc ions. The study demonstrates that Mdm2 can mediate its own ubiquitination in a RING finger-dependent manner, requiring only the ubiquitin-activating enzyme (E1) and ubiquitin-conjugating enzyme (E2). Additionally, the RING finger mutations that abolish Mdm2's intrinsic E3 activity also stabilize p53 and Mdm2 in cells. A heterologous RING finger from Praja1 can substitute for the Mdm2 RING finger in mediating Mdm2's own ubiquitination and proteasomal degradation but not p53 ubiquitination or degradation. These findings suggest that the RING finger of Mdm2 may have substrate specificity in recognizing heterologous substrates.Mdm2, a protein that regulates p53 stability by targeting it for proteasomal degradation, has been shown to be an E3 ubiquitin protein ligase (E3) for both itself and p53. The activity of Mdm2 as an E3 is dependent on its RING finger domain, which coordinates zinc ions. The study demonstrates that Mdm2 can mediate its own ubiquitination in a RING finger-dependent manner, requiring only the ubiquitin-activating enzyme (E1) and ubiquitin-conjugating enzyme (E2). Additionally, the RING finger mutations that abolish Mdm2's intrinsic E3 activity also stabilize p53 and Mdm2 in cells. A heterologous RING finger from Praja1 can substitute for the Mdm2 RING finger in mediating Mdm2's own ubiquitination and proteasomal degradation but not p53 ubiquitination or degradation. These findings suggest that the RING finger of Mdm2 may have substrate specificity in recognizing heterologous substrates.