Mdm2 has been thought to regulate the tumor suppressor p53 in two ways: by 
masking p53's access to transcriptional machinery, and by ubiquitinating p53, 
targeting it for proteasomal degradation. This dogma was recently challenged by 
data generated from knockin mice in which Mdm2's RING E3 ubiquitin ligase 
activity was abrogated by a single point mutation. The RING mutant Mdm2 is fully 
capable of binding with p53, yet cannot suppress p53 activity, suggesting that 
Mdm2 cannot block p53 by binding alone, without ubiquitination. Data from the 
RING knockin mice also revealed that endogenous Mdm2 does not, as previously 
thought, regulate its own stability by self-ubiquitination. In this review, we 
will discuss these findings and their relevance to the field, including 
potential reasons for the discrepancies between previous data and that generated 
by our knockin mice, as well as the feasibility of targeting Mdm2's E3 ubiquitin 
ligase activity in cancer. We will also discuss additional research questions 
that may be addressed using our mouse model.