p53 is a critical coordinator of a wide range of stress responses. To facilitate 
a rapid response to stress, p53 is produced constitutively but is negatively 
regulated by MDM2. MDM2 can inhibit p53 in multiple independent ways: by binding 
to its transcription activation domain, inhibiting p53 acetylation, promoting 
nuclear export, and probably most importantly by promoting proteasomal 
degradation of p53. The latter is achieved via MDM2's E3 ubiquitin ligase 
activity harbored within the MDM2 RING finger domain. We have discovered that 
MTBP promotes MDM2-mediated ubiquitination and degradation of p53 and also MDM2 
stabilization in an MDM2 RING finger-dependent manner. Moreover, using small 
interfering RNA to down-regulate endogenous MTBP in unstressed cells, we have 
found that MTBP significantly contributes to MDM2-mediated regulation of p53 
levels and activity. However, following exposure of cells to UV, but not 
gamma-irradiation, MTBP is destabilized as part of the coordinated cellular 
response. Our findings suggest that MTBP differentially regulates the E3 
ubiquitin ligase activity of MDM2 towards two of its most critical targets 
(itself and p53) and in doing so significantly contributes to MDM2-dependent p53 
homeostasis in unstressed cells.