The MDM2 RING-finger domain is required to promote p53 nuclear export

MDM2 can bind to p53 and promote its ubiquitination and subsequent degradat ion by the proteasome. Current models propose that nuclear export of p53 is required for MDM2-mediated degradation, although the function of MDM2 in p 53 nuclear export has not been clarified. Here we show that MDM2 can promot e the nuclear export of p53 in transiently transfected cells. This activity requires the nuclear-export signal (NES) of p53, but not the NES of MDM2. A mutation within the MDM2 RING-finger domain that inhibits p53 ubiquitinat ion also inhibits the ability of MDM2 to promote p53 nuclear export. Finall y, inhibition of nuclear export stabilizes wild-type p53 and leads to accum ulation of ubiquitinated p53 in the nucleus. Our results indicate that MDM2 -mediated ubiquitination, or other activities associated with the RING-fing er domain, can stimulate the export of p53 to the cytoplasm through the act ivity of the p53 NES.