The levels of MDM2 protein are decreased by a proteasome-mediated proteolysis prior to caspase-3-dependent pRb and PARP cleavages

MDM2 is a substrate of caspase-3 in p53-mediated apoptosis. In addition, MD M2 mediates its own ubiquitination in a RING finger-dependent manner. Thus, we investigated whether MDM2 is degraded through a ubiquitin-dependent pro teasome pathway in the absence of p53. When HL-60 cells, p53 null, were tre ated with etoposide, MDM2 was markedly decreased prior to caspase-3-depende nt retinoblastoma tumor suppressor protein (pRb) and poly (ADP-ribose) poly merase (PARP) cleavages. Moreover, down-regulation of MDM2 level was not co upled with its mRNA down-regulation. However, the level of MDM2 was partial ly restored by proteasome inhibitors such as LLnL and lactacystin, even in the presence of etoposide. Our results suggest that, in the p53 null status , MDM2 protein level is decreased by proteasome-mediated proteolysis prior to caspase-3-dependent PARP and pRb cleavages.