The Mdm2 proto-oncoprotein is the primary negative regulator for p53. While it is believed that Mdm2 degradation is regulated via its own E3 ubiquitin ligase activity, recent development of knock-in mouse models demonstrates that Mdm2 E3 ligase function is dispensable for self-degradation in vivo. Here, we show that the anaphase-promoting complex/cyclosome (APC/C) is an E3 ubiquitin ligase for Mdm2 degradation. We demonstrate that APC2, a scaffold subunit of APC/C, binds to Mdm2 and is required for Mdm2 polyubiquitination and proteasomal degradation. Downregulation of APC2 by RNAi results in transcription-independent accumulation of Mdm2 and attenuation of stress-induced p53 stabilization, leading to decreased senescence and increased cell survival. Furthermore, APC2 expression is frequently downregulated in human cancers; in tumor cell lines, APC2 downregulation correlates with Mdm2 overexpression. Our study shows the regulation of Mdm2 by the E3 ubiquitin ligase APC/C and has important therapeutic implications for tumors with Mdm2 overexpression
