Runt-related transcription factor RUNX3 is a target of MDM2-mediated ubiquitination

The p14^ARF-MDM2-p53 pathway constitutes an effective mechanism for protecting cells from oncogenic stimuli such as activated Ras and Myc. Importantly, Ras activation induces p14^ARF andoft en occurs earlier than p53 inactivation during cancer development. Here, we show that RUNX3, a tumor suppressor in various tumors including stomach, bladder, colon, andlung, is stabilizedby Ras activation through the p14^ARF-MDM2 signaling pathway. RUNX3 directly binds MDM2 through its Runt-related DNA-binding domain. MDM2 blocks RUNX3 transcriptional activity by interacting with RUNX3 through an acidic domain adjacent to the p53-binding domain of MDM2 andubiquitinat es RUNX3 on key lysine residues to mediate nuclear export and proteasomal degradation. Our data indicate that the lineage-specific tumor suppressor RUNX3 andthe ubiquitous p53 protein are both principal responders of the p14 ^ARF-MDM2 cell surveillance pathway that prevents pathologic consequences of abnormal oncogene activation.