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Runt-Related Transcription Factor RUNX3 Is a Target of MDM2-Mediated Ubiquitination

Departments of ¹ Biochemistry and ² Urology, College of Medicine, Institute of Tumor Research, Chungbuk National University; ³ Department of Radiation Oncology, Chungbuk National University College of Medicine, Cheongju, South Korea; ⁴ Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, Inchon, South Korea; ⁵ Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, Worcester, Massachusetts; and ⁶ Institute of Molecular and Cell Biology, Proteos, Singapore, Singapore

Requests for reprints: Suk-Chul Bae, Department of Biochemistry, College of Medicine, Institute of Tumor Research, Chungbuk National University, 410 Sung Bong-Ro, Cheongju, Chungbuk 361-763, Korea. Phone: 82-43-261-2842; Fax: 82-43-274-8705; E-mail: scbae{at}chungbuk.ac.kr or Andre J. van Wijnen, Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655. E-mail: Andre.VanWijnen{at}umassmed.edu.

Key Words: RUNX3 • Ras • p14ARF • MDM2 • 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 and often occurs earlier than p53 inactivation during cancer development. Here, we show that RUNX3, a tumor suppressor in various tumors including stomach, bladder, colon, and lung, is stabilized by 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 and ubiquitinates RUNX3 on key lysine residues to mediate nuclear export and proteasomal degradation. Our data indicate that the lineage-specific tumor suppressor RUNX3 and the ubiquitous p53 protein are both principal responders of the p14^ARF-MDM2 cell surveillance pathway that prevents pathologic consequences of abnormal oncogene activation. [Cancer Res 2009;69(20):8111–9]