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

Abstract

The p14ARF -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]

Runx3 is required for the differentiation of lung epithelial cells and suppression of lung cancer

“…This may indicate that K-ras mutation is a secondary event associated with the progression of adenoma to adenocarcinoma in individuals with reduced levels of Runx3. This possibility is supported by our earlier observation that Runx3 is induced by the oncogenic ras mutation and stimulates apoptosis, suggesting that Runx3 is involved in the oncogene surveillance mechanism (Chi et al, 2009). Therefore, downregulation of Runx3 may induce lung adenoma development by disturbing lineage-specific differentiation of lung epithelial cells and by promoting progression to adenocarcinoma by allowing oncogenic mutations.…”

RUNX3 is multifunctional in carcinogenesis of multiple solid tumors

“…ubiquitination of RUNX3, resulting in its cytoplasmic translocation and degradation (Chi et al, 2009). Src kinase phosphorylates tyrosine residues in RUNX3, and overexpression of activated Src correlates with RUNX3 cytoplasmic localization (Goh et al, 2010).…”

“…We have earlier found that RUNX3 mRNA transcripts in GIT are relatively low compared with peripheral blood . Moreover, RUNX3 was recently shown to interact with MDM2, which mediates ubiquitinylation and proteolytic degradation of RUNX3 (Chi et al, 2009). MDM2 is one of the E3 ligases in the ubiquitin-proteasome system and is known to ubiquitinate and degrade p53 tumor suppressor.…”

“…Aside from mismatch repair, Runx3 was found to interact with DNA repair protein Ku70 (Tanaka et al, 2007), a component of the major repair mechanism for double-strand DNA breaks, the non-homologous end-joining repair. The report detailing the interaction of RUNX3 and MDM2 at the Runt domain (see above) provides another interesting viewpoint that RUNX3, in addition to p53, is negatively regulated by p14 ARF -MDM2 surveillance pathway in response to aberrant Ras oncogene activation (Chi et al, 2009). …”

Stabilization of RNT-1 Protein, Runt-related Transcription Factor (RUNX) Protein Homolog of Caenorhabditis elegans, by Oxidative Stress through Mitogen-activated Protein Kinase Pathway

“…In addition, diverse cellular signaling events that modify both the transcriptional and posttranscriptional status of the RUNX genes affect the amount and the activity of RUNX proteins in response to developmental or environmental cues. Transcriptional regulation, such as chromatin remodeling (6) and DNA methylation (7)(8)(9)(10), and posttranscriptional regulation, such as acetylation (11,12), ubiquitination (13)(14)(15), and phosphorylation (16,17), have been reported as the regulation mechanisms of RUNX activity.…”