Abstract
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.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Apoptosis
-
Blotting, Western
-
Cell Transformation, Neoplastic
-
Cells, Cultured
-
Core Binding Factor Alpha 3 Subunit / antagonists & inhibitors
-
Core Binding Factor Alpha 3 Subunit / genetics
-
Core Binding Factor Alpha 3 Subunit / metabolism*
-
Gene Expression Regulation, Neoplastic
-
Humans
-
Immunoprecipitation
-
Kidney / cytology
-
Kidney / metabolism
-
Mutation / genetics
-
Proto-Oncogene Proteins c-mdm2 / genetics
-
Proto-Oncogene Proteins c-mdm2 / metabolism*
-
RNA, Small Interfering / pharmacology
-
Transcription, Genetic
-
Transcriptional Activation
-
Transfection
-
Tumor Suppressor Protein p14ARF / metabolism
-
Tumor Suppressor Protein p53 / genetics
-
Tumor Suppressor Protein p53 / metabolism
-
Ubiquitination
-
Ubiquitins / metabolism*
-
ras Proteins / physiology
Substances
-
Core Binding Factor Alpha 3 Subunit
-
RNA, Small Interfering
-
Runx3 protein, human
-
TP53 protein, human
-
Tumor Suppressor Protein p14ARF
-
Tumor Suppressor Protein p53
-
Ubiquitins
-
MDM2 protein, human
-
Proto-Oncogene Proteins c-mdm2
-
ras Proteins