Runx3 Inactivation Is a Crucial Early Event in the Development of Lung Adenocarcinoma

Summary Targeted inactivation of Runx3 in mouse lung induced mucinous and nonmucinous adenomas and markedly shortened latency of adenocarcinoma formation induced by oncogenic K-Ras. RUNX3 was frequently inactivated in K-RAS mutated human lung adenocarcinomas. A functional genetic screen of a fly mutant library and molecular analysis in cultured cell lines revealed that Runx3 forms a complex with BRD2 in a K-Ras-dependent manner in the early phase of the cell cycle; this complex induces expression of p14 ARF / p19 Arf and p21 WAF/CIP . When K-Ras was constitutively activated, the Runx3-BRD2 complex was stably maintained and expression of both p14 ARF and p21 WAF/CIP was prolonged. These results provide a missing link between oncogenic K-Ras and the p14 ARF -p53 pathway, and may explain how cells defend against oncogenic K-Ras .