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 p14ARF-p53 pathway, and may explain how cells defend against oncogenic K-Ras. [Copyright &y& Elsevier]