Department of Biochemistry, College of Medicine, Chungbuk National University, Cheongju 361-763, South Korea.
Cancer Cell. 2013 Nov 11;24(5):603-16. doi: 10.1016/j.ccr.2013.10.003.
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.
靶向敲除小鼠肺中的 Runx3 可诱导黏液性和非黏液性腺瘤，并显著缩短致癌性 K-Ras 诱导的腺癌形成的潜伏期。RUNX3 在 K-RAS 突变的人类肺腺癌中经常失活。对果蝇突变文库的功能遗传筛选和培养细胞系中的分子分析表明，在细胞周期的早期，Runx3 以依赖于 K-Ras 的方式与 BRD2 形成复合物；该复合物诱导 p14(ARF)/p19(Arf)和 p21(WAF/CIP)的表达。当 K-Ras 持续激活时，Runx3-BRD2 复合物稳定维持，p14(ARF)和 p21(WAF/CIP)的表达延长。这些结果提供了致癌性 K-Ras 与 p14(ARF)-p53 通路之间缺失的联系，并可能解释了细胞如何抵抗致癌性 K-Ras。
