Runx3 Inactivation Is a Crucial Early Event in the Development of Lung Adenocarcinoma
Runx3 Inactivation Is a Crucial Early Event in the Development of Lung Adenocarcinoma
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DOI：
10.1016/j.ccr.2013.10.003
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发表时间：
2013-11-11
期刊：
影响因子：
50.3
通讯作者：
Bael, Suk-Chul
中科院分区：
文献类型：
--
作者：
Lee, You-Soub;Lee, Jung-Won;Bael, Suk-Chul
靶向灭活小鼠肺内Runx3诱导的粘液性和非粘液性腺瘤，并显著缩短致癌K-RAS诱导的腺癌形成的潜伏期。RUNX3在K-RAS基因突变的人肺腺癌中经常失活。苍蝇突变体库的功能遗传筛选和培养细胞系的分子分析表明，在细胞周期的早期，Runx3以K-RAS依赖的方式与BRD2形成复合体，该复合体诱导p14(Arf)/p19(Arf)和p21(Waf/CIP)的表达。当K-RAS被结构性激活时，Runx3-BRD2复合体保持稳定，p14(ARF)和p21(WAF/CIP)的表达延长。这些结果提供了致癌K-RAS和p14(ARF)-P53途径之间缺失的联系，并可能解释细胞如何防御致癌K-RAS。
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.