Chi X-Z, Lee J-W, Lee Y-S, Park I Y, Ito Y, Bae S-C
Department of Biochemistry, School of Medicine, and Institute for Tumor Research, Chungbuk National University, Cheongju, South Korea.
College of Pharmacy, Chungbuk National University, Cheongju, South Korea.
Oncogene. 2017 Dec 14;36(50):6884-6894. doi: 10.1038/onc.2017.290. Epub 2017 Aug 28.
The restriction (R)-point decision is fundamental to normal differentiation and the G-S transition, and the decision-making machinery is perturbed in nearly all cancer cells. The mechanisms underlying the cellular context-dependent R-point decision remain poorly understood. We found that the R-point was dysregulated in Runx3mouse embryonic fibroblasts (MEFs), which formed tumors in nude mice. Ectopic expression of Runx3 restored the R-point and abolished the tumorigenicity of Runx3MEFs and K-Ras-activated Runx3MEFs (Runx3;K-Ras). During the R-point, Runx3 transiently formed a complex with pRb and Brd2 and induced Cdkn1a (p21; p21), a key regulator of the R-point transition. Cyclin D-CDK4/6 promoted dissociation of the pRb-Runx3-Brd2 complex, thus turning off p21 expression. However, cells harboring oncogenic K-Ras maintained the pRb-Runx3-Brd2 complex and p21 expression even after introduction of Cyclin D1. Thus, Runx3 plays a critical role in R-point regulation and defense against cellular transformation.
限制（R）点决策对于正常分化和G-S转换至关重要，并且几乎在所有癌细胞中决策机制都会受到干扰。细胞背景依赖性R点决策的潜在机制仍知之甚少。我们发现，Runx3基因敲除小鼠胚胎成纤维细胞（MEFs）中的R点失调，这些细胞在裸鼠中形成肿瘤。Runx3的异位表达恢复了R点，并消除了Runx3基因敲除MEFs和K-Ras激活的Runx3基因敲除MEFs（Runx3；K-Ras）的致瘤性。在R点期间，Runx3与pRb和Brd2短暂形成复合物，并诱导R点转换的关键调节因子Cdkn1a（p21；p21）。细胞周期蛋白D-CDK4/6促进pRb-Runx3-Brd2复合物的解离，从而关闭p21的表达。然而，携带致癌K-Ras的细胞即使在引入细胞周期蛋白D1后仍维持pRb-Runx3-Brd2复合物和p21的表达。因此，Runx3在R点调节和抵御细胞转化中起关键作用。
