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Runx3 plays a critical role in restriction-point and defense against cellular transformation.


ABSTRACT: The restriction (R)-point decision is fundamental to normal differentiation and the G1-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 Runx3-/-mouse embryonic fibroblasts (MEFs), which formed tumors in nude mice. Ectopic expression of Runx3 restored the R-point and abolished the tumorigenicity of Runx3-/-MEFs and K-Ras-activated Runx3-/-MEFs (Runx3-/-;K-RasG12D/+). During the R-point, Runx3 transiently formed a complex with pRb and Brd2 and induced Cdkn1a (p21Waf1/Cip1/Sdi1; 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.

SUBMITTER: Chi XZ 

PROVIDER: S-EPMC5735299 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Runx3 plays a critical role in restriction-point and defense against cellular transformation.

Chi X-Z XZ   Lee J-W JW   Lee Y-S YS   Park I Y IY   Ito Y Y   Bae S-C SC  

Oncogene 20170828 50


The restriction (R)-point decision is fundamental to normal differentiation and the G<sub>1</sub>-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 Runx3<sup>-/-</sup>mouse embryonic fibroblasts (MEFs), which formed tumors in nude mice. Ectopic expression of Runx3 restored the R-point and abolished the tumorigenic  ...[more]

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