期刊
CANCER CELL
卷 20, 期 5, 页码 620-634出版社
CELL PRESS
DOI: 10.1016/j.ccr.2011.10.001
关键词
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资金
- Swedish Wenner-Gren Foundations
- NIH [R01 CA083688, RL1 DE019022]
- Susan G. Komen for the Cure
- Ellison Foundation, Boston
- DFCI Strategic Initiative
- CCSB
Cyclin D-dependent kinases (CDK4 and CDK6) are positive regulators of cell cycle entry and they are over-active in the majority of human cancers. However, it is currently not completely understood by which cellular mechanisms CDK4/6 promote tumorigenesis, largely due to the limited number of identified substrates. Here we performed a systematic screen for substrates of cyclin D1-CDK4 and cyclin D3-CDK6. We identified the Forkhead Box M1 (FOXM1) transcription factor as a common critical phosphorylation target. CDK4/6 stabilize and activate FOXM1, thereby maintain expression of G1/S phase genes, suppress the levels of reactive oxygen species (ROS), and protect cancer cells from senescence. Melanoma cells, unlike melanocytes, are highly reliant on CDK4/6-mediated senescence suppression, which makes them particularly susceptible to CDK4/6 inhibition.
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