期刊
STEM CELL REPORTS
卷 4, 期 3, 页码 374-389出版社
CELL PRESS
DOI: 10.1016/j.stemcr.2015.01.019
关键词
-
资金
- NIH [R01CA136717, U01 DK089541, R01 GM101180]
- UCSF BOP Atwater Award
- V-Foundation Scholar Award
- Helmsley Trust
- CBCRP Pre-doctoral Fellowship
- NSF Pre-doctoral Fellowship
- JDRF postdoctoral fellowship
- American Cancer Society Research Scholar Award
- Harrington Discovery Institute Scholar Innovator Award
- Damon Runyon Cancer Research Foundation [DRG-109-10]
- NIH NCI [5K08CA172288]
- [RO1CA136577]
- [NIHR01 DK095306]
Embryonic stem cells (ESCs) have adopted an accelerated cell-cycle program with shortened gap phases and precocious expression of cell-cycle regulatory proteins, including cyclins and cyclin-dependent kinases (CDKs). We examined the effect of CDK inhibition on the pathways regulating proliferation and survival of ESCs. We found that inhibiting cyclin-dependent kinase 1 (CDK1) leads to activation of the DNA damage response, nuclear p53 stabilization, activation of a subset of p53 target genes including NOXA, and negative regulation of the anti-apoptotic protein MCL1 in human and mouse ESCs, but not differentiated cells. We demonstrate that MCL1 is highly expressed in ESCs and loss of MCL1 leads to ESC death. Finally, we show that clinically relevant CDK1 inhibitors prevent formation of ESC-derived tumors and induce necrosis in established ESC-derived tumors. Our data demonstrate that ES cells are uniquely sensitive to CDK1 inhibition via a p53/NOXA/MCL1 pathway.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据