Department of Cell and Tissue Biology and Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA.
Stem Cell Reports. 2015 Mar 10;4(3):374-89. doi: 10.1016/j.stemcr.2015.01.019. Epub 2015 Feb 26.
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.
胚胎干细胞 (ESCs) 采用了加速的细胞周期程序，缩短了间隙期，并过早表达细胞周期调节蛋白，包括细胞周期蛋白和细胞周期蛋白依赖性激酶 (CDKs)。我们研究了 CDK 抑制对调节 ESC 增殖和存活的途径的影响。我们发现，抑制周期蛋白依赖性激酶 1 (CDK1) 会导致 DNA 损伤反应的激活、核 p53 的稳定、包括 NOXA 在内的一组 p53 靶基因的激活以及抗凋亡蛋白 MCL1 的负调控在人和小鼠 ESCs 中，但不是分化细胞。我们证明 MCL1 在 ESCs 中高度表达，并且缺失 MCL1 会导致 ESC 死亡。最后，我们表明，临床相关的 CDK1 抑制剂可防止 ESC 衍生肿瘤的形成，并诱导已建立的 ESC 衍生肿瘤的坏死。我们的数据表明，ES 细胞通过 p53/NOXA/MCL1 途径对 CDK1 抑制具有独特的敏感性。
