Zhao Rui, Deibler Richard W, Lerou Paul H, Ballabeni Andrea, Heffner Garrett C, Cahan Patrick, Unternaehrer Juli J, Kirschner Marc W, Daley George Q
Stem Cell Transplantation Program, Division of Pediatric Hematology/Oncology, Manton Center for Orphan Disease Research, Boston Children's Hospital, Dana-Farber Cancer Institute, Department of Biological Chemistry and Molecular Pharmacology, Harvard Stem Cell Institute, and Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115;
Department of Systems Biology, Harvard Medical School, Boston, MA 02115; and.
Proc Natl Acad Sci U S A. 2014 Nov 4;111(44):15768-73. doi: 10.1073/pnas.1417518111. Epub 2014 Oct 16.
Rapid progression through the cell cycle and a very short G1 phase are defining characteristics of embryonic stem cells. This distinct cell cycle is driven by a positive feedback loop involving Rb inactivation and reduced oscillations of cyclins and cyclin-dependent kinase (Cdk) activity. In this setting, we inquired how ES cells avoid the potentially deleterious consequences of premature mitotic entry. We found that the pluripotency transcription factor Oct4 (octamer-binding transcription factor 4) plays an unappreciated role in the ES cell cycle by forming a complex with cyclin-Cdk1 and inhibiting Cdk1 activation. Ectopic expression of Oct4 or a mutant lacking transcriptional activity recapitulated delayed mitotic entry in HeLa cells. Reduction of Oct4 levels in ES cells accelerated G2 progression, which led to increased chromosomal missegregation and apoptosis. Our data demonstrate an unexpected nontranscriptional function of Oct4 in the regulation of mitotic entry.
快速通过细胞周期以及极短的G1期是胚胎干细胞的典型特征。这种独特的细胞周期由一个正反馈环驱动，该反馈环涉及Rb失活以及细胞周期蛋白和细胞周期蛋白依赖性激酶（Cdk）活性振荡的减少。在此背景下，我们探究了胚胎干细胞如何避免过早进入有丝分裂的潜在有害后果。我们发现多能性转录因子Oct4（八聚体结合转录因子4）通过与细胞周期蛋白-Cdk1形成复合物并抑制Cdk1激活，在胚胎干细胞周期中发挥了未被重视的作用。Oct4或缺乏转录活性的突变体的异位表达在HeLa细胞中重现了有丝分裂延迟进入的现象。胚胎干细胞中Oct4水平的降低加速了G2期进程，这导致染色体错分离和细胞凋亡增加。我们的数据证明了Oct4在有丝分裂进入调控中具有意想不到的非转录功能。
