Oct-4 controls cell-cycle progression of embryonic stem cells

Laboratory of Molecular and Cellular Biology, Department of Life Science, Sogang University, Seoul 121-742, Republic of Korea.
Biochemical Journal (Impact Factor: 4.4). 12/2009; 426(2):171-81. DOI: 10.1042/BJ20091439
Source: PubMed


Mouse and human ES (embryonic stem) cells display unusual proliferative properties and can produce pluripotent stem cells indefinitely. Both processes might be important for maintaining the 'stemness' of ES cells; however, little is known about how the cell-cycle fate is regulated in ES cells. Oct-4, a master switch of pluripotency, plays an important role in maintaining the pluripotent state of ES cells and may prevent the expression of genes activated during differentiation. Using ZHBTc4 ES cells, we have investigated the effect of Oct-4 on ES cell-cycle control, and we found that Oct-4 down-regulation in ES cells inhibits proliferation by blocking cell-cycle progression in G0/G1. Deletion analysis of the functional domains of Oct-4 indicates that the overall integrity of the Oct-4 functional domains is important for the stimulation of S-phase entry. We also show in the present study that the p21 gene is a target for Oct-4 repression. Furthermore, p21 protein levels were repressed by Oct-4 and were induced by the down-regulation of Oct-4 in ZHBTc4 ES cells. Therefore the down-regulation of p21 by Oct-4 may contribute to the maintenance of ES cell proliferation.

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    • "We confirmed two putative Nanog binding sites in the 5'-UAS of the p27 KIP1 gene (Chen et al., 2008;Marson et al., 2008) by ChIP analyses both, in ES cells and Nanog-transduced MEF cells. Recently, it has been reported that Oct4 represses p21 expression to contribute to ES cell proliferation and self-renewal (Lee et al., 2010). p27 KIP1 together with p21 CIP/WAF represent the major cyclin-dependent kinase inhibitors (CKIs) regulating G1 to S transition. "
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    ABSTRACT: A comprehensive analysis of the molecular network of cellular factors establishing and maintaining pluripotency as well as self renewal of pluripotent stem cells is key for further progress in understanding basic stem cell biology. Nanog is necessary for the natural induction of pluripotency in early mammalian development but dispensable for both, its maintenance as well as its artificial induction. To gain further insight into the molecular activity of Nanog we analyzed the gain-of-function of Nanog in various cell models employing a recently developed biologically active recombinant cell-permeant protein, Nanog-TAT. We found that Nanog enhances proliferation of both, NIH 3T3 as well as primary fibroblast cells. Nanog transduction into primary fibroblasts results in suppression of senescence‑associated β‑galactosidase activity. Investigation of cell cycle factors revealed that transient activation of Nanog correlates with consistent down-regulation of cell cycle inhibitor p27(KIP1). By chromatin immunoprecipitation analysis we confirmed bona fide Nanog binding sites upstream to the p27(KIP1) gene, establishing a direct link between physical occupancy and functional regulation. Our data demonstrates that Nanog enhances proliferation of fibroblasts via transcriptional regulation of cell cycle inhibitor p27 gene.
    Preview · Article · Jan 2016 · Journal of Cell Science
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    • "Apart from embryonic stem cells, the Su Jin Kim et al. expression of Oct4 is also found in other cell types including mesenchymal stem cells (Fan et al., 2013), early embryonic tissues (DeVeale et al., 2013) and cancer cells (Li et al., 2012), although its roles and underlying mechanisms are still unclear. Recently, several reports have shown that the expression of Oct4 controls cell-cycle progression and enhances the proliferation of the cells for both embryonic stem cells (Lee et al., 2010) and other cell types (Li et al., 2012; DeVeale et al., 2013; Fan et al., 2013). "
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    ABSTRACT: Octamer-binding transcription factor 4 (Oct4) is a critical molecule for the self-renewal and pluripotency of embryonic stem cells. Recent reports have shown that Oct4 also controls cell-cycle progression and enhances the proliferation of various types of cells. As the high proliferation of donor fibroblasts is critical to the production of transgenic pigs, using the somatic cell nuclear transfer technique, we analysed the effect of Oct4 overexpression on the proliferation of porcine fibroblasts and embryos. Porcine endogenous Oct4 cDNA was cloned, sequenced and inserted into an expression vector. The vector was transfected into porcine fibroblasts, and a stable Oct4-overexpressed cell line was established by antibiotic selection. Oct4 expression was validated by the immunostaining of Oct4. Cell morphology was changed to sharp, and both proliferation and migration abilities were enhanced in Oct4-overexpressed cells. Real-time RT-PCR results showed that p16, Bcl2 and Myc were upregulated in Oct4-overexpressed cells. Somatic cell nuclear transfer was performed using Oct4-overexpressed cells, and the development of Oct4 embryos was compared with that of wild-type cloned embryos. The cleavage and blastocyst formation rates were improved in the Oct4 embryos. Interestingly, blastocyst formation of the Oct4 embryos was observed as early as day 5 in culture, while blastocysts were observed from day 6 in wild-type cloned embryos. In conclusion, the overexpression of Oct4 enhanced the proliferation of both porcine fibroblasts and embryos.
    Full-text · Article · Sep 2014 · Zygote
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    • "In the process of ES cell self-renewal, the expression of Oct4 promotes cell cycle progression by suppressing its target gene p21, a cyclin-dependent kinase inhibitor [13]. In contrast, downregulation of Oct4 results in blocking of cell cycle progression followed by differentiation [13]. Oct4 has been proposed as a biomarker for cancer stem cell (CSC)-like cells [14]. "
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    ABSTRACT: Antitumor antibiotic lidamycin (LDM) is widely used in the treatment of a variety of cancers. Here we demonstrated that LDM up-regulates the expression of the tumor suppressor p53 gene by repressing Oct4 transcription. We showed that low dose LDM- induced increase of p53 expression and decrease of Oct4 expression in P19 and HCT116-p53(+/+) cells. Knockdown of Oct4 expression by siRNA led to activation of p53 in both cell lines, whereas ectopical expression of Oct4 significantly inhibited p53 expression in P19 cells. LDM-induced p53 activation was blocked by ectopical expression of Oct4.
    Preview · Article · Apr 2014 · Biochemical and Biophysical Research Communications
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