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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    • "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.
    Zygote 09/2014; 23(5). DOI:10.1017/S0967199414000355 · 1.42 Impact Factor
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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.
    Biochemical and Biophysical Research Communications 04/2014; 447(2). DOI:10.1016/j.bbrc.2014.03.082 · 2.30 Impact Factor
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    • "NANOG directly activates transcription of CDK6 and CDC25A and therefore stimulates the beginning of the S-phase (Zhang et al., 2009b). Down-regulation of POU5F1 results in a decrease of cyclins and increase in CKI p21 in human mesenchymal stem cells and hESC, while up-regulation of POU5F1 correlates with an increase in specific CDK4 and CDC25A (Greco et al., 2007; Lee et al., 2010). Increased cell cycle duration, in particular the G1 phase, has been associated with the onset of neural differentiation in mESC and hESC (Lange et al., 2009; Borghese et al., 2010), e.g. "
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    ABSTRACT: During human pre-implantation development the totipotent zygote divides and undergoes a number of changes that lead to the first lineage differentiation in the blastocyst displaying trophectoderm and inner cell mass on day 5. The trophectoderm is a differentiated epithelium needed for implantation and the inner cell mass (ICM) forms the embryo proper and serves as a source for pluripotent embryonic stem cells. The blastocyst implants around day 7. The second lineage differentiation occurs in the ICM after implantation resulting in specification of primitive endoderm and epiblast. Knowledge on human pre-implantation development is limited due to ethical and legal restrictions on embryo research and scarcity of materials. Studies in the human are mainly descriptive and lack functional evidence. Most information on embryo development is obtained from animal models and embryonic stem cell cultures and should be extrapolated with caution. This paper reviews totipotency and the molecular determinants and pathways involved in lineage segregation in the human embryo, as well as the role of embryonic genome activation, cell cycle features and epigenetic modifications.
    Molecular Human Reproduction 04/2014; 20(7). DOI:10.1093/molehr/gau027 · 3.75 Impact Factor
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