Abstract
Self-renewal is a feature common to both adult and embryonic stem (ES) cells, as well as tumor stem cells (TSCs). The cyclin-dependent kinase inhibitor, p18INK4c, is a known tumor suppressor that can inhibit self-renewal of tumor cells or adult stem cells. Here, we demonstrate an opposite effect of p18 on ES cells in comparison with teratoma cells. Our results unexpectedly showed that overexpression of p18 accelerated the growth of mouse ES cells and embryonic bodies (EB); on the contrary, inhibited the growth of late stage teratoma. Up-regulation of ES cell markers (i.e., Oct4, Nanog, Sox2, and Rex1) were detected in both ES and EB cells, while concomitant down-regulation of various differentiation markers was observed in EB cells. These results demonstrate that p18 has an opposite effect on ES cells as compared with tumor cells and adult stem cells. Mechanistically, expression of CDK4 was significantly increased with overexpression of p18 in ES cells, likely leading to a release of CDK2 from the inhibition by p21 and p27. As a result, self-renewal of ES cells was enhanced. Our current study suggests that targeting p18 in different cell types may yield different outcomes, thereby having implications for therapeutic manipulations of cell cycle machinery in stem cells.
Highlights
Embryonic stem (ES) cells are pluripotent cells with the capacity to self-renew and differentiate into different tissues/cell types present in three germ layers [1,2]
IP assays revealed a higher level of binding of p21 and p27 withCDK4, relative to CDK2, in the ES cells overexpressing p18 compared to WT control cells (Fig. 5, E & F).Taken together, these results suggest an paradigm in ES cells (Fig. 5G), where overexpression of p18 significantly up-regulates CDK4 expression (Fig. 5, D & F) and induces binding of p21 and p27 to CDK4 rather than CDK2
Overexpression of p18 was found to enhance the growth of embryonic bodies (EB) (Fig. 4) whereas it inhibited the growth of teratoma (Fig. 2)
Summary
Embryonic stem (ES) cells are pluripotent cells with the capacity to self-renew and differentiate into different tissues/cell types present in three germ layers [1,2]. ES cells typically exhibit a short G1 phase (approximately 1.5 h in mouse ES cells), primarily owing to high CDK2 activity that mediates self-renewing proliferation whereas pluripotent differentiation potential is maintained [19]. P18, an INK4 family member, suppresses CDK4 or CDK6 during the G1 stage in somatic cells. It is a known haploinsufficient tumor suppressor and inhibits the self-renewal of adult stem cells [11]. Genetic manipulations of p18 were performed in a series of embryonic models to define the effect of p18 in ES cell growth as opposed to the previous documented roles of p18 in adult stem cells and tumor cells
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