An Opposite Effect of the CDK Inhibitor, p18INK4c on Embryonic Stem Cells Compared with Tumor and Adult Stem Cells
Journal
PLoS ONE
Journal Volume
7
Journal Issue
9
Date Issued
2012
Author(s)
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. ? 2012 Li et al.
SDGs
Other Subjects
cyclin dependent kinase 2; cyclin dependent kinase 4; cyclin dependent kinase inhibitor 2C; octamer transcription factor 4; protein p21; protein p27; transcription factor NANOG; transcription factor Sox2; adult stem cell; animal cell; article; cancer stem cell; cell cycle progression; cell differentiation; cell growth; cell renewal; comparative study; controlled study; down regulation; ectopic expression; embryo; embryonic stem cell; enzyme activity; enzyme release; gain of function mutation; gene expression; gene overexpression; loss of function mutation; mouse; nonhuman; protein expression; proteinase inhibition; teratoma; upregulation; Adult Stem Cells; Animals; Biological Markers; Cell Proliferation; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase Inhibitor p18; Embryonic Stem Cells; Female; Gene Expression Regulation; Genetic Vectors; Lentivirus; Mice; Mice, Transgenic; Neoplastic Stem Cells; Organ Specificity; p21-Activated Kinases; Proliferating Cell Nuclear Antigen; Signal Transduction; Skin Neoplasms; Teratoma; Transduction, Genetic
Type
journal article