Stem cells 2013 July-8

 

An opposite effect of the CDK inhibitor, p18INK4c on embryonic stem cells compared with tumor and adult stem cells

Plos One 2012, 7(9)-e45212:1-10.

Yanxin Li, Rekha Pal, Li-Ying Sung, Haizhong Feng, Weimin Miao, Shi-Yuan Cheng, Cindy Tian and Tao Cheng.

State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, China.

Abstract

BACKGROUND: Stem cells constantly face the choices of self-renewal, differentiation, migration, quiescence and cell death. Cell cycle regulation is one of the fundamental processes modulating cell fate choices and it represents a unique angle to dissect the relationship between tumorigenesis and stemness. 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. In contrast, there is virtually little expression of p18 and almost no detectable CDK4-associated activity of p18 protein in mouse ES cells.

METHODS: To determine the role of p18 in ES cell growth versus tumor growth, p18-/- ES cells labeled with green fluorescent protein (GFP) were derived from p18-/- GFP transgenic mice, and p18 and a p18-GFP fusion protein were each overexpressed in their corresponding wild types. For the mechanisms study, Immunoprecipitation (IP) assays were further performed to investigate whether interactions of p18, p21, and p27 with CDK2 or CDK4 were affected.

RESULTS: Our results unexpectedly show that overexpression of p18 accelerates the growth of ES cells and embryonic bodies (EBs); on the contrary, inhibite the growth of late stage teratomas. Up-regulation of ES cell markers (i.e., Oct4, Nanog, Sox2, and Rex1) are detected in both ES and EB cells, while concomitant down-regulation of various differentiation markers is observed in EB cells. Mechanistically, expression of CDK4 is significantly increased with overexpression of p18 in ES cells, likely leading to a release of CDK2 from the inhibition by p21 and p27.

CONCLUSION: We demonstrate an opposite effect of p18 on ES cells in comparison with teratoma cells. It further reinforces the notion that cell cycle regulation in ES cells is distinct from that in somatic cells and cell cycle regulators have distinct effects on ES cells vs. somatic cells including adult stem cells and tumor cells. Therefore, targeting p18 in these different stem cell types may yield cell type-specific outcomes, thereby having therapeutic implications. 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.

 

Supplemental picture:

Yanxin Li

A model for a proposed mechanism by which p18 enhances the self-renewal of ES cells, while inhibits their differentiation potential.

 

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