An opposite effect of the CDK inhibitor, p18(INK4c) on embryonic stem cells compared with tumor and adult stem cells.
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, p18(INK4c), 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.
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, China.
Yanxin
Y
Li
Rekha
R
Pal
Li-Ying
LY
Sung
Haizhong
H
Feng
Weimin
W
Miao
Shi-Yuan
SY
Cheng
Cindy
C
Tian
Tao
T
Cheng
D053687:Adult Stem Cells / Q000166:cytology / Q000378:metabolism*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D049109:Cell Proliferation; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics / Q000378:metabolism; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000235:genetics* / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D016086:Lentivirus; D051379:Mice; D008822:Mice, Transgenic; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000378:metabolism*; D009928:Organ Specificity; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D013724:Teratoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014161:Transduction, Genetic; D054462:p21-Activated Kinases / Q000235:genetics / Q000378:metabolism
D015415:Biomarkers; C493972:Cdkn2c protein, mouse; D050763:Cyclin-Dependent Kinase Inhibitor p18; D018809:Proliferating Cell Nuclear Antigen; C413374:p27 antigen; D054462:p21-Activated Kinases; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4