An opposite effect of the CDK inhibitor, p18(INK4c) on embryonic stem cells compared with tumor and adult stem cells.
An opposite effect of the CDK inhibitor, p18(INK4c) on embryonic stem cells compared with tumor and adult stem cells.
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DOI：
10.1371/journal.pone.0045212
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Cheng T
中科院分区：
文献类型：
--
作者：
Li Y;Pal R;Sung LY;Feng H;Miao W;Cheng SY;Tian C;Cheng T
自我更新是成体干细胞和胚胎干细胞以及肿瘤干细胞的共同特征。细胞周期蛋白依赖的激酶抑制剂p18INK4c是一种已知的肿瘤抑制因子，可以抑制肿瘤细胞或成体干细胞的自我更新。在这里，我们展示了与畸胎瘤细胞相比，p18对ES细胞的相反作用。我们的结果意外地发现，p18的过表达促进了小鼠胚胎干细胞和胚胎体的生长；相反，抑制了晚期畸胎瘤的生长。ES细胞标志物(Oct4、Nanog、Sox2和Rex1)在ES细胞和EB细胞中表达上调，而EB细胞中各种分化标志物表达下调。这些结果表明，与肿瘤细胞和成体干细胞相比，p18对ES细胞的作用相反。在机制上，随着p18的过度表达，CDK4在ES细胞中的表达显著增加，可能导致CDK2从p21和p27的抑制中释放出来。结果，ES细胞的自我更新能力增强。我们目前的研究表明，在不同的细胞类型中靶向p18可能会产生不同的结果，从而对干细胞中细胞周期机制的治疗操作具有意义。
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.
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