Egozi Dana, Shapira Maanit, Paor Galit, Ben-Izhak Ofer, Skorecki Karl, Hershko Dan D
Department of Plastic Surgery, Rambam Medical Center and the Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
FASEB J. 2007 Sep;21(11):2807-17. doi: 10.1096/fj.06-7758com. Epub 2007 May 2.
Embryonic stem cells combine the features of robust proliferation with precise differentiation capacity. p27 is a cell cycle inhibitor that is involved in the regulation of proliferation and differentiation in many developing tissues. Recent studies in murine embryonic stem cells have suggested that p27 is involved in the progression of normal differentiation programs in these cells. However, the expression and regulation of p27 and its role in the differentiation of human embryonic stem cells (hESc) has not been previously explored. Herein we show that p27 expression was low in undifferentiated hESc, but increased markedly in differentiated cells. The expression of Skp2, the ubiquitin ligase that targets p27 for degradation, was inversely related to p27 expression. Moreover, embryoid bodies (EBs) with low p27 expression and high Skp2/p27 ratio showed poorer differentiation than those with high p27 expression. Modulation of Skp2 expression is mainly regulated by its rate of degradation. In contrast to somatic cells, which have high levels of Skp2 mainly in S and G2/M, in undifferentiated hESc Skp2 levels were also high in G1. These results point to a potentially important role for p27 regulation in hESc.
胚胎干细胞兼具强大的增殖能力和精确的分化能力。p27是一种细胞周期抑制剂，参与许多发育中组织的增殖和分化调控。最近对小鼠胚胎干细胞的研究表明，p27参与这些细胞正常分化程序的进程。然而，p27在人胚胎干细胞（hESc）中的表达、调控及其在分化中的作用此前尚未被探索。在此我们表明，p27在未分化的hESc中表达较低，但在分化细胞中显著增加。靶向p27进行降解的泛素连接酶Skp2的表达与p27表达呈负相关。此外，p27表达低且Skp2/p27比值高的胚状体（EBs）比p27表达高的胚状体分化能力更差。Skp2表达的调节主要受其降解速率的调控。与主要在S期和G2/M期具有高水平Skp2的体细胞不同，在未分化的hESc中，G1期Skp2水平也很高。这些结果表明p27调控在hESc中可能具有重要作用。
