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Regulation of the cell cycle inhibitor p27 and its ubiquitin ligase Skp2 in differentiation of human embryonic stem cells

Dana Egozi^*,||,1, Maanit Shapira^,||,1, Galit Paor^||, Ofer Ben-Izhak, Karl Skorecki^,|| and Dan D. Hershko^,||,2

Departments of
^* Plastic Surgery,

Surgery,

Nephrology, and

Pathology, Rambam Medical Center and the Ruth and Bruce Rappaport Faculty of Medicine and

^|| Research Institute, Technion-Israel Institute of Technology, Haifa, Israel

²Correspondence: Department of Surgery, Rambam Medical Center, Haifa 31096, Israel. E-mail: d_hershko{at}rambam.health.gov.il

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.—Egozi, D., Shapira, M., Paor, G., Ben-Izhak, O., Skorecki, K., Hershko, D. D. Regulation of the cell cycle inhibitor p27 and its ubiquitin ligase Skp2 in differentiation of human embryonic stem cells.

Key Words: tumorigenesis • cyclin-dependent kinase • hESc differentiation • F-box protein • ubiquitin system

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