Cyclin D2 and the CDK substrate p220NPAT are required for self‐renewal of human embryonic stem cells |
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Authors: | Klaus A Becker Prachi N Ghule Jane B Lian Janet L Stein Andre J van Wijnen Gary S Stein |
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Institution: | Department of Cell Biology and Cancer Center, University of Massachusetts Medical School, Worcester, Massachusetts |
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Abstract: | Self‐renewal of pluripotent human embryonic stem (hES) cells utilizes an abbreviated cell cycle that bypasses E2F/pRB‐dependent growth control. We investigated whether self‐renewal is alternatively regulated by cyclin/CDK phosphorylation of the p220NPAT/HiNF‐P complex to activate histone gene expression at the G1/S phase transition. We show that cyclin D2 is prominently expressed in pluripotent hES cells, but cyclin D1 eclipses cyclin D2 during differentiation. Depletion of cyclin D2 or p220NPAT causes a cell cycle defect in G1 reflected by diminished phosphorylation of p220NPAT, decreased cell cycle dependent histone H4 expression and reduced S phase progression. Thus, cyclin D2 and p220NPAT are principal cell cycle regulators that determine competency for self‐renewal in pluripotent hES cells. While pRB/E2F checkpoint control is relinquished in human ES cells, fidelity of physiological regulation is secured by cyclin D2 dependent activation of the p220NPAT/HiNF‐P mechanism that may explain perpetual proliferation of hES cells without transformation or tumorigenesis. J. Cell. Physiol. 222: 456–464, 2010. © 2009 Wiley‐Liss, Inc. |
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