Cyclin D2 and the CDK substrate p220(NPAT) are required for self-renewal of human embryonic stem cells
Department of Cell Biology
Medical Subject Headings
*Cell Cycle; Cell Cycle Proteins; Cell Differentiation; Cell Line; *Cell Proliferation; Cyclin D1; Cyclin D2; Cyclin-Dependent Kinase 4; Embryonic Stem Cells; Histones; Humans; Nuclear Proteins; Phosphorylation; Pluripotent Stem Cells; RNA Interference; RNA, Messenger; Repressor Proteins; Time Factors
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 p220(NPAT)/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 p220(NPAT) causes a cell cycle defect in G1 reflected by diminished phosphorylation of p220(NPAT), decreased cell cycle dependent histone H4 expression and reduced S phase progression. Thus, cyclin D2 and p220(NPAT) 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 p220(NPAT)/HiNF-P mechanism that may explain perpetual proliferation of hES cells without transformation or tumorigenesis.
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Citation: J Cell Physiol. 2010 Feb;222(2):456-64. Link to article on publisher's site