Cyclin D2 and the CDK substrate p220(NPAT) are required for self-renewal of human embryonic stem cells
Department of Cell Biology
*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.
DOI of Published Version
J Cell Physiol. 2010 Feb;222(2):456-64. Link to article on publisher's site
Journal of cellular physiology
Becker KA, Ghule PN, Lian JB, Stein JL, Van Wijnen AJ, Stein GS. (2010). Cyclin D2 and the CDK substrate p220(NPAT) are required for self-renewal of human embryonic stem cells. Stein, Stein, Lian, vanWijnen Lab Publications. https://doi.org/10.1002/jcp.21967. Retrieved from https://escholarship.umassmed.edu/stein/24