Cyclin D2 and the CDK Substrate p220NPAT Are Required for Self-Renewal of Human Embryonic Stem Cells

被引:32
作者
Becker, Klaus A.
Ghule, Prachi N.
Lian, Jane B.
Stein, Janet L.
Van Wijnen, Andre J.
Stein, Gary S. [1 ]
机构
[1] Univ Massachusetts, Med Ctr, Dept Cell Biol, Worcester, MA 01655 USA
关键词
TRANSCRIPTIONAL REGULATORY CIRCUITRY; HISTONE GENE-TRANSCRIPTION; ES CELLS; SUBNUCLEAR ORGANIZATION; PROTEIN EXPRESSION; S TRANSITION; HINF-P; PLURIPOTENCY; PHASE; DIFFERENTIATION;
D O I
10.1002/jcp.21967
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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 GI/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 p22(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. J. Cell. Physiol. 222: 456-464, 2010. (C) 2009 Wiley-Liss, Inc.
引用
收藏
页码:456 / 464
页数:9
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