Cyclin D2 and the CDK substrate p220NPAT are required for self-renewal of human embryonic stem cells

Klaus A. Becker, Prachi N. Ghule, Jane B. Lian, Janet L. Stein, Andre J. Van Wijnen, Gary S. Stein

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

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. Weshow 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 p220 NPAT, 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.

Original languageEnglish (US)
Pages (from-to)456-464
Number of pages9
JournalJournal of Cellular Physiology
Volume222
Issue number2
DOIs
StatePublished - Feb 2010

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Cell Biology

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