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

✍ Scribed by Klaus A. Becker; Prachi N. Ghule; Jane B. Lian; Janet L. Stein; Andre J. van Wijnen; Gary S. Stein

• Publisher: John Wiley and Sons
• Year: 2010
• Tongue: English
• Weight: 476 KB
• Volume: 222
• Category: Article
• ISSN: 0021-9541
• DOI: 10.1002/jcp.21967

✦ Synopsis

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 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. J. Cell. Physiol. 222: 456–464, 2010. © 2009 Wiley‐Liss, Inc.