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EMBRYONIC STEM CELLS |
aCenter for Development & Differentiation, KRIBB, Yuseong-gu, Daejeon, Republic of Korea;
bDepartment of Biological Sciences, KAIST, Yuseong-gu, Daejeon, Republic of Korea
Key Words. Mouse embryonic stem cells • Self-renewal • Simvastatin • Geranylgeranyl pyrophosphate • RhoA
Correspondence: Yong-Mahn Han, Ph.D., Department of Biological Sciences, KAIST, 373-1 Guseong-dong, Yuseong-gu, Daejeon 305-701, Republic of Korea. Telephone: 82-42-869-2640; Fax: 82-42-869-2610; e-mail: ymhan{at}kaist.ac.kr; or Yee Sook Cho, Ph.D., Center for Development & Differentiation, KRIBB, 52 Eoeun-dong, Yuseong-gu, Daejeon 305-806, Republic of Korea. Telephone: 82-42-860-4479; Fax: 82-42-860-4608; e-mail: june{at}kribb.re.kr
Received on November 20, 2006;
accepted for publication on April 10, 2007.
First published online in STEM CELLS EXPRESS April 26, 2007.
Statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, were originally developed to lower cholesterol. Their pleiotropic (or cholesterol-independent) effects at the cellular and molecular levels are highly related to numerous cellular functions, such as proliferation and differentiation. However, they are hardly studied in embryonic stem cells. In this study, we evaluated the effects of statins on mouse ESCs (J1, D3, and RW.4) to enhance our understanding of the molecular basis of ESC self-renewal. Treatment of ESCs with simvastatin, mevastatin, atorvastatin, or pravastatin induced morphological change and decreased cell proliferation. We observed that the use of simvastatin was most effective in all three ESCs. Loss of ESC self-renewal by simvastatin was determined by marked downregulation of ESC markers alkaline phosphatase, Oct4, Nanog, Rex-1, and SSEA-1. Simvastatin effects were selectively reversed by either mevalonate or its metabolite geranylgeranyl pyrophosphate (GGPP) but not by cholesterol or farnesyl pyrophosphate. These results suggest that simvastatin effects were mainly derived from depletion of intracellular pools of GGPP, the substrate required for the geranylgeranylation. Using this approach, we found that GGPP, a derivative of the mevalonate pathway, is critical for ESC self-renewal. Furthermore, we identified that simvastatin selectively blocked cytosol-to-membrane translocalization of RhoA small guanosine triphosphate-binding protein, known to be the major target for geranylgeranylation, and lowered the levels of Rho-kinase (ROCK)2 protein in ESCs. In addition, simvastatin downregulated the ROCK activity, and this effect was reversed by addition of GGPP. Our data suggest that simvastatin, independently of its cholesterol-lowering properties, impairs the ESC self-renewal by modulating RhoA/ROCK-dependent cell-signaling.
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  R. Damoiseaux, S. P. Sherman, J. A. Alva, C. Peterson, and A. D. Pyle Integrated Chemical Genomics Reveals Modifiers of Survival in Human Embryonic Stem Cells Stem Cells, March 1, 2009; 27(3): 533 - 542. [Abstract] [Full Text] [PDF]
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 S. Waiczies, I. Bendix, T. Prozorovski, M. Ratner, I. Nazarenko, C. F. Pfueller, A. U. Brandt, J. Herz, S. Brocke, O. Ullrich, et al. Geranylgeranylation but Not GTP Loading Determines Rho Migratory Function in T Cells J. Immunol., November 1, 2007; 179(9): 6024 - 6032. [Abstract] [Full Text] [PDF]
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