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First published online August 23, 2007
Stem Cells Vol. 25 No. 12 December 2007, pp. 2996 -3004
doi:10.1634/stemcells.2007-0066; www.StemCells.com
© 2007 AlphaMed Press

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EMBRYONIC STEM CELLS

Self-Renewal of Murine Embryonic Stem Cells Is Supported by the Serine/Threonine Kinases Pim-1 and Pim-3

Irène Aksoya,b,c, Caline Sakabedoyana,b,c, Pierre-Yves Bourillota,b,c, Anna B. Malashichevaa,b,c, Jimmy Mancipa,b,c, Kenneth Knoblaucha,b,c, Marielle Afanassieffa,b,c, Pierre Savatiera,b,c

aInstitut National de la Santé et de la Recherche Médicale and
bStem Cell and Brain Research Institute, Bron, France;
cUniversité de Lyon, Lyon, France

Key Words. Embryonic stem cells • Leukemia inhibitory factor • STAT3 transcription factor • Pim kinases • Cell cycle

Correspondence: Pierre Savatier, Ph.D., INSERM U846, 18 avenue Doyen Lépine, 69500 Bron, France. Telephone: 33-472-91-34-42; Fax: 33-472-91-34-61; e-mail: savatier{at}lyon.inserm.fr

Received January 29, 2007; accepted for publication August 10, 2007.
First published online in STEM CELLS EXPRESS   August 23, 2007.



pim-1 and pim-3 encode serine/threonine kinases involved in the regulation of cell proliferation and apoptosis in response to cytokine stimulation. We analyzed the regulation of pim-1 and pim-3 by the leukemia inhibitory factor (LIF)/gp130/signal transducer and activator of transcription-3 (STAT3) pathway and the role of Pim-1 and Pim-3 kinases in mouse embryonic stem (ES) cell self-renewal. Making use of ES cells expressing a granulocyte colony-stimulating factor:gp130 chimeric receptor and a hormone-dependent signal transducer and activator of transcription-3 estrogen receptor (STAT3-ERT2), we showed that expression of pim-1 and pim-3 was upregulated by LIF/gp130-dependent signaling and the STAT3 transcription factor. ES cells overexpressing pim-1 and pim-3 had a greater capacity to self-renew and displayed a greater resistance to LIF starvation based on a clonal assay. In contrast, knockdown of pim-1 and pim-3 increased the rate of spontaneous differentiation in a self-renewal assay. Knockdown of pim-1 and pim-3 was also detrimental to the growth of undifferentiated ES cell colonies and increased the rate of apoptosis. These findings provide a novel role of Pim-1 and Pim-3 kinases in the control of self-renewal of ES cells.

Disclosure of potential conflicts of interest is found at the end of this article.






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