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EMBRYONIC STEM CELLS: CHARACTERIZATION SERIES |
aDivision of Hematology,
bVascular Biology Research Center, and
cDepartment of Obstetrics and Gynecology, The University of Texas Health Science Center at Houston, Houston, Texas, USA;
dNational Health Research Institutes, Zhunan, Miaoli, Taiwan
Key Words. Mouse embryonic stem cell • Cyclooxygenase-2 • PGE2 • EP2 receptor • Apoptosis • Akt
Correspondence: Kenneth K. Wu, M.D., Ph.D., Division of Hematology and Vascular Biology Research Center, The University of Texas Health Science Center at Houston, 6431 Fannin, MSB 5.016, Houston, Texas 77030, USA. Telephone: 713-500-6801; Fax: 713-500-6812; e-mail: Kenneth.K.Wu{at}uth.tmc.edu
Received August 10, 2006;
accepted for publication January 4, 2007.
Disclosure of potential conflicts of interest is found at the end of this article.
First published online in STEM CELLS EXPRESS January 18, 2007.
Little is known about prostaglandin synthesis and function in embryonic stem cells. We postulated that mouse embryonic stem (mES) cells possess enzymes to synthesize protective prostaglandins. Compared with differentiated adult cells, mES cells were less susceptible to H2O2-induced apoptosis. However, their apoptosis was enhanced by indomethacin or SC-236, a selective inhibitor of cyclooxygenase (COX)-2. Analysis of COX pathway enzymes by Western blotting revealed expression of COX-2 and cytosolic and microsomal prostaglandin E2 (PGE2) synthases. COX-1 and prostacyclin (PGI2) synthases were undetectable. mES cells produced PGE2 but not PGI2. Importantly, PGE2 rescued mES cells from apoptosis. To elucidate the signaling mechanism by which PGE2 inhibits apoptosis, we analyzed E-type prostaglandin (EP) receptors by Western blots. All EP isoforms were detected except EP4. Butaprost, a specific EP2 agonist, rescued mES cells from apoptosis, whereas sulprostone, an EP1/EP3 agonist, had no effect, suggesting selective interaction of PGE2 with EP2. The antiapoptotic effect of PGE2 was abrogated by Ly-294002 or wortmannin but not H-89 or a specific inhibitor of protein kinase A, suggesting signaling via phosphatidylinositol-3 kinase (PI-3K). Akt was constitutively active in mES cells, which were inhibited by indomethacin and rescued by PGE2. The rescuing effect of PGE2 was abrogated by Ly-294002. These results indicate that mES cells constitutively express COX-2 and PGE synthases and produce PGE2, which confers resistance to apoptosis via EP2-mediated activation of PI-3K to the Akt pathway.
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