4.7 Article

Estradiol-17β stimulates proliferation of mouse embryonic stem cells:: involvement of MAPKs and CDKs as well as protooncogenes

Journal

AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
Volume 290, Issue 4, Pages C1067-C1075

Publisher

AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpcell.00222.2005

Keywords

cyclin-dependent kinase; mitogen-activated protein kinase

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Although the importance of estradiol-17 beta ( E-2) in many physiological processes has been reported, to date no researchers have investigated the effects of E-2 on embryonic stem ( ES) cell proliferation. Therefore, in the present study, we have examined the effect of E-2 on the DNA synthesis of murine ES ( ES-E14TG2a) cells and its related signaling pathways. The results of this study show that E-2 ( 10(-9) M) significantly increased [ H-3] thymidine incorporation at > 4 h and that E2 ( > 10(-12) M) induced an increase of [ H-3] thymidine incorporation after 8-h incubation. Moreover, E-2 ( > 10(-12) M) also increased 5'-bromo-2'-deoxyuridine ( BrdU) incorporation and cell number. Indeed, E-2 stimulated estrogen receptor ( ER)-alpha and -beta protein levels and increased mRNA expression levels of protooncogenes ( c-fos, c-jun, and c-myc). Tamoxifen ( antiestrogen) completely inhibited E-2-induced increases in [ H-3] thymidine incorporation. In addition, estradiol-6-O-carboxymethyl oxime-BSA ( E-2-BSA; 10(-9) M) increased [ H-3] thymidine incorporation at > 1 h, and E-2-BSA ( > 10(-12) M) increased [ H-3] thymidine incorporation after 1-h incubation. E-2-BSA-induced increase in BrdU incorporation also occurred in a dose-dependent manner. Tamoxifen had no effect on E-2-BSA-induced increase of [ H-3] thymidine incorporation. Also, E-2 and E-2-BSA displayed maximal phosphorylation of p44/42 MAPKs at 10 and 5 min, respectively. E-2 increased cyclins D1 and E as well as cyclin-dependent kinase ( CDK)2 and CDK4. In contrast, E-2 decreased the levels of p21(cip1) and p27(kip1) ( CDK-inhibitory proteins). Increases of these cell cycle regulators were blocked by 10(-5) M PD-98059 ( MEK inhibitor). Moreover, E-2-induced increase of [ H-3] thymidine incorporation was inhibited by PD-98059 or butyrolactone I ( CDK2 inhibitor). In conclusion, estradiol-17 beta stimulates the proliferation of murine ES cells, and this action is mediated by MAPKs, CDKs, or protooncogenes.

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