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

Ho Jae Han, Jung Sun Heo, Yun Jung Lee
American Journal of Physiology. Cell Physiology 2006, 290 (4): C1067-75
Although the importance of estradiol-17beta (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 [(3)H]thymidine incorporation at >4 h and that E(2) (>10(-12) M) induced an increase of [(3)H]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 [(3)H]thymidine incorporation. In addition, estradiol-6-O-carboxymethyl oxime-BSA (E(2)-BSA; 10(-9) M) increased [(3)H]thymidine incorporation at >1 h, and E(2)-BSA (>10(-12) M) increased [(3)H]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 [(3)H]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 [(3)H]thymidine incorporation was inhibited by PD-98059 or butyrolactone I (CDK2 inhibitor). In conclusion, estradiol-17beta stimulates the proliferation of murine ES cells, and this action is mediated by MAPKs, CDKs, or protooncogenes.

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