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Previous studies showed that store\u2010operated calcium channels (SOCCs) but not voltage\u2010operated calcium channels are present in mouse ESCs (mESCs). In this study, store\u2010operated calcium entry (SOCE) was found to exist in mESCs using confocal microscopy. SOCC blockers lanthanum, 2\u2010aminoethoxydiphenyl borate (2\u2010APB) and SKF\u201096365 reduced mESC proliferation in a concentration\u2010dependent manner, suggesting that SOCE is important for ESC proliferation. Pluripotent markers, Sox\u20102, Klf\u20104, and Nanog, were down\u2010regulated by 2\u2010APB, suggesting that self\u2010renewal property of mESCs relies on SOCE. 17\u03b2\u2010estradiol (E2) enhanced mESC proliferation. This enhanced proliferation was associated with an increment of SOCE. Both stimulated proliferation and increased SOCE could be reversed by SOCC blockers suggesting that E2 mediates its stimulatory effect on proliferation via enhancing SOCE. Also, cyclosporin A and INCA\u20106, inhibitors of calcineurin [phosphatase that de\u2010phosphorylates and activates nuclear factor of activated T\u2010cells (NFAT)], reversed the proliferative effect of E2, indicating that NFAT is involved in E2\u2010stimulated proliferation. Interestingly, E2 caused the nuclear translocation of NFATc4, and this could be reversed by 2\u2010APB. These results suggested that NFATc4 is the downstream target of E2\u2010induced SOCE. The present investigation provides the first line of evidence that SOCE and NFAT are crucial for ESCs to maintain their unique characteristics. In addition, the present investigation also provides novel information on the mechanisms of how E2, an important female sex hormone, affects ESC proliferation. J. Cell. Physiol. 227: 2519\u20132530, 2012. \u00a9 2011 Wiley Periodicals, Inc.<\/jats:p>","DOI":"10.1002\/jcp.22990","type":"journal-article","created":{"date-parts":[[2011,8,31]],"date-time":"2011-08-31T23:48:08Z","timestamp":1314834488000},"page":"2519-2530","source":"Crossref","is-referenced-by-count":35,"title":["Estrogen Controls embryonic stem cell proliferation via store\u2010operated calcium entry and the nuclear factor of activated T\u2010cells 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