{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T00:00:52Z","timestamp":1791158452874,"version":"4.1.0"},"reference-count":41,"publisher":"The Endocrine Society","issue":"10","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2009,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The adaptive growth of the uterus during gestation involves gradual changes in cellular phenotypes from the early proliferative to the intermediate synthetic phase of cellular hypertrophy, ending in the final contractile\/labour phenotype. The mammalian target of rapamycin (mTOR) signaling pathway regulates cell growth and proliferation in many tissues. We hypothesized that mTOR was a mediator of hormone-initiated myometrial hyperplasia during gestation. The protein expression and phosphorylation levels of mTOR, its upstream regulators [insulin receptor substrate-1, phosphoinositide-3-kinase (PI3K), Akt], and downstream effectors [S6-kinase-1 (S6K1) and eI4FE-binding protein 1 (4EBP1)] were analyzed throughout normal pregnancy in rats. In addition, we used an ovariectomized (OVX) rat model to analyze the modulation of the mTOR pathway and proliferative activity of the uterine myocytes by estradiol alone and in combination with the mTOR-specific inhibitor rapamycin. Our results demonstrate that insulin receptor substrate-1 protein levels and the phosphorylated (activated) forms of PI3K, mTOR, and S6K1 were significantly up-regulated in the rat myometrium during the proliferative phase of pregnancy. Treatment of the OVX rats with estradiol caused a transient increase in IGF-I followed by an up-regulation of the PI3K\/mTOR pathway, which became apparent by a cascade of phosphorylation reactions (P-P85, P-Akt, P-mTOR, P-S6K1, and P-4EBP1). Rapamycin blocked activation of P-mTOR, P-S6K1, and P-4EBP1 proteins and significantly reduced the number of proliferating cells in the myometrium of OVX rats. Our in vivo data demonstrate that estradiol was able to activate the PI3K\/mTOR signaling pathway in uterine myocytes and suggest that this activation is responsible for the induction of myometrial hyperplasia during early gestation.<\/jats:p>","DOI":"10.1210\/en.2009-0419","type":"journal-article","created":{"date-parts":[[2009,7,10]],"date-time":"2009-07-10T00:54:38Z","timestamp":1247187278000},"page":"4672-4680","source":"Crossref","is-referenced-by-count":50,"title":["Mammalian Target of Rapamycin Is Activated in Association with Myometrial Proliferation during Pregnancy"],"prefix":"10.1210","volume":"150","author":[{"given":"Shabana","family":"Jaffer","sequence":"first","affiliation":[{"name":"Samuel Lunenfeld Research Institute (S.J., O.S., S.L.), Mount Sinai Hospital, Toronto, Canada M5G 1X5"},{"name":"Department of Physiology (S.J., S.L.), University of Toronto, Canada M5S 1A1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oksana","family":"Shynlova","sequence":"first","affiliation":[{"name":"Samuel Lunenfeld Research Institute (S.J., O.S., S.L.), Mount Sinai Hospital, Toronto, Canada M5G 1X5"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Lye","sequence":"first","affiliation":[{"name":"Samuel Lunenfeld Research Institute (S.J., O.S., S.L.), Mount Sinai Hospital, Toronto, Canada M5G 1X5"},{"name":"Department of Physiology (S.J., S.L.), University of Toronto, Canada M5S 1A1"},{"name":"Department of Obstetrics and Gynecology (S.L.), University of Toronto, Canada M5S 1A1"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2009,7,9]]},"reference":[{"key":"2020071612252234900_B1","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1196\/annals.1389.038","article-title":"Myocytes, myometrium, and uterine contractions.","volume":"1101","author":"Young","year":"2007","journal-title":"Ann NY Acad Sci"},{"key":"2020071612252234900_B2","doi-asserted-by":"crossref","first-page":"III64","DOI":"10.1161\/01.HYP.6.6_Pt_2.III64","article-title":"Different types of smooth muscle hypertrophy","volume":"6","author":"Johansson","year":"1984","journal-title":"Hypertension"},{"key":"2020071612252234900_B3","first-page":"455","author":"Cole","year":"1989"},{"key":"2020071612252234900_B4","first-page":"E543","article-title":"Influence of mechanical stretch on growth and protein turnover of rat uterus","volume":"254","author":"Douglas","year":"1988","journal-title":"Am J Physiol"},{"key":"2020071612252234900_B5","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1095\/biolreprod47.5.698","article-title":"Growth and microvascular development of the uterus during early pregnancy in ewes.","volume":"47","author":"Reynolds","year":"1992","journal-title":"Biol Reprod"},{"key":"2020071612252234900_B6","first-page":"221","article-title":"Myometrial physiology and parturition","volume":"London","author":"Lye","year":"1999","journal-title":"In: Rodeck CH, Whittle MJ, eds. 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