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We identified that G protein-coupled receptor 10 [GPR10, a putative signaling protein upstream of the phosphoinositide 3-kinase\u2013protein kinase B\/AKT\u2013mammalian target of rapamycin (PI3K\/AKT\u2013mTOR) pathway] is aberrantly expressed in uterine fibroids. The activation of GPR10 by its cognate ligand, prolactin releasing peptide, promotes PI3K\u2013AKT\u2013mTOR pathways and cell proliferation specifically in cultured primary leiomyoma cells. Additionally, we report that RE1 suppressing transcription factor\/neuron-restrictive silencing factor (REST\/NRSF), a known tumor suppressor, transcriptionally represses GPR10 in the normal myometrium, and that the loss of REST in fibroids permits GPR10 expression. Importantly, mice overexpressing human GPR10 in the myometrium develop myometrial hyperplasia with excessive extracellular matrix deposition, a hallmark of uterine fibroids. We demonstrate previously unrecognized roles for GPR10 and its upstream regulator REST in the pathogenesis of uterine fibroids. Importantly, we report a unique genetically modified mouse model for a gene that is misexpressed in uterine fibroids.<\/jats:p>","DOI":"10.1073\/pnas.1215759110","type":"journal-article","created":{"date-parts":[[2013,1,3]],"date-time":"2013-01-03T02:18:08Z","timestamp":1357179488000},"page":"2187-2192","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":84,"title":["Loss of the repressor REST in uterine fibroids promotes aberrant G protein-coupled receptor 10 expression and activates mammalian target of rapamycin pathway"],"prefix":"10.1073","volume":"110","author":[{"given":"Binny V.","family":"Varghese","sequence":"first","affiliation":[{"name":"Departments of aMolecular and Integrative Physiology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Faezeh","family":"Koohestani","sequence":"additional","affiliation":[{"name":"Departments of aMolecular and Integrative Physiology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"McWilliams","sequence":"additional","affiliation":[{"name":"Departments of aMolecular and Integrative Physiology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arlene","family":"Colvin","sequence":"additional","affiliation":[{"name":"Departments of aMolecular and Integrative Physiology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sumedha","family":"Gunewardena","sequence":"additional","affiliation":[{"name":"Departments of aMolecular and Integrative Physiology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William H.","family":"Kinsey","sequence":"additional","affiliation":[{"name":"Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS 66160; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romana A.","family":"Nowak","sequence":"additional","affiliation":[{"name":"Department of Animal Sciences, University of Illinois, Urbana\u2013Champaign, IL 61801"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Warren B.","family":"Nothnick","sequence":"additional","affiliation":[{"name":"Departments of aMolecular and Integrative Physiology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vargheese M.","family":"Chennathukuzhi","sequence":"additional","affiliation":[{"name":"Departments of aMolecular and Integrative Physiology and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2013,1,2]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1126\/science.1112063","article-title":"Uterine fibroids: The elephant in the room","volume":"308","author":"Walker CL","year":"2005","unstructured":"CL Walker, EA Stewart, Uterine fibroids: The elephant in the room. 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