title: Loss of the repressor REST in uterine fibroids promotes aberrant G protein-coupled receptor 10 expression and activates mammalian target of rapamycin pathway.
abstract: Uterine fibroids (leiomyomas) are the most common tumors of the female reproductive tract, occurring in up to 77% of reproductive-aged women, yet molecular pathogenesis remains poorly understood. A role for atypically activated mammalian target of rapamycin (mTOR) pathway in the pathogenesis of uterine fibroids has been suggested in several studies. We identified that G protein-coupled receptor 10 [GPR10, a putative signaling protein upstream of the phosphoinositide 3-kinase-protein kinase B/AKT-mammalian target of rapamycin (PI3K/AKT-mTOR) pathway] is aberrantly expressed in uterine fibroids. The activation of GPR10 by its cognate ligand, prolactin releasing peptide, promotes PI3K-AKT-mTOR 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.
authors.affiliation: Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Binny V
authors.initials: BV
authors.lastname: Varghese
authors.forename: Faezeh
authors.initials: F
authors.lastname: Koohestani
authors.forename: Michelle
authors.initials: M
authors.lastname: McWilliams
authors.forename: Arlene
authors.initials: A
authors.lastname: Colvin
authors.forename: Sumedha
authors.initials: S
authors.lastname: Gunewardena
authors.forename: William H
authors.initials: WH
authors.lastname: Kinsey
authors.forename: Romana A
authors.initials: RA
authors.lastname: Nowak
authors.forename: Warren B
authors.initials: WB
authors.lastname: Nothnick
authors.forename: Vargheese M
authors.initials: VM
authors.lastname: Chennathukuzhi
mesh_terms: D000818:Animals; D001483:Base Sequence; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D053263:Gene Regulatory Networks; D006801:Humans; D007889:Leiomyoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D034741:RNA, Small Interfering / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014594:Uterine Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000099229:RE1-Silencing Transcription Factor
chemical_list: D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled; D011994:Recombinant Proteins; D012097:Repressor Proteins; D058570:TOR Serine-Threonine Kinases; D000099229:RE1-Silencing Transcription Factor; C112345:PRLHR protein, human; C546842:MTOR protein, human