Document Detail


Loss of the repressor REST in uterine fibroids promotes aberrant G protein-coupled receptor 10 expression and activates mammalian target of rapamycin pathway.
MedLine Citation:
PMID:  23284171     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Binny V Varghese; Faezeh Koohestani; Michelle McWilliams; Arlene Colvin; Sumedha Gunewardena; William H Kinsey; Romana A Nowak; Warren B Nothnick; Vargheese M Chennathukuzhi
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2013-01-02
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  110     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-02-06     Completed Date:  2013-04-09     Revised Date:  2013-07-11    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2187-92     Citation Subset:  IM    
Affiliation:
Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS 66160, USA.
Data Bank Information
Bank Name/Acc. No.:
GEO/GSE41386
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Animals
Base Sequence
Disease Models, Animal
Female
Gene Expression
Gene Knockdown Techniques
Gene Regulatory Networks
Humans
Leiomyoma / genetics,  metabolism*,  pathology
Mice
Mice, Transgenic
RNA, Small Interfering / genetics
Receptors, G-Protein-Coupled / genetics,  metabolism*
Recombinant Proteins / genetics,  metabolism
Repressor Proteins / antagonists & inhibitors,  genetics,  metabolism*
Signal Transduction
TOR Serine-Threonine Kinases / metabolism*
Tumor Cells, Cultured
Uterine Neoplasms / genetics,  metabolism*,  pathology
Grant Support
ID/Acronym/Agency:
P01HD057877/HD/NICHD NIH HHS; P20 GM103418/GM/NIGMS NIH HHS; P20 RR016475/RR/NCRR NIH HHS
Chemical
Reg. No./Substance:
0/PRLHR protein, human; 0/RE1-silencing transcription factor; 0/RNA, Small Interfering; 0/Receptors, G-Protein-Coupled; 0/Recombinant Proteins; 0/Repressor Proteins; EC 2.7.1.1/MTOR protein, human; EC 2.7.1.1/TOR Serine-Threonine Kinases
Comments/Corrections
Comment In:
Proc Natl Acad Sci U S A. 2013 Feb 5;110(6):1980-1   [PMID:  23355686 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  High-pressure NMR reveals close similarity between cold and alcohol protein denaturation in ubiquiti...
Next Document:  RAC1P29S is a spontaneously activating cancer-associated GTPase.