PMID- 23284171
OWN - NLM
STAT- MEDLINE
DCOM- 20130409
LR  - 20211203
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 110
IP  - 6
DP  - 2013 Feb 5
TI  - Loss of the repressor REST in uterine fibroids promotes aberrant G 
      protein-coupled receptor 10 expression and activates mammalian target of 
      rapamycin pathway.
PG  - 2187-92
LID - 10.1073/pnas.1215759110 [doi]
AB  - 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.
FAU - Varghese, Binny V
AU  - Varghese BV
AD  - Department of Molecular and Integrative Physiology, University of Kansas Medical 
      Center, Kansas City, KS 66160, USA.
FAU - Koohestani, Faezeh
AU  - Koohestani F
FAU - McWilliams, Michelle
AU  - McWilliams M
FAU - Colvin, Arlene
AU  - Colvin A
FAU - Gunewardena, Sumedha
AU  - Gunewardena S
FAU - Kinsey, William H
AU  - Kinsey WH
FAU - Nowak, Romana A
AU  - Nowak RA
FAU - Nothnick, Warren B
AU  - Nothnick WB
FAU - Chennathukuzhi, Vargheese M
AU  - Chennathukuzhi VM
LA  - eng
SI  - GEO/GSE41386
GR  - P01 HD057877/HD/NICHD NIH HHS/United States
GR  - P20 GM103418/GM/NIGMS NIH HHS/United States
GR  - P20 RR016475/RR/NCRR NIH HHS/United States
GR  - P01HD057877/HD/NICHD NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20130102
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (PRLHR protein, human)
RN  - 0 (RE1-silencing transcription factor)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Receptors, G-Protein-Coupled)
RN  - 0 (Recombinant Proteins)
RN  - 0 (Repressor Proteins)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
CIN - Proc Natl Acad Sci U S A. 2013 Feb 5;110(6):1980-1. PMID: 23355686
MH  - Animals
MH  - Base Sequence
MH  - Disease Models, Animal
MH  - Female
MH  - Gene Expression
MH  - Gene Knockdown Techniques
MH  - Gene Regulatory Networks
MH  - Humans
MH  - Leiomyoma/genetics/*metabolism/pathology
MH  - Mice
MH  - Mice, Transgenic
MH  - RNA, Small Interfering/genetics
MH  - Receptors, G-Protein-Coupled/genetics/*metabolism
MH  - Recombinant Proteins/genetics/metabolism
MH  - Repressor Proteins/antagonists & inhibitors/genetics/*metabolism
MH  - Signal Transduction
MH  - TOR Serine-Threonine Kinases/*metabolism
MH  - Tumor Cells, Cultured
MH  - Uterine Neoplasms/genetics/*metabolism/pathology
PMC - PMC3568308
COIS- The authors declare no conflict of interest.
EDAT- 2013/01/04 06:00
MHDA- 2013/04/10 06:00
PMCR- 2013/01/02
CRDT- 2013/01/04 06:00
PHST- 2013/01/04 06:00 [entrez]
PHST- 2013/01/04 06:00 [pubmed]
PHST- 2013/04/10 06:00 [medline]
PHST- 2013/01/02 00:00 [pmc-release]
AID - 1215759110 [pii]
AID - 201215759 [pii]
AID - 10.1073/pnas.1215759110 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2013 Feb 5;110(6):2187-92. doi: 
      10.1073/pnas.1215759110. Epub 2013 Jan 2.