title: The human myometrium differentially expresses mTOR signalling components before and during pregnancy: evidence for regulation by progesterone.
abstract: Emerging studies implicate the signalling of the mammalian target of rapamycin (mTOR) in a number of reproductive functions. To this date, there are no data regarding the expression of mTOR signalling components in the human myometrium during pregnancy. We hypothesized that mTOR-related genes might be differentially expressed in term or preterm labour as well as in labour or non-labour myometria during pregnancy. Using quantitative RT-PCR we demonstrate for first time that there is a significant downregulation of mTOR, DEPTOR, and Raptor in preterm labouring myometria when compared to non-pregnant tissues taken from the same area (lower segment). We used an immortalized myometrial cell line (ULTR) as an in vitro model to dissect further mTOR signalling. In ULTR cells DEPTOR and Rictor had a cytoplasmic distribution, whereas mTOR and Raptor were detected in the cytoplasm and the nucleus, indicative of mTORC1 shuttling. Treatment with inflammatory cytokines caused only minor changes in gene expression of these components, whereas progesterone caused significant down-regulation. We performed a non-biased gene expression analysis of ULTR cells using Nimblegen human gene expression microarray (n=3), and selected genes were validated by quantitative RT-PCR in progesterone treated myometrial cells. Progesterone significantly down-regulated key components of the mTOR pathway. We conclude that the human myometrium differentially expresses mTOR signalling components and they can be regulated by progesterone. This article is part of a Special Issue entitled 'Pregnancy and Steroids'.
authors.affiliation: Biosciences, Centre for Cell and Chromosome Biology, Brunel University, Uxbridge UB8 3PH, UK.
authors.forename: Helen A
authors.initials: HA
authors.lastname: Foster
authors.forename: Julie
authors.initials: J
authors.lastname: Davies
authors.forename: Ryan C
authors.initials: RC
authors.lastname: Pink
authors.forename: Serife
authors.initials: S
authors.lastname: Turkcigdem
authors.forename: Anastasia
authors.initials: A
authors.lastname: Goumenou
authors.forename: David R
authors.initials: DR
authors.lastname: Carter
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Saunders
authors.forename: Peter
authors.initials: P
authors.lastname: Thomas
authors.forename: Emmanouil
authors.initials: E
authors.lastname: Karteris
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000502:physiology; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D018836:Inflammation Mediators / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D009215:Myometrium / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011247:Pregnancy; D011374:Progesterone / Q000502:physiology*; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D000076223:Regulatory-Associated Protein of mTOR; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D059467:Transcriptome
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D016207:Cytokines; D018836:Inflammation Mediators; D047908:Intracellular Signaling Peptides and Proteins; C492571:RICTOR protein, human; C463659:RPTOR protein, human; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D000076223:Regulatory-Associated Protein of mTOR; D011374:Progesterone; C556139:DEPTOR protein, human; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: Myometrium; Preterm labour; Progesterone; mTOR
references.citation: J Biol Chem. 2006 Mar 17;281(11):7357-63
references.pmid: 16407298
references.citation: Cell Biochem Funct. 2007 Jan-Feb;25(1):45-53
references.pmid: 16927414
references.citation: Nat Rev Nephrol. 2012 Feb 28;8(5):265-74
references.pmid: 22371245
references.citation: Am J Obstet Gynecol. 2008 May;198(5):530.e1-10
references.pmid: 18279826
references.citation: Nat Cell Biol. 2004 Nov;6(11):1122-8
references.pmid: 15467718
references.citation: Int J Mol Med. 2010 Jan;25(1):65-9
references.pmid: 19956903
references.citation: J Physiol. 2007 Jul 1;582(Pt 1):449-59
references.pmid: 17463046
references.citation: Methods Mol Biol. 2012;821:105-24
references.pmid: 22125063
references.citation: Arterioscler Thromb Vasc Biol. 2009 Feb;29(2):232-8
references.pmid: 19074484
references.citation: Exp Cell Res. 2009 Jun 10;315(10):1724-33
references.pmid: 19331815
references.citation: Biochem Soc Trans. 2009 Feb;37(Pt 1):295-8
references.pmid: 19143650
references.citation: Nature. 1994 Jun 30;369(6483):756-8
references.pmid: 8008069
references.citation: Eur J Immunol. 2012 Oct;42(10):2683-96
references.pmid: 22740122
references.citation: Reprod Sci. 2013 Feb;20(2):154-67
references.pmid: 22614625
references.citation: Mol Endocrinol. 2006 Nov;20(11):2724-33
references.pmid: 16772530
references.citation: Endocrinology. 2009 Oct;150(10):4672-80
references.pmid: 19589861
references.citation: Semin Fetal Neonatal Med. 2012 Feb;17(1):12-9
references.pmid: 21944863
references.citation: Reproduction. 2008 Apr;135(4):569-79
references.pmid: 18367515
references.citation: Int J Oncol. 2012 May;40(5):1358-64
references.pmid: 22294087
references.citation: Horm Behav. 2012 Apr;61(4):487-95
references.pmid: 22265866
references.citation: Placenta. 2005 Apr;26 Suppl A:S63-9
references.pmid: 15837070
references.citation: Cell. 2009 May 29;137(5):873-86
references.pmid: 19446321
references.citation: Anticancer Res. 2010 Sep;30(9):3529-34
references.pmid: 20944133
references.citation: Cancer Res. 2009 Aug 1;69(15):6171-8
references.pmid: 19622772
references.citation: World J Biol Chem. 2012 Jun 26;3(6):110-20
references.pmid: 22905289
references.citation: Reproduction. 2010 Jul;140(1):11-22
references.pmid: 20457595
references.citation: Eur J Obstet Gynecol Reprod Biol. 2009 May;144 Suppl 1:S2-10
references.pmid: 19299064
references.citation: Steroids. 2012 Jun;77(7):791-7
references.pmid: 22465879
references.citation: Clin Sci (Lond). 2012 Apr;122(7):349-59
references.pmid: 21992080
references.citation: Science. 2001 Nov 2;294(5544):1102-5
references.pmid: 11691993
references.citation: Am J Obstet Gynecol. 2003 Feb;188(2):553-9
references.pmid: 12592271