title: Contact inhibition modulates intracellular levels of miR-223 in a p27kip1-dependent manner.
abstract: MicroRNAs (miRs) are a large class of small regulatory RNAs that function as nodes of signaling networks. This implicates that miRs expression has to be finely tuned, as observed during cell cycle progression. Here, using an expression profiling approach, we provide evidence that the CDK inhibitor p27Kip1 regulates miRs expression following cell cycle exit. By using wild type and p27KO cells harvested in different phases of the cell cycle we identified several miRs regulated by p27Kip1 during the G1 to S phase transition. Among these miRs, we identified miR-223 as a miR specifically upregulated by p27Kip1 in G1 arrested cells. Our data demonstrate that p27Kip1 regulated the expression of miR-223, via two distinct mechanisms. p27Kip1 directly stabilized mature miR-223 expression, acting as a RNA binding protein and it controlled E2F1 expression that, in turn, regulated miR-223 promoter activity. The resulting elevated miR-223 levels ultimately participated to arresting cell cycle progression following contact inhibition. Importantly, this mechanism of growth control was conserved in human cells and deranged in breast cancers. Here, we identify a novel and conserved function of p27Kip1 that, by modulating miR-223 expression, contributes to proper regulation of cell cycle exit following contact inhibition. Thus we propose a new role for miR-223 in the regulation of breast cancer progression.
authors.affiliation: Division of Experimental Oncology 2, CRO, National Cancer Institute, Aviano, Italy.
authors.forename: Joshua
authors.initials: J
authors.lastname: Armenia
authors.forename: Linda
authors.initials: L
authors.lastname: Fabris
authors.forename: Francesca
authors.initials: F
authors.lastname: Lovat
authors.forename: Stefania
authors.initials: S
authors.lastname: Berton
authors.forename: Ilenia
authors.initials: I
authors.lastname: Segatto
authors.forename: Sara
authors.initials: S
authors.lastname: D'Andrea
authors.forename: Cristina
authors.initials: C
authors.lastname: Ivan
authors.forename: Luciano
authors.initials: L
authors.lastname: Cascione
authors.forename: George A
authors.initials: GA
authors.lastname: Calin
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
authors.forename: Alfonso
authors.initials: A
authors.lastname: Colombatti
authors.forename: Andrea
authors.initials: A
authors.lastname: Vecchione
authors.forename: Barbara
authors.initials: B
authors.lastname: Belletti
authors.forename: Gustavo
authors.initials: G
authors.lastname: Baldassarre
mesh_terms: D000818:Animals; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003260:Contact Inhibition / Q000502:physiology*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics* / Q000378:metabolism; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts; D059585:G1 Phase Cell Cycle Checkpoints; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D006207:Half-Life; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D059748:Proteolysis; D059807:S Phase Cell Cycle Checkpoints; D014158:Transcription, Genetic; D015854:Up-Regulation
chemical_list: D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C544877:MIRN223 microRNA, mouse; D035683:MicroRNAs; D050760:Cyclin-Dependent Kinase Inhibitor p27
references.citation: Cell. 2005 Dec 2;123(5):819-31
references.pmid: 16325577
references.citation: Cell. 2007 Jan 26;128(2):269-80
references.pmid: 17254966
references.citation: Cancer Cell. 2005 Jun;7(6):591-8
references.pmid: 15950907
references.citation: Oncogene. 2012 Sep 20;31(38):4207-20
references.pmid: 22179826
references.citation: Cell. 2007 May 4;129(3):617-31
references.pmid: 17482553
references.citation: Trends Biochem Sci. 2012 Oct;37(10):436-46
references.pmid: 22921610
references.citation: Blood. 2010 Mar 4;115(9):1768-78
references.pmid: 20029046
references.citation: Sci Signal. 2010 Jun 01;3(124):ra43
references.pmid: 20516477
references.citation: Science. 1996 May 10;272(5263):877-80
references.pmid: 8629023
references.citation: Curr Med Chem. 2005;12(14):1589-605
references.pmid: 16022660
references.citation: Cell. 1996 May 31;85(5):733-44
references.pmid: 8646781
references.citation: Curr Biol. 2011 Mar 8;21(5):369-76
references.pmid: 21353554
references.citation: Nature. 2008 Feb 28;451(7182):1125-9
references.pmid: 18278031
references.citation: Genes Dev. 1994 Jan;8(1):9-22
references.pmid: 8288131
references.citation: Curr Mol Med. 2012 Jan;12(1):27-33
references.pmid: 22082479
references.citation: Nature. 2012 May 16;486(7403):400-4
references.pmid: 22722201
references.citation: Cancer Cell. 2005 Jan;7(1):51-63
references.pmid: 15652749
references.citation: EMBO J. 2007 Aug 8;26(15):3699-708
references.pmid: 17627278
references.citation: Cell Cycle. 2012 Oct 1;11(19):3701-2
references.pmid: 22895010
references.citation: PLoS One. 2011 Mar 14;6(3):e17673
references.pmid: 21423803
references.citation: Mol Cell. 2011 Sep 16;43(6):993-1004
references.pmid: 21925387
references.citation: Cancer Res. 2006 Feb 15;66(4):2162-72
references.pmid: 16489017
references.citation: Hum Mol Genet. 2001 Apr;10(7):699-703
references.pmid: 11257102
references.citation: Mol Cell Biol. 2010 Jun;30(12):2983-95
references.pmid: 20404092
references.citation: Nature. 2012 Oct 4;490(7418):61-70
references.pmid: 23000897
references.citation: Oncogene. 2011 Jun 23;30(25):2846-58
references.pmid: 21317921
references.citation: Cancer Cell. 2008 Mar;13(3):272-86
references.pmid: 18328430
references.citation: Nat Protoc. 2006;1(1):302-7
references.pmid: 17406249
references.citation: Biochim Biophys Acta. 2011 May;1812(5):592-601
references.pmid: 21315819
references.citation: EMBO J. 2004 Oct 13;23(20):4051-60
references.pmid: 15372072
references.citation: Nat Rev Mol Cell Biol. 2010 Apr;11(4):252-63
references.pmid: 20216554
references.citation: Proc Natl Acad Sci U S A. 2010 Feb 16;107(7):3240-4
references.pmid: 20133739
references.citation: EMBO J. 1997 Sep 1;16(17):5334-44
references.pmid: 9311993
references.citation: Nature. 1979 Sep 27;281(5729):259-62
references.pmid: 551275
references.citation: Nat Med. 2002 Oct;8(10):1153-60
references.pmid: 12244302
references.citation: Nucleic Acids Res. 2011 Jul;39(13):5692-703
references.pmid: 21447562