title: New roles for cyclin E in megakaryocytic polyploidization.
abstract: Megakaryocytes are platelet precursor cells that undergo endomitosis. During this process, repeated rounds of DNA synthesis are characterized by lack of late anaphase and cytokinesis. Physiologically, the majority of the polyploid megakaryocytes in the bone marrow are cell cycle arrested. As previously reported, cyclin E is essential for megakaryocyte polyploidy; however, it has remained unclear whether up-regulated cyclin E is an inducer of polyploidy in vivo. We found that cyclin E is up-regulated upon stimulation of primary megakaryocytes by thrombopoietin. Transgenic mice in which elevated cyclin E expression is targeted to megakaryocytes display an increased ploidy profile. Examination of S phase markers, specifically proliferating cell nuclear antigen, cyclin A, and 5-bromo-2-deoxyuridine reveals that cyclin E promotes progression to S phase and cell cycling. Interestingly, analysis of Cdc6 and Mcm2 indicates that cyclin E mediates its effect by promoting the expression of components of the pre-replication complex. Furthermore, we show that up-regulated cyclin E results in the up-regulation of cyclin B1 levels, suggesting an additional mechanism of cyclin E-mediated ploidy increase. These findings define a key role for cyclin E in promoting megakaryocyte entry into S phase and hence, increase in the number of cell cycling cells and in augmenting polyploidization.
authors.affiliation: Department of Medicine and Biochemistry, Evans Center for Interdisciplinary Biomedical Research, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
authors.forename: Alexia
authors.initials: A
authors.lastname: Eliades
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Papadantonakis
authors.forename: Katya
authors.initials: K
authors.lastname: Ravid
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000378:metabolism; D001853:Bone Marrow / Q000378:metabolism; D056744:Cyclin B1 / Q000378:metabolism; D019927:Cyclin E / Q000737:chemistry*; D016213:Cyclins / Q000378:metabolism; D004247:DNA / Q000737:chemistry*; D003857:Deoxyuridine / Q000031:analogs & derivatives / Q000378:metabolism; D005786:Gene Expression Regulation; D008533:Megakaryocytes / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D011123:Polyploidy; D016196:S Phase; D013926:Thrombopoietin / Q000378:metabolism
chemical_list: D056744:Cyclin B1; D019927:Cyclin E; D016213:Cyclins; C032447:5-bromoethynyl-2'-deoxyuridine; D004247:DNA; D013926:Thrombopoietin; D003857:Deoxyuridine
references.citation: Br J Haematol. 2006 Sep;134(5):453-66
references.pmid: 16856888
references.citation: Mol Cell. 2007 Jan 12;25(1):127-39
references.pmid: 17218276
references.citation: Mol Cell Biol. 1997 Dec;17(12):7248-59
references.pmid: 9372957
references.citation: Oncogene. 1996 Aug 15;13(4):695-703
references.pmid: 8761290
references.citation: Cancer Metastasis Rev. 2003 Dec;22(4):435-49
references.pmid: 12884917
references.citation: Biochem Biophys Res Commun. 1997 Jul 9;236(1):118-25
references.pmid: 9223437
references.citation: Oncogene. 2002 May 13;21(21):3359-67
references.pmid: 12032774
references.citation: Proc Natl Acad Sci U S A. 1991 Feb 15;88(4):1521-5
references.pmid: 1899930
references.citation: Blood. 2009 Aug 6;114(6):1243-9
references.pmid: 19471020
references.citation: J Cell Physiol. 2002 Jan;190(1):7-20
references.pmid: 11807806
references.citation: EMBO J. 2003 Sep 15;22(18):4794-803
references.pmid: 12970191
references.citation: Cell. 2003 Aug 22;114(4):431-43
references.pmid: 12941272
references.citation: Semin Thromb Hemost. 2004 Oct;30(5):513-23
references.pmid: 15497094
references.citation: Cell Cycle. 2006 Mar;5(5):538-45
references.pmid: 16552179
references.citation: Mol Cell Biol. 1999 Jan;19(1):612-22
references.pmid: 9858585
references.citation: Mol Cell Biol. 1998 Feb;18(2):753-61
references.pmid: 9447971
references.citation: Br J Haematol. 1998 Aug;102(3):812-9
references.pmid: 9722312
references.citation: Blood. 2004 Aug 15;104(4):1017-24
references.pmid: 15130946
references.citation: Bioessays. 1999 Apr;21(4):353-60
references.pmid: 10377897
references.citation: Blood. 1998 May 15;91(10):3711-23
references.pmid: 9573008
references.citation: Blood. 2008 Oct 15;112(8):3164-74
references.pmid: 18684864
references.citation: J Biol Chem. 1998 Jan 16;273(3):1387-92
references.pmid: 9430673
references.citation: Curr Biol. 2002 Aug 20;12(16):1368-78
references.pmid: 12194817
references.citation: Blood. 2008 Apr 15;111(8):4092-5
references.pmid: 18245663
references.citation: Cell. 1999 Sep 17;98(6):859-69
references.pmid: 10499802
references.citation: Nat Rev Mol Cell Biol. 2005 Jun;6(6):476-86
references.pmid: 15928711
references.citation: J Clin Invest. 2005 Dec;115(12):3339-47
references.pmid: 16322778
references.citation: Oncogene. 1998 Nov 26;17(21):2787-98
references.pmid: 9840943
references.citation: Blood. 1995 Nov 15;86(10):3783-8
references.pmid: 7579345
references.citation: Oncogene. 2005 Apr 18;24(17):2776-86
references.pmid: 15838514
references.citation: J Thromb Haemost. 2007 Jul;5 Suppl 1:18-23
references.pmid: 17635704
references.citation: Cell Cycle. 2008 Aug;7(15):2352-6
references.pmid: 18677109
references.citation: J Biol Chem. 2000 Mar 3;275(9):6337-45
references.pmid: 10692433
references.citation: J Cell Biol. 2007 Jul 30;178(3):371-85
references.pmid: 17664332
references.citation: Genes Dev. 2000 Sep 15;14(18):2265-70
references.pmid: 10995383
references.citation: Blood. 1970 Mar;35(3):298-311
references.pmid: 5437680
references.citation: Blood. 2005 Sep 1;106(5):1559-64
references.pmid: 15890684
references.citation: J Cell Biol. 1997 Oct 20;139(2):449-57
references.pmid: 9334347
references.citation: Mol Cell Biol. 1995 May;15(5):2612-24
references.pmid: 7739542
references.citation: Haematologica. 2001 Jan;86(1):17-23
references.pmid: 11146565
references.citation: Oncogene. 2000 Mar 30;19(14):1820-33
references.pmid: 10777216
references.citation: J Cell Physiol. 2001 Sep;188(3):291-303
references.pmid: 11473355
references.citation: Cell. 2005 Sep 23;122(6):915-26
references.pmid: 16153703
references.citation: Cell. 1997 Jan 10;88(1):109-19
references.pmid: 9019396
references.citation: Blood. 2004 Nov 1;104(9):2722-7
references.pmid: 15198950
references.citation: J Biol Chem. 1996 Feb 23;271(8):4266-72
references.pmid: 8626773
references.citation: Blood. 2009 Jul 2;114(1):153-6
references.pmid: 19339696
references.citation: Cell Growth Differ. 1998 Aug;9(8):639-50
references.pmid: 9716181
references.citation: Philos Trans R Soc Lond B Biol Sci. 2004 Jan 29;359(1441):31-8
references.pmid: 15065654
references.citation: EMBO J. 1997 Sep 1;16(17):5322-33
references.pmid: 9311992
references.citation: Blood. 2007 Jun 15;109(12):5199-207
references.pmid: 17317855
references.citation: Int J Biochem Cell Biol. 2004 Aug;36(8):1424-39
references.pmid: 15147722
references.citation: Annu Rev Biochem. 2002;71:333-74
references.pmid: 12045100
references.citation: Genes Dev. 1998 Jul 15;12(14):2120-30
references.pmid: 9679057
references.citation: Blood. 2004 May 15;103(10):3717-26
references.pmid: 14751927
references.citation: J Biol Chem. 1996 Sep 20;271(38):22976-82
references.pmid: 8798484
references.citation: Blood. 2001 Apr 15;97(8):2238-47
references.pmid: 11290584