New roles for cyclin E in megakaryocytic polyploidization.
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.
Eliades
Alexia
A
Department of Medicine and Biochemistry, Evans Center for Interdisciplinary Biomedical Research, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Papadantonakis
Nikolaos
N
Ravid
Katya
K
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
D056744:Cyclin B1; D019927:Cyclin E; D016213:Cyclins; C032447:5-bromoethynyl-2'-deoxyuridine; D004247:DNA; D013926:Thrombopoietin; D003857:Deoxyuridine
Br J Haematol. 2006 Sep;134(5):453-66
16856888
Mol Cell. 2007 Jan 12;25(1):127-39
17218276
Mol Cell Biol. 1997 Dec;17(12):7248-59
9372957
Oncogene. 1996 Aug 15;13(4):695-703
8761290
Cancer Metastasis Rev. 2003 Dec;22(4):435-49
12884917
Biochem Biophys Res Commun. 1997 Jul 9;236(1):118-25
9223437
Oncogene. 2002 May 13;21(21):3359-67
12032774
Proc Natl Acad Sci U S A. 1991 Feb 15;88(4):1521-5
1899930
Blood. 2009 Aug 6;114(6):1243-9
19471020
J Cell Physiol. 2002 Jan;190(1):7-20
11807806
EMBO J. 2003 Sep 15;22(18):4794-803
12970191
Cell. 2003 Aug 22;114(4):431-43
12941272
Semin Thromb Hemost. 2004 Oct;30(5):513-23
15497094
Cell Cycle. 2006 Mar;5(5):538-45
16552179
Mol Cell Biol. 1999 Jan;19(1):612-22
9858585
Mol Cell Biol. 1998 Feb;18(2):753-61
9447971
Br J Haematol. 1998 Aug;102(3):812-9
9722312
Blood. 2004 Aug 15;104(4):1017-24
15130946
Bioessays. 1999 Apr;21(4):353-60
10377897
Blood. 1998 May 15;91(10):3711-23
9573008
Blood. 2008 Oct 15;112(8):3164-74
18684864
J Biol Chem. 1998 Jan 16;273(3):1387-92
9430673
Curr Biol. 2002 Aug 20;12(16):1368-78
12194817
Blood. 2008 Apr 15;111(8):4092-5
18245663
Cell. 1999 Sep 17;98(6):859-69
10499802
Nat Rev Mol Cell Biol. 2005 Jun;6(6):476-86
15928711
J Clin Invest. 2005 Dec;115(12):3339-47
16322778
Oncogene. 1998 Nov 26;17(21):2787-98
9840943
Blood. 1995 Nov 15;86(10):3783-8
7579345
Oncogene. 2005 Apr 18;24(17):2776-86
15838514
J Thromb Haemost. 2007 Jul;5 Suppl 1:18-23
17635704
Cell Cycle. 2008 Aug;7(15):2352-6
18677109
J Biol Chem. 2000 Mar 3;275(9):6337-45
10692433
J Cell Biol. 2007 Jul 30;178(3):371-85
17664332
Genes Dev. 2000 Sep 15;14(18):2265-70
10995383
Blood. 1970 Mar;35(3):298-311
5437680
Blood. 2005 Sep 1;106(5):1559-64
15890684
J Cell Biol. 1997 Oct 20;139(2):449-57
9334347
Mol Cell Biol. 1995 May;15(5):2612-24
7739542
Haematologica. 2001 Jan;86(1):17-23
11146565
Oncogene. 2000 Mar 30;19(14):1820-33
10777216
J Cell Physiol. 2001 Sep;188(3):291-303
11473355
Cell. 2005 Sep 23;122(6):915-26
16153703
Cell. 1997 Jan 10;88(1):109-19
9019396
Blood. 2004 Nov 1;104(9):2722-7
15198950
J Biol Chem. 1996 Feb 23;271(8):4266-72
8626773
Blood. 2009 Jul 2;114(1):153-6
19339696
Cell Growth Differ. 1998 Aug;9(8):639-50
9716181
Philos Trans R Soc Lond B Biol Sci. 2004 Jan 29;359(1441):31-8
15065654
EMBO J. 1997 Sep 1;16(17):5322-33
9311992
Blood. 2007 Jun 15;109(12):5199-207
17317855
Int J Biochem Cell Biol. 2004 Aug;36(8):1424-39
15147722
Annu Rev Biochem. 2002;71:333-74
12045100
Genes Dev. 1998 Jul 15;12(14):2120-30
9679057
Blood. 2004 May 15;103(10):3717-26
14751927
J Biol Chem. 1996 Sep 20;271(38):22976-82
8798484
Blood. 2001 Apr 15;97(8):2238-47
11290584