title: WEE1 murine deficiency induces hyper-activation of APC/C and results in genomic instability and carcinogenesis.
abstract: The tyrosine kinase WEE1 controls the timing of entry into mitosis in eukaryotes and its genetic deletion leads to pre-implantation lethality in mice. Here, we show that besides the premature mitotic entry phenotype, Wee1 mutant murine cells fail to complete mitosis properly and exhibit several additional defects that contribute to the deregulation of mitosis, allowing mutant cells to progress through mitosis at the expense of genomic integrity. WEE1 interacts with the anaphase promoting complex, functioning as a negative regulator, and the deletion of Wee1 results in hyper-activation of this complex. Mammary specific knockout mice overcome the DNA damage response pathway triggered by the mis-coordination of the cell cycle in mammary epithelial cells and heterozygote mice spontaneously develop mammary tumors. Thus, WEE1 functions as a haploinsufficient tumor suppressor that coordinates distinct cell division events to allow correct segregation of genetic information into daughter cells and maintain genome integrity.
authors.affiliation: 1] Genetics of Development and Disease Branch, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA [2] Department of Radiation Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: A
authors.initials: A
authors.lastname: Vassilopoulos
authors.affiliation: Genetics of Development and Disease Branch, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Tominaga
authors.affiliation: 1] Genetics of Development and Disease Branch, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA [2] Department of Life Science, Ewha Womans University, Seoul, South Korea.
authors.forename: H-Seok
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Genetics of Development and Disease Branch, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: T
authors.initials: T
authors.lastname: Lahusen
authors.affiliation: Department of Pharmacology, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: B
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Pharmacology, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: H
authors.initials: H
authors.lastname: Yu
authors.affiliation: Department of Radiation Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: D
authors.initials: D
authors.lastname: Gius
authors.affiliation: Genetics of Development and Disease Branch, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: C-X
authors.initials: CX
authors.lastname: Deng
mesh_terms: D064173:Anaphase-Promoting Complex-Cyclosome / Q000378:metabolism*; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004847:Epithelial Cells / Q000473:pathology; D005260:Female; D017353:Gene Deletion; D042822:Genomic Instability; D008321:Mammary Glands, Animal / Q000166:cytology / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D008938:Mitosis; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism*; D013629:Tamoxifen
chemical_list: D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D013629:Tamoxifen; D064173:Anaphase-Promoting Complex-Cyclosome; D011505:Protein-Tyrosine Kinases; C499348:Wee1 protein, mouse
references.citation: Cell Div. 2009 Jan 19;4:2
references.pmid: 19152694
references.citation: Cell. 1993 Aug 13;74(3):463-74
references.pmid: 8348613
references.citation: Mol Cancer Ther. 2009 Nov;8(11):2992-3000
references.pmid: 19887545
references.citation: Nucleic Acids Res. 1997 Nov 1;25(21):4323-30
references.pmid: 9336464
references.citation: Cancer Biol Ther. 2004 Mar;3(3):305-13
references.pmid: 14726685
references.citation: Cell Cycle. 2002 Nov-Dec;1(6):362-8
references.pmid: 12548006
references.citation: Cancer Biol Ther. 2010 Apr 1;9(7):514-22
references.pmid: 20107315
references.citation: J Biol Chem. 2010 May 28;285(22):16978-90
references.pmid: 20360007
references.citation: Clin Cancer Res. 2011 May 1;17(9):2799-806
references.pmid: 21389100
references.citation: Cell. 2005 Aug 12;122(3):407-20
references.pmid: 16096060
references.citation: Proc Natl Acad Sci U S A. 1992 Apr 1;89(7):2917-21
references.pmid: 1372994
references.citation: Anal Biochem. 2011 May 1;412(1):92-5
references.pmid: 21255551
references.citation: Mol Cancer Ther. 2004 Apr;3(4):513-9
references.pmid: 15078995
references.citation: Cell Cycle. 2009 Sep 1;8(17):2697-702
references.pmid: 19652546
references.citation: PLoS One. 2009;4(4):e5120
references.pmid: 19357772
references.citation: Mol Cell. 2009 Apr 24;34(2):135-6
references.pmid: 19394289
references.citation: Nat Rev Mol Cell Biol. 2010 Mar;11(3):220-8
references.pmid: 20177397
references.citation: Nature. 2004 Nov 18;432(7015):316-23
references.pmid: 15549093
references.citation: Cell. 1991 Oct 4;67(1):189-96
references.pmid: 1655274
references.citation: Hum Mutat. 2013 Mar;34(3):439-45
references.pmid: 23161852
references.citation: BMC Cancer. 2011 Apr 29;11:156
references.pmid: 21529352
references.citation: Cell Cycle. 2010 Aug 1;9(15):3046-53
references.pmid: 20714223
references.citation: Cell. 1991 Mar 8;64(5):903-14
references.pmid: 1825803
references.citation: Cancer Biol Ther. 2014 Apr;15(4):380-8
references.pmid: 24365782
references.citation: Structure. 2005 Apr;13(4):541-50
references.pmid: 15837193
references.citation: Nature. 1989 May 25;339(6222):280-6
references.pmid: 2566918
references.citation: Cancer Metastasis Rev. 2013 Jun;32(1-2):25-37
references.pmid: 23093327
references.citation: Nature. 1989 Nov 2;342(6245):39-45
references.pmid: 2682257
references.citation: Dev Biol. 2002 Apr 15;244(2):305-18
references.pmid: 11944939
references.citation: Nature. 1975 Aug 14;256(5518):547-51
references.pmid: 1165770
references.citation: Trends Cell Biol. 2006 Jan;16(1):55-63
references.pmid: 16337124
references.citation: DNA Repair (Amst). 2004 Aug-Sep;3(8-9):997-1007
references.pmid: 15279786
references.citation: Nat Cell Biol. 2008 Jul;10(7):802-11
references.pmid: 18552834
references.citation: Cancer Cell. 2010 Sep 14;18(3):244-57
references.pmid: 20832752
references.citation: Mol Cell. 2004 Sep 10;15(5):799-811
references.pmid: 15350223
references.citation: Cancer Res. 2001 Nov 15;61(22):8211-7
references.pmid: 11719452
references.citation: Exp Cell Res. 1978 Sep;115(2):317-29
references.pmid: 689088
references.citation: Int J Biol Sci. 2009 Nov 26;5(7):758-62
references.pmid: 20011137
references.citation: Oncogene. 2008 Feb 7;27(7):907-17
references.pmid: 17700535
references.citation: Cancer Cell. 2011 Oct 18;20(4):487-99
references.pmid: 22014574
references.citation: Int J Biol Sci. 2006;2(4):161-70
references.pmid: 16810330
references.citation: Cell. 1991 Oct 4;67(1):197-211
references.pmid: 1913817
references.citation: Br J Cancer. 2008 Feb 12;98(3):523-8
references.pmid: 18231106
references.citation: Curr Opin Genet Dev. 2002 Feb;12(1):53-9
references.pmid: 11790555
references.citation: Nat Rev Mol Cell Biol. 2006 Sep;7(9):644-56
references.pmid: 16896351
references.citation: Nature. 2000 Nov 9;408(6809):248-54
references.pmid: 11089982
references.citation: Science. 1991 Jul 5;253(5015):49-53
references.pmid: 1905840
references.citation: Nature. 1991 Feb 28;349(6312):808-11
references.pmid: 1825699
references.citation: Nature. 1991 May 16;351(6323):242-5
references.pmid: 1828290
references.citation: Nature. 2006 Nov 30;444(7119):633-7
references.pmid: 17136093
references.citation: Proc Natl Acad Sci U S A. 1995 Oct 10;92(21):9638-42
references.pmid: 7568188
references.citation: Science. 1992 Sep 25;257(5078):1955-7
references.pmid: 1384126
references.citation: Nucleic Acids Res. 2006 Mar 06;34(5):1416-26
references.pmid: 16522651
references.citation: Mol Gen Genet. 1978 May 3;161(2):215-20
references.pmid: 672898
references.citation: J Cell Biol. 2013 Jun 10;201(6):843-62
references.pmid: 23751495
references.citation: PLoS Genet. 2011 Aug;7(8):e1002263
references.pmid: 21901114
references.citation: EMBO J. 1991 Dec;10(13):4301-9
references.pmid: 1756737
references.citation: Curr Biol. 2005 Sep 6;15(17):1525-34
references.pmid: 16139207
references.citation: Cell. 1991 Mar 22;64(6):1111-22
references.pmid: 1706223