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Genetic mouse models to investigate cell cycle regulation

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Abstract

Early studies on cell cycle regulation were based on experiments in model systems (Yeast, Xenopus, Starfish, Drosophila) and have shaped the way we understand many events that control the cell cycle. Although these model systems are of great value, the last decade was highlighted by studies done in human cells and using in vivo mouse models. Mouse models are irreplaceable tools for understanding the genetics, development, and survival strategies of mammals. New developments in generating targeting vectors and mutant mice have improved our approaches to study cell cycle regulation and cancer. Here we summarize the most recent advances of mouse model approaches in dissecting the mechanisms of cell cycle regulation and the relevance to human disease.

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References

  • Aleem E, Kaldis P (2006) Mouse models of cell cycle regulators: new paradigms. Results Probl Cell Differ 42:271–328

    Article  PubMed  CAS  Google Scholar 

  • Artus J, Babinet C, Cohen-Tannoudji M (2006) The cell cycle of early mammalian embryos: lessons from genetic mouse models. Cell Cycle 5:499–502

    PubMed  CAS  Google Scholar 

  • Berthet C, Kaldis P (2006) Cdk2 and Cdk4 cooperatively control the expression of Cdc2. Cell Div 1:10

    Article  PubMed  Google Scholar 

  • Berthet C, Aleem E, Coppola V, Tessarollo L, Kaldis P (2003) Cdk2 knockout mice are viable. Curr Biol 13:1775–1785

    Article  PubMed  CAS  Google Scholar 

  • Buchholz F, Ringrose L, Angrand PO, Rossi F, Stewart AF (1996) Different thermostabilities of FLP and Cre recombinases: implications for applied site-specific recombination. Nucleic Acids Res 24:4256–4262

    Article  PubMed  CAS  Google Scholar 

  • Buchholz F, Angrand PO, Stewart AF (1998) Improved properties of FLP recombinase evolved by cycling mutagenesis. Nat Biotechnol 16:657–662

    Article  PubMed  CAS  Google Scholar 

  • Capecchi MR (2005) Gene targeting in mice: functional analysis of the mammalian genome for the twenty-first century. Nat Rev Genet 6:507–512

    Article  PubMed  CAS  Google Scholar 

  • Carthon BC, Neumann CA, Das M, Pawlyk B, Li T, Geng Y, Sicinski P (2005) Genetic replacement of cyclin D1 function in mouse development by cyclin D2. Mol Cell Biol 25:1081–1088

    Article  PubMed  CAS  Google Scholar 

  • Christophorou MA, Martin-Zanca D, Soucek L, Lawlor ER, Brown-Swigart L, Verschuren EW, Evan GI (2005) Temporal dissection of p53 function in vitro and in vivo. Nat Genet 37:718–726

    Article  PubMed  CAS  Google Scholar 

  • Ciemerych MA, Sicinski P (2005) Cell cycle in mouse development. Oncogene 24:2877–2898

    Article  PubMed  CAS  Google Scholar 

  • Copeland NG, Jenkins NA, Court DL (2001) Recombineering: a powerful new tool for mouse functional genomics. Nat Rev Genet 2:769–779

    Article  PubMed  CAS  Google Scholar 

  • Court DL, Swaminathan S, Yu D, Wilson H, Baker T, Bubunenko M, Sawitzke J, Sharan SK (2003) Mini-lambda: a tractable system for chromosome and BAC engineering. Gene 315:63–69

    Article  PubMed  CAS  Google Scholar 

  • Dankort D, Filenova E, Collado M, Serrano M, Jones K, McMahon M (2007) A new mouse model to explore the initiation, progression, and therapy of BRAFV600E-induced lung tumors. Genes Dev 21:379–384

    Article  PubMed  CAS  Google Scholar 

  • Dankort D, Curley DP, Cartlidge RA, Nelson B, Karnezis AN, Damsky WE Jr, You MJ, Depinho RA, McMahon M, Bosenberg M (2009). BrafV600E cooperates with Pten loss to induce metastatic melanoma. Nat Genet 41:544–552

    Article  PubMed  CAS  Google Scholar 

  • Datta S, Costantino N, Court DL (2006) A set of recombineering plasmids for gram-negative bacteria. Gene 379:109–115

    Article  PubMed  CAS  Google Scholar 

  • Dickins RA, McJunkin K, Hernando E, Premsrirut PK, Krizhanovsky V, Burgess DJ, Kim SY, Cordon-Cardo C, Zender L, Hannon GJ et al (2007) Tissue-specific and reversible RNA interference in transgenic mice. Nat Genet 39:914–921

    Article  PubMed  CAS  Google Scholar 

  • Fisher DL, Nurse P (1996) A sigle fission yeast mitotic cyclin B p34cdc2 kinase promotes both S-phase and mitosis in the absence of G1 cyclins. EMBO J 15:850–860

    PubMed  CAS  Google Scholar 

  • Frescas D, Pagano M (2008) Deregulated proteolysis by the F-box proteins SKP2 and beta-TrCP: tipping the scales of cancer. Nat Rev Cancer 8:438–449

    Article  PubMed  CAS  Google Scholar 

  • Geng Y, Whoriskey W, Park MY, Bronson RT, Medema RH, Li T, Weinberg RA, Sicinski P (1999) Rescue of cyclin D1 deficiency by knockin cyclin E. Cell 97:767–777

    Article  PubMed  CAS  Google Scholar 

  • Gingrich JR, Roder J (1998) Inducible gene expression in the nervous system of transgenic mice. Annu Rev Neurosci 21:377–405

    Article  PubMed  CAS  Google Scholar 

  • Gossen M, Bujard H (1992) Tight control of gene expression in mammalian cells by tetracycline-responsive promoters. Proc Natl Acad Sci USA 89:5547–5551

    Article  PubMed  CAS  Google Scholar 

  • Gossen M, Freudlieb S, Bender G, Muller G, Hillen W, Bujard H (1995) Transcriptional activation by tetracyclines in mammalian cells. Science 268:1766–1769

    Article  PubMed  CAS  Google Scholar 

  • Hartwell LH, Culotti J, Reid B (1970) Genetic control of the cell-division cycle in yeast. I. Detection of mutants. Proc Natl Acad Sci USA 66:352–359

    Article  PubMed  CAS  Google Scholar 

  • Hochegger H, Takeda S, Hunt T (2008) Cyclin-dependent kinases and cell-cycle transitions: does one fit all? Nat Rev Mol Cell Biol 9:910–916

    Article  PubMed  CAS  Google Scholar 

  • Jonkers J, Berns A (2002) Conditional mouse models of sporadic cancer. Nat Rev Cancer 2:251–265

    Article  PubMed  CAS  Google Scholar 

  • Kolb AF (2002) Genome engineering using site-specific recombinases. Cloning Stem Cells 4:65–80

    Article  PubMed  CAS  Google Scholar 

  • Lee YM, Sicinski P (2006) Targeting cyclins and cyclin-dependent kinases in cancer: lessons from mice, hopes for therapeutic applications in human. Cell Cycle 5:2110–2114

    PubMed  CAS  Google Scholar 

  • Lee E-C, Yu D, Martinez de Velasco J, Tessarollo L, Swing DA, Court DL, Jenkins NA, Copeland NG (2001) A highly efficient Escherichia coli-based chromosome engineering system adapted for recombinogenic targeting and subcloning of BAC DNA. Genomics 73:56–65

    Article  PubMed  CAS  Google Scholar 

  • Lewandoski M (2001) Conditional control of gene expression in the mouse. Nat Rev Genet 2:743–755

    Article  PubMed  CAS  Google Scholar 

  • Li W, Kotoshiba S, Berthet C, Hilton MB, Kaldis P (2009) Rb/Cdk2/Cdk4 triple mutant mice elicit an alternative mechanism for regulation of the G1/S transition. Proc Natl Acad Sci USA 106:486–491

    Article  PubMed  CAS  Google Scholar 

  • Malumbres M, Barbacid M (2007) Cell cycle kinases in cancer. Curr Opin Genet Dev 17:60–65

    Article  PubMed  CAS  Google Scholar 

  • Malumbres M, Barbacid M (2009) Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer 9:153–166

    Article  PubMed  CAS  Google Scholar 

  • Matzuk MM, Lamb DJ (2008) The biology of infertility: research advances and clinical challenges. Nat Med 14:1197–1213

    Article  PubMed  CAS  Google Scholar 

  • Morgan DO (1997) Cyclin-dependent kinases: engines, clocks, and microprocessors. Annu Rev Cell Dev Biol 13:261–291

    Article  PubMed  CAS  Google Scholar 

  • Muller U (1999) Ten years of gene targeting: targeted mouse mutants, from vector design to phenotype analysis. Mech Dev 82:3–21

    Article  PubMed  CAS  Google Scholar 

  • Murata T, Furushima K, Hirano M, Kiyonari H, Nakamura M, Suda Y, Aizawa S (2004) ang is a novel gene expressed in early neuroectoderm, but its null mutant exhibits no obvious phenotype. Gene Expr Patterns 5:171–178

    Article  PubMed  CAS  Google Scholar 

  • Murphy KC (1998) Use of bacteriophage lambda recombination functions to promote gene replacement in Escherichia coli. J Bacteriol 180:2063–2071

    PubMed  CAS  Google Scholar 

  • Nagy A (2000) Cre recombinase: the universal reagent for genome tailoring. Genesis 26:99–109

    Article  PubMed  CAS  Google Scholar 

  • Nakayama KI, Nakayama K (2006) Ubiquitin ligases: cell-cycle control and cancer. Nat Rev Cancer 6:369–381

    Article  PubMed  CAS  Google Scholar 

  • Nurse P, Thuriaux P, Nasmyth K (1976) Genetic control of the cell division cycle in the fission yeast Schizosaccharomyces pombe. Mol Gen Genet 146:167–178

    Article  PubMed  CAS  Google Scholar 

  • Orford KW, Scadden DT (2008) Deconstructing stem cell self-renewal: genetic insights into cell-cycle regulation. Nat Rev Genet 9:115–128

    Article  PubMed  CAS  Google Scholar 

  • Ortega S, Prieto I, Odajima J, Martin A, Dubus P, Sotillo R, Barbero JL, Malumbres M, Barbacid M (2003) Cyclin-dependent kinase 2 is essential for meiosis but not for mitotic cell division in mice. Nat Genet 35:25–31

    Article  PubMed  CAS  Google Scholar 

  • Padmakumar VC, Aleem E, Berthet C, Hilton MB, Kaldis P (2009). Cdk2 and Cdk4 activities are dispensable for tumorigenesis caused by the loss of p53. Mol Cell Biol 29. doi:10.1128/MCB.00952-08

  • Pelengaris S, Khan M, Evan GI (2002) Suppression of Myc-induced apoptosis in beta cells exposes multiple oncogenic properties of Myc and triggers carcinogenic progression. Cell 109:321–334

    Article  PubMed  CAS  Google Scholar 

  • Rane SG, Dubus P, Mettus RV, Galbreath EJ, Boden G, Reddy EP, Barbacid M (1999) Loss of Cdk4 expression causes insulin-deficient diabetes and Cdk4 activation results in β-islet cell hyperplasia. Nat Genet 22:44–52

    Article  PubMed  CAS  Google Scholar 

  • Rane SG, Cosenza SC, Mettus RV, Reddy EP (2002) Germ line transmission of the Cdk4R24C mutation facilitates tumorigenesis and escape from cellular senescence. Mol Cell Biol 22:644–656

    Article  PubMed  CAS  Google Scholar 

  • Sage J, Miller AL, Perez-Mancera PA, Wysocki JM, Jacks T (2003) Acute mutation of retinoblastoma gene function is sufficient for cell cycle re-entry. Nature 424:223–228

    Article  PubMed  CAS  Google Scholar 

  • Santamaria D, Ortega S (2006) Cyclins and CDKS in development and cancer: lessons from genetically modified mice. Front Biosci 11:1164–1188

    Article  PubMed  CAS  Google Scholar 

  • Santamaria D, Barriere C, Cerqueira A, Hunt S, Tardy C, Newton K, Caceres JF, Dubus P, Malumbres M, Barbacid M (2007) Cdk1 is sufficient to drive the mammalian cell cycle. Nature 448:811–815

    Article  PubMed  CAS  Google Scholar 

  • Satyanarayana A, Berthet C, Lopez-Molina J, Coppola V, Tessarollo L, Kaldis P (2008) Genetic substitution of Cdk1 by Cdk2 leads to embryonic lethality and loss of meiotic function of Cdk2. Development 135:3389–3400

    Article  PubMed  CAS  Google Scholar 

  • Sharan SK, Thomason LC, Kuznetsov SG, Court DL (2009) Recombineering: a homologous recombination-based method of genetic engineering. Nat Protoc 4:206–223

    Article  PubMed  CAS  Google Scholar 

  • Sherr CJ, Roberts JM (1999) Cdk inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 13:1501–1512

    Article  PubMed  CAS  Google Scholar 

  • Sherr CJ, Roberts JM (2004) Living with or without cyclins and cyclin-dependent kinases. Genes Dev 18:2699–2711

    Article  PubMed  CAS  Google Scholar 

  • Shizuya H, Birren B, Kim UJ, Mancino V, Slepak T, Tachiiri Y, Simon M (1992) Cloning and stable maintenance of 300-kilobase-pair fragments of human DNA in Escherichia coli using an F-factor-based vector. Proc Natl Acad Sci USA 89:8794–8797

    Article  PubMed  CAS  Google Scholar 

  • Sotillo R, Dubus P, Martin J, de la Cueva E, Ortega S, Malumbres M, Barbacid M (2001a) Wide spectrum of tumors in knock-in mice carrying a Cdk4 protein insensitive to INK4 inhibitors. EMBO J 20:6637–6647

    Article  PubMed  CAS  Google Scholar 

  • Sotillo R, Garcia JF, Ortega S, Martin J, Dubus P, Barbacid M, Malumbres M (2001b) Invasive melanoma in Cdk4-targeted mice. Proc Natl Acad Sci USA 98:13312–13317

    Article  PubMed  CAS  Google Scholar 

  • Susaki E, Nakayama K, Yamasaki L, Nakayama KI (2009) Common and specific roles of the related CDK inhibitors p27 and p57 revealed by a knock-in mouse model. Proc Natl Acad Sci USA 106:5152–5197

    Article  Google Scholar 

  • Van Dyke T, Jacks T (2002) Cancer modeling in the modern era: progress and challenges. Cell 108:135–144

    Article  PubMed  Google Scholar 

  • van Leuken R, Clijsters L, Wolthuis R (2008) To cell cycle, swing the APC/C. Biochim Biophys Acta 1786:49–59

    PubMed  Google Scholar 

  • Ventura A, Kirsch DG, McLaughlin ME, Tuveson DA, Grimm J, Lintault L, Newman J, Reczek EE, Weissleder R, Jacks T (2007) Restoration of p53 function leads to tumour regression in vivo. Nature 445:661–665

    Article  PubMed  CAS  Google Scholar 

  • Waterston RH, Lindblad-Toh K, Birney E, Rogers J, Abril JF, Agarwal P, Agarwala R, Ainscough R, Alexandersson M, An P et al (2002) Initial sequencing and comparative analysis of the mouse genome. Nature 420:520–562

    Article  PubMed  CAS  Google Scholar 

  • Wu S, Ying G, Wu Q, Capecchi MR (2008) A protocol for constructing gene targeting vectors: generating knockout mice for the cadherin family and beyond. Nat Protoc 3:1056–1076

    Article  PubMed  CAS  Google Scholar 

  • Yu D, Ellis HM, Lee EC, Jenkins NA, Copeland NG, Court DL (2000) An efficient recombination system for chromosome engineering in Escherichia coli. Proc Natl Acad Sci USA 97:5978–5983

    Article  PubMed  CAS  Google Scholar 

  • Zhang Y, Buchholz F, Muyrers JP, Stewart AF (1998) A new logic for DNA engineering using recombination in Escherichia coli. Nat Genet 20:123–128

    Article  PubMed  CAS  Google Scholar 

  • Zhao S, Shatsman S, Ayodeji B, Geer K, Tsegaye G, Krol M, Gebregeorgis E, Shvartsbeyn A, Russell D, Overton L et al (2001) Mouse BAC ends quality assessment and sequence analyses. Genome Res 11:1736–1745

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Cell Division and Cancer Laboratory (PRK), Institute of Molecular and Cell Biology (IMCB), 61 Biopolis Drive, Proteos #03-09, Singapore, 138673, Singapore

    Shuhei Kotoshiba & Philipp Kaldis

  2. Department of Pharmacology, University of Wisconsin-Madison, 3725 MSC, 1300 University Avenue, Madison, WI, 53706, USA

    Weimin Li

Authors
  1. Weimin Li
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  2. Shuhei Kotoshiba
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  3. Philipp Kaldis
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Correspondence to Philipp Kaldis.

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W. Li and S. Kotoshiba contributed equally.

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Li, W., Kotoshiba, S. & Kaldis, P. Genetic mouse models to investigate cell cycle regulation. Transgenic Res 18, 491–498 (2009). https://doi.org/10.1007/s11248-009-9276-x

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  • DOI: https://doi.org/10.1007/s11248-009-9276-x

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