Skip to main content
SpringerLink
Log in
SpringerLink
Log in

Insertional Mutagenesis for Generating Mouse Models of Cancer

  • Chapter
  • First Online:
Genetically Engineered Mice for Cancer Research

  • 1349 Accesses

Abstract

Methods for modeling cancer in mice are extremely varied. Exposure to chemicals, radiation, or viruses, and the use of transgenic technologies have been employed, sometimes in combinations, to generate models of nearly every type of cancer that afflicts people. In some cases, scientists have sought information about the cancer causing capabilities of specific agents, including specific types and doses of radiation, chemicals or specific genes or mutant genes. In other studies, specific genes that can cause cancer were sought. Some approaches start with specific candidate genes. We can consider these approaches “reverse cancer genetics,” that is, studies that start with one or more specific genes whose biological activities will be studied in a mouse. In many cases, the genes studied came from those suspected to contribute to human cancer when mutated or misexpressed in some way. A completely different type of approach for modeling cancer asks “what genes, when mutated, can cause cancer?” These “forward cancer genetics” approaches frequently use random, somatic insertional mutagenesis to induce or accelerate cancer in mice. Thus, cancer genes can be discovered by looking for somatically acquired, tumor-specific insertion mutations near or within genes in tumor genomic DNA. By studying a whole panel of tumors induced this way, one can find genes that are altered by insertion mutation in multiple, independent tumors and thus discover excellent cancer gene candidates and cancer pathways. This chapter reviews available approaches for modeling cancer by insertional mutagenesis in mice. Details about setting up such a screen, identifying insertion sites, interpreting the results and leveraging the information gained to better understand tumor progression and human cancer are described.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Acha-Orbea H, MacDonald HR (1995) Superantigens of mouse mammary tumor virus. Annu Rev Immunol 13:459–486

    Article  PubMed  CAS  Google Scholar 

  • Akagi K, Suzuki T et al (2004) RTCGD: retroviral tagged cancer gene database. Nucleic Acids Res 32(Database issue): D523–D527

    Google Scholar 

  • An W, Han JS et al (2006) Active retrotransposition by a synthetic L1 element in mice. Proc Natl Acad Sci USA 103(49):18662–18667

    Article  PubMed  CAS  Google Scholar 

  • Balciunas D, Wangensteen KJ et al (2006) Harnessing a high cargo-capacity transposon for genetic applications in vertebrates. PLoS Genet 2(11):e169

    Article  PubMed  CAS  Google Scholar 

  • Bartholomew C, Ihle JN (1991) Retroviral insertions 90 kilobases proximal to the Evi-1 myeloid transforming gene activate transcription from the normal promoter. Mol Cell Biol 11(4):1820–1828

    PubMed  CAS  Google Scholar 

  • Baum C, von Kalle C et al (2004) Chance or necessity? Insertional mutagenesis in gene therapy and its consequences. Mol Ther 9(1):5–13

    Article  PubMed  CAS  Google Scholar 

  • Bedigian HG, Shepel LA et al (1993) Transplacental transmission of a leukemogenic murine leukemia virus. J Virol 67(10):6105–6109

    PubMed  CAS  Google Scholar 

  • Beinke S, Deka J et al (2003) NF-kappaB1 p105 negatively regulates TPL-2 MEK kinase activity. Mol Cell Biol 23(14):4739–4752

    Article  PubMed  CAS  Google Scholar 

  • Ben-David Y, Giddens EB et al (1990) Identification and mapping of a common proviral integration site Fli-1 in erythroleukemia cells induced by Friend murine leukemia virus. Proc Natl Acad Sci USA 87(4):1332–1336

    Article  PubMed  CAS  Google Scholar 

  • Ben-David Y, Giddens EB et al (1991) Erythroleukemia induction by Friend murine leukemia virus: insertional activation of a new member of the ets gene family, Fli-1, closely linked to c-ets-1. Genes Dev 5(6):908–918

    Article  PubMed  CAS  Google Scholar 

  • Berns A (1988) Provirus tagging as an instrument to identify oncogenes and to establish synergism between oncogenes. Arch Virol 102(1–2):1–18

    Article  PubMed  CAS  Google Scholar 

  • Bosze Z, Thiesen HJ et al (1986) A transcriptional enhancer with specificity for erythroid cells is located in the long terminal repeat of the Friend murine leukemia virus. EMBO J 5(7):1615–1623

    PubMed  CAS  Google Scholar 

  • Brouha B, Schustak J et al (2003) Hot L1s account for the bulk of retrotransposition in the human population. Proc Natl Acad Sci USA 100(9):5280–5285

    Article  PubMed  CAS  Google Scholar 

  • Buchberg AM, Bedigian HG et al (1990) Evi-2, a common integartion site involved in murine myeloid leukemogenesis. Mol Cell Biol 10:4658–4666

    PubMed  CAS  Google Scholar 

  • Callahan R, Smith GH (2000) MMTV-induced mammary tumorigenesis: gene discovery, progression to malignancy and cellular pathways. Oncogene 19(8):992–1001

    Article  PubMed  CAS  Google Scholar 

  • Callahan R, Smith GH (2008) J Mammary Gland Biol Neoplasia 13(3):309–321

    Article  PubMed  Google Scholar 

  • Carlson CM, Dupuy AJ et al (2003) Transposon mutagenesis of the mouse germline. Genetics 165(1):243–256

    PubMed  CAS  Google Scholar 

  • Cherry SR, Biniszkiewicz D et al (2000) Retroviral expression in embryonic stem cells and hematopoietic stem cells. Mol Cell Biol 20(20):7419–7426

    Article  PubMed  CAS  Google Scholar 

  • Collier LS, Carlson CM et al (2005) Cancer gene discovery in solid tumours using transposon-based somatic mutagenesis in the mouse. Nature 436(7048):272–276

    Article  PubMed  CAS  Google Scholar 

  • Cook WD, McCaw BJ (2000) Accommodating haploinsufficient tumor suppressor genes in Knudson’s model. Oncogene 19(30):3434–3438

    Article  PubMed  CAS  Google Scholar 

  • Dave UP, Jenkins NA et al (2004) Gene therapy insertional mutagenesis insights. Science 303(5656):333

    Article  PubMed  Google Scholar 

  • de Parseval N, Heidmann T (2005) Human endogenous retroviruses: from infectious elements to human genes. Cytogenet Genome Res 110(1–4):318–332

    Article  PubMed  CAS  Google Scholar 

  • de Ridder J, Uren A et al (2006) Detecting statistically significant common insertion sites in retroviral insertional mutagenesis screens. PLoS Comput Biol 2(12):e166

    Article  PubMed  CAS  Google Scholar 

  • Dewannieux M, Heidmann T (2005) LINEs, SINEs and processed pseudogenes: parasitic strategies for genome modeling. Cytogenet Genome Res 110(1–4):35–48

    Article  PubMed  CAS  Google Scholar 

  • Ding S, Wu X et al (2005) Efficient transposition of the piggyBac (PB) transposon in mammalian cells and mice. Cell 122(3):473–483

    Article  PubMed  CAS  Google Scholar 

  • Du Y, Jenkins NA et al (2005a) Insertional mutagenesis identifies genes that promote the immortalization of primary bone marrow progenitor cells. Blood 106(12):3932–3939

    Article  PubMed  CAS  Google Scholar 

  • Du Y, Spence SE et al (2005b) Cooperating cancer gene identification via oncogenic retrovirus-induced insertional mutagenesis. Blood 106(7):2498–2505

    Article  PubMed  CAS  Google Scholar 

  • Dupuy AJ, Akagi K et al (2005) Mammalian mutagenesis using a highly mobile somatic Sleeping Beauty transposon system. Nature 436(7048):221–226

    Article  PubMed  CAS  Google Scholar 

  • Dupuy AJ, Fritz S et al (2001) Transposition and gene disruption in the male germline of the mouse. Genesis 30(2):82–88

    Article  PubMed  CAS  Google Scholar 

  • Elenbaas B, Spirio L et al (2001) Human breast cancer cells generated by oncogenic transformation of primary mammary epithelial cells. Genes Dev 15(1):50–65

    Article  PubMed  CAS  Google Scholar 

  • Erkeland SJ, Verhaak RG et al (2006) Significance of murine retroviral mutagenesis for identification of disease genes in human acute myeloid leukemia. Cancer Res 66(2):622–626

    Article  PubMed  CAS  Google Scholar 

  • Ferletta M, Uhrbom L et al (2007) Sox10 has a broad expression pattern in gliomas and enhances platelet-derived growth factor-B-induced gliomagenesis. Mol Cancer Res 5(9):891–897

    Article  PubMed  CAS  Google Scholar 

  • Fischer SE, Wienholds E et al (2001) Regulated transposition of a fish transposon in the mouse germ line. Proc Natl Acad Sci USA 98(12):6759–6764

    Article  PubMed  CAS  Google Scholar 

  • Gardner MB (1978) Type C viruses of wild mice: characterization and natural history of amphotropic, ecotropic, and xenotropic MuLv. Curr Top Microbiol Immunol 79:215–259

    Article  PubMed  CAS  Google Scholar 

  • Geurts AM, Collier LS et al (2006a) Gene mutations and genomic rearrangements in the mouse as a result of transposon mobilization from chromosomal concatemers. PLoS Genet 2(9):e156

    Article  PubMed  CAS  Google Scholar 

  • Geurts AM, Hackett CS et al (2006b) Structure-based prediction of insertion-site preferences of transposons into chromosomes. Nucleic Acids Res 34(9):2803–2811

    Article  PubMed  CAS  Google Scholar 

  • Gilbert DJ, Neumann PE et al (1993) Susceptibility of AKXD recombinant inbred mouse strains to lymphomas. J Virol 67(4):2083–2090

    PubMed  CAS  Google Scholar 

  • Glover JF, Darbre PD (1989) Multihormone regulation of MMTV-LTR in transfected T-47-D human breast cancer cells. J Steroid Biochem 32(3):357–363

    Article  PubMed  CAS  Google Scholar 

  • Gross L (1978) Viral etiology of cancer and leukemia: a look into the past, present and future – G.H.A. Clowes Memorial Lecture. Cancer Res 38(3):485–493

    PubMed  CAS  Google Scholar 

  • Hacein-Bey-Abina S, Von Kalle C et al (2003) LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science 302(5644):415–419

    Article  PubMed  CAS  Google Scholar 

  • Hahn WC, Dessain SK et al (2002) Enumeration of the simian virus 40 early region elements necessary for human cell transformation. Mol Cell Biol 22(7):2111–2123

    Article  PubMed  CAS  Google Scholar 

  • Hansen GM, Justice MJ (1999) Activation of Hex and mEg5 by retroviral insertion may contribute to mouse B-cell leukemia. Oncogene 18(47):6531–6539

    Article  PubMed  CAS  Google Scholar 

  • Hawley RG, Lieu FH et al (1994) Versatile retroviral vectors for potential use in gene therapy. Gene Ther 1(2):136–138

    PubMed  CAS  Google Scholar 

  • Hayward WS, Neel BG et al (1981) Activation of a cellular onc gene by promoter insertion in ALV-induced lymphoid leukosis. Nature 290(5806):475–480

    Article  PubMed  CAS  Google Scholar 

  • Herr W, Gilbert W (1983) Somatically acquired recombinant murine leukemia proviruses in thymic leukemias of AKR/J mice. J Virol 46(1):70–82

    PubMed  CAS  Google Scholar 

  • Herschkowitz JI, Simin K et al (2007) Identification of conserved gene expression features between murine mammary carcinoma models and human breast tumors. Genome Biol 8(5):R76

    Article  PubMed  CAS  Google Scholar 

  • Himmel KL, Bi F et al (2002) Activation of Clg, a novel Dbl family guanine nucleotide exchange factor gene, by proviral insertion at Evi24, a common integration site in B cell and myeloid Leukemia. J Biol Chem 11:11

    Google Scholar 

  • Hirai H, Izutsu K et al (2001) Oncogenic mechanisms of Evi-1 protein. Cancer Chemother Pharmacol 48(Suppl 1):S35–S40

    Article  PubMed  CAS  Google Scholar 

  • Horie K, Kuroiwa A et al (2001) Efficient chromosomal transposition of a Tc1/mariner-like transposon Sleeping Beauty in mice. Proc Natl Acad Sci USA 98(16):9191–9196

    Article  PubMed  CAS  Google Scholar 

  • Horie K, Yusa K et al (2003) Characterization of Sleeping Beauty transposition and its application to genetic screening in mice. Mol Cell Biol 23(24):9189–9207

    Article  PubMed  CAS  Google Scholar 

  • Indik S, Gunzburg WH et al (2005) A novel, mouse mammary tumor virus encoded protein with Rev-like properties. Virology 337(1):1–6

    Article  PubMed  CAS  Google Scholar 

  • Ishimoto A, Takimoto M et al (1987) Sequences responsible for erythroid and lymphoid leukemia in the long terminal repeats of Friend-mink cell focus-forming and Moloney murine leukemia viruses. J Virol 61(6):1861–1866

    PubMed  CAS  Google Scholar 

  • Ivics Z, Hackett PB et al (1997) Molecular reconstruction of Sleeping Beauty, a Tc1-like transposon from fish, and its transposition in human cells. Cell 91(4):501–510

    Article  PubMed  CAS  Google Scholar 

  • Ivics Z, Kaufman CD et al (2004) The Sleeping Beauty transposable element: evolution, regulation and genetic applications. Curr Issues Mol Biol 6(1):43–55

    PubMed  CAS  Google Scholar 

  • Izsvak Z, Ivics Z (2004) Sleeping beauty transposition: biology and applications for molecular therapy. Mol Ther 9(2):147–156

    Article  PubMed  CAS  Google Scholar 

  • Johansson FK, Brodd J et al (2004) Identification of candidate cancer-causing genes in mouse brain tumors by retroviral tagging. Proc Natl Acad Sci USA 101(31):11334–11337

    Article  PubMed  CAS  Google Scholar 

  • Johnson P, Benchimol S (1992) Friend virus induced murine erythroleukaemia: the p53 locus. Cancer Surv 12:137–151

    PubMed  CAS  Google Scholar 

  • Jonkers J, Berns A (1996) Retroviral insertional mutagenesis as a strategy to identify cancer genes. Biochim Biophys Acta 1287(1):29–57

    PubMed  Google Scholar 

  • Jonkers J, Korswagen HC et al (1997) Activation of a novel proto-oncogene, Frat1, contributes to progression of mouse T-cell lymphomas. EMBO J 16(3):441–450

    Article  PubMed  CAS  Google Scholar 

  • Joosten M, Vankan-Berkhoudt Y et al (2002) Large-scale identification of novel potential disease loci in mouse leukemia applying an improved strategy for cloning common virus integration sites. Oncogene 21(47):7247–7255

    Article  PubMed  CAS  Google Scholar 

  • Kogan SC, Ward JM et al (2002) Bethesda proposals for classification of nonlymphoid hematopoietic neoplasms in mice. Blood 100(1):238–245

    Article  PubMed  CAS  Google Scholar 

  • Kroon E, Krosl J et al (1998) Hoxa9 transforms primary bone marrow cells through specific collaboration with Meis1a but not Pbx1b. EMBO J 17(13):3714–3725

    Article  PubMed  CAS  Google Scholar 

  • Kubota S, Siomi H et al (1996) Cis/trans-activation of the interleukin-9 receptor gene in an HTLV-I-transformed human lymphocytic cell. Oncogene 12(7):1441–1447

    PubMed  CAS  Google Scholar 

  • Kung HJ, Boerkoel C et al (1991) Retroviral mutagenesis of cellular oncogenes: a review with insights into the mechanisms of insertional activation. Curr Top Microbiol Immunol 171:1–25

    Article  PubMed  CAS  Google Scholar 

  • Largaespada DA (2003) Generating and manipulating transgenic animals using transposable elements. Reprod Biol Endocrinol 1(1):80

    Article  PubMed  Google Scholar 

  • Largaespada DA, Collier LS (2008) Transposon-mediated mutagenesis in somatic cells: identification of transposon-genomic DNA junctions. Methods Mol Biol 435:95–108

    Article  PubMed  CAS  Google Scholar 

  • Largaespada DA, Shaughnessy JD Jr et al (1995) Retroviral integration at the Evi-2 locus in BXH-2 myeloid leukemia cell lines disrupts Nf1 expression without changes in steady-state Ras-GTP levels. J Virol 69(8):5095–5102

    PubMed  CAS  Google Scholar 

  • Lawrence HJ, Rozenfeld S et al (1999) Frequent co-expression of the HOXA9 and MEIS1 homeobox genes in human myeloid leukemias. Leukemia 13(12):1993–1999

    Article  PubMed  CAS  Google Scholar 

  • Lazo PA, Lee JS et al (1990) Long-distance activation of the Myc protooncogene by provirus insertion in Mlvi-1 or Mlvi-4 in rat T-cell lymphomas. Proc Natl Acad Sci USA 87(1):170–173

    Article  PubMed  CAS  Google Scholar 

  • Lee BK, Eicher EM (1990) Segregation patterns of endogenous mouse mammary tumor viruses in five recombinant inbred strain sets. J Virol 64(9):4568–4572

    PubMed  CAS  Google Scholar 

  • Li J, Shen H et al (1999) Leukaemia disease genes: large-scale cloning and pathway predictions [see comments]. Nat Genet 23(3):348–353

    Article  PubMed  CAS  Google Scholar 

  • Liu G, Geurts AM et al (2005) Target-site preferences of Sleeping Beauty transposons. J Mol Biol 346(1):161–173

    Article  PubMed  CAS  Google Scholar 

  • Lu M, Zhang N et al (1996) Retrovirus-mediated gene expression in hematopoietic cells correlates inversely with growth factor stimulation. Hum Gene Ther 7(18):2263–2271

    Article  PubMed  CAS  Google Scholar 

  • Lundberg AS, Randell SH et al (2002) Immortalization and transformation of primary human airway epithelial cells by gene transfer. Oncogene 21(29):4577–4586

    Article  PubMed  CAS  Google Scholar 

  • Maeda N, Fan H et al (2008) Oncogenesis by retroviruses: old and new paradigms. Rev Med Virol 18(6):387–405

    Article  PubMed  CAS  Google Scholar 

  • Mercader N, Leonardo E et al (1999) Conserved regulation of proximodistal limb axis development by Meis1/Hth. Nature 402(6760):425–429

    Article  PubMed  CAS  Google Scholar 

  • Mertz JA, Simper MS et al (2005) Mouse mammary tumor virus encodes a self-regulatory RNA export protein and is a complex retrovirus. J Virol 79(23):14737–14747

    Article  PubMed  CAS  Google Scholar 

  • Mikkers H, Berns A (2003) Retroviral insertional mutagenesis: tagging cancer pathways. Adv Cancer Res 88:53–99

    Article  PubMed  CAS  Google Scholar 

  • Miller DG, Adam MA et al (1990) Gene transfer by retrovirus vectors occurs only in cells that are actively replicating at the time of infection. Mol Cell Biol 10(8):4239–4242

    PubMed  CAS  Google Scholar 

  • Miskey C, Izsvak Z et al (2005) DNA transposons in vertebrate functional genomics. Cell Mol Life Sci 62(6):629–641

    Article  PubMed  CAS  Google Scholar 

  • Morin R, Bainbridge M et al (2008) Profiling the HeLa S3 transcriptome using randomly primed cDNA and massively parallel short-read sequencing. Biotechniques 45(1):81–94

    Article  PubMed  CAS  Google Scholar 

  • Morse HC 3rd, Anver MR et al (2002) Bethesda proposals for classification of lymphoid neoplasms in mice. Blood 100(1):246–258

    Article  PubMed  CAS  Google Scholar 

  • Moskow JJ, Bullrich F et al (1995) Meis1, a PBX1-related homeobox gene involved in myeloid leukemia in BXH-2 mice. Mol Cell Biol 15(10):5434–5443

    PubMed  CAS  Google Scholar 

  • Mucenski ML, Bedigian HG et al (1988) Comparative molecular genetic analysis of lymphomas from six inbred mouse strains. J Virol 62(3):839–846

    PubMed  CAS  Google Scholar 

  • Mucenski ML, Taylor BA et al (1986) AKXD recombinant inbred strains: models for studying the molecular genetic basis of murine lymphomas. Mol Cell Biol 6(12):4236–4243

    PubMed  CAS  Google Scholar 

  • Mukhopadhyaya R, Wolff L (1992) New sites of proviral integration associated with murine promonocytic leukemias and evidence for alternate modes of c-myb activation [published erratum appears in J Virol 1993 May;67(5):2960]. J Virol 66(10):6035–6044

    PubMed  CAS  Google Scholar 

  • Murakami Y, Saigo K et al (2005) Large scaled analysis of hepatitis B virus (HBV) DNA integration in HBV related hepatocellular carcinomas. Gut 54(8):1162–1168

    Article  PubMed  CAS  Google Scholar 

  • Nakamura T, Largaespada DA et al (1996) Cooperative activation of Hoxa and Pbx1-related genes in murine myeloid leukaemias. Nat Genet 12(2):149–153

    Article  PubMed  CAS  Google Scholar 

  • Nakamura Y, Moriuchi R et al (1994) Altered expression of a novel cellular gene as a consequence of integration of human T cell lymphotropic virus type 1. J Gen Virol 75(Pt 10):2625–2633

    Article  PubMed  CAS  Google Scholar 

  • Nishigaki K, Hanson C et al (2002) Analysis of the disease potential of a recombinant retrovirus containing Friend murine leukemia virus sequences and a unique long terminal repeat from feline leukemia virus. J Virol 76(3):1527–1532

    Article  PubMed  CAS  Google Scholar 

  • Ostertag EM, DeBerardinis RJ et al (2002) A mouse model of human L1 retrotransposition. Nat Genet 32(4):655–660

    Article  PubMed  CAS  Google Scholar 

  • Ostertag EM, Kazazian HH Jr (2001) Biology of mammalian L1 retrotransposons. Annu Rev Genet 35:501–538

    Article  PubMed  CAS  Google Scholar 

  • Pang R, Tse E et al (2006) Molecular pathways in hepatocellular carcinoma. Cancer Lett 240(2):157–169, Epub 2005 Oct 17

    Article  PubMed  CAS  Google Scholar 

  • Payne GS, Bishop JM et al (1982) Multiple arrangements of viral DNA and an activated host oncogene in bursal lymphomas. Nature 295(5846):209–214

    Article  PubMed  CAS  Google Scholar 

  • Roberg-Perez K, Carlson CM et al (2003) MTID: a database of Sleeping Beauty transposon insertions in mice. Nucleic Acids Res 31(1):78–81

    Article  PubMed  CAS  Google Scholar 

  • Ru M, Shustik C et al (1993) Graffi murine leukemia virus: molecular cloning and characterization of the myeloid leukemia-inducing agent. J Virol 67(8):4722–4731

    PubMed  CAS  Google Scholar 

  • Sauvageau M, Miller M et al (2008) Quantitative expression profiling guided by common retroviral insertion sites reveals novel and cell type specific cancer genes in leukemia. Blood 111(2):790–799

    Article  PubMed  CAS  Google Scholar 

  • Selten G, Cuypers HT et al (1985) Proviral activation of the putative oncogene Pim-1 in MuLV induced T-cell lymphomas. EMBO J 4(7):1793–1798

    PubMed  CAS  Google Scholar 

  • Shackleford GM, MacArthur CA et al (1993) Mouse mammary tumor virus infection accelerates mammary carcinogenesis in Wnt-1 transgenic mice by insertional activation of int-2/Fgf-3 and hst/Fgf-4. Proc Natl Acad Sci USA 90(2):740–744

    Article  PubMed  CAS  Google Scholar 

  • Shen WF, Rozenfeld S et al (1999) HOXA9 forms triple complexes with PBX2 and MEIS1 in myeloid cells. Mol Cell Biol 19(4):3051–3061

    PubMed  CAS  Google Scholar 

  • Silver JE, Fredrickson TN (1983) Susceptibility to Friend helper virus leukemias in CXB recombinant inbred mice. J Exp Med 158(5):1693–1702

    Article  PubMed  CAS  Google Scholar 

  • Sinn E, Muller W et al (1987) Coexpression of MMTV/v-Ha-ras and MMTV/c-myc genes in transgenic mice: synergistic action of oncogenes in vivo. Cell 49(4):465–475

    Article  PubMed  CAS  Google Scholar 

  • Sjoblom T, Jones S et al (2006) The consensus coding sequences of human breast and colorectal cancers. Science 314(5797):268–274, Epub 2006 Sep 7

    Article  PubMed  CAS  Google Scholar 

  • Slater EP, Posseckert G et al (1989) Binding of steroid receptors to the HREs of mouse mammary tumor virus, chicken and xenopus vitellogenin and rabbit uteroglobin genes: correlation with induction. J Steroid Biochem 34(1–6):11–16

    Article  PubMed  CAS  Google Scholar 

  • Starr TK, Largaespada DA (2005) Cancer gene discovery using the Sleeping Beauty transposon. Cell Cycle 4(12):1744–1748

    Article  PubMed  CAS  Google Scholar 

  • Subramanian A, Tamayo P et al (2005) Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA 102(43):15545–15550

    Article  PubMed  CAS  Google Scholar 

  • Tamori A, Nishiguchi S et al (2005a) Hepatitis B virus DNA integration in hepatocellular carcinoma after interferon-induced disappearance of hepatitis C virus. Am J Gastroenterol 100(8):1748–1753

    Article  PubMed  CAS  Google Scholar 

  • Tamori A, Yamanishi Y et al (2005b) Alteration of gene expression in human hepatocellular carcinoma with integrated hepatitis B virus DNA. Clin Cancer Res 11(16):5821–5826

    Article  PubMed  CAS  Google Scholar 

  • Tanaka M, Jin G et al (2008) Identification of candidate cooperative genes of the Apc mutation in transformation of the colon epithelial cell by retroviral insertional mutagenesis. Cancer Sci 99(5):979–985

    Article  PubMed  CAS  Google Scholar 

  • Theodorou V, Kimm MA et al (2007) MMTV insertional mutagenesis identifies genes, gene families and pathways involved in mammary cancer. Nat Genet 39(6):759–769

    Article  PubMed  CAS  Google Scholar 

  • Thorsteinsdottir U, Kroon E et al (2001) Defining roles for HOX and MEIS1 genes in induction of acute myeloid leukemia. Mol Cell Biol 21(1):224–234

    Article  PubMed  CAS  Google Scholar 

  • Touw IP, Erkeland SJ (2007) Retroviral insertion mutagenesis in mice as a comparative oncogenomics tool to identify disease genes in human leukemia. Mol Ther 15(1):13–19

    Article  PubMed  CAS  Google Scholar 

  • Uhrbom L, Hesselager G et al (1998) Induction of brain tumors in mice using a recombinant platelet-derived growth factor B-chain retrovirus. Cancer Res 58(23):5275–5279

    PubMed  CAS  Google Scholar 

  • Uren AG, Kool J et al (2005) Retroviral insertional mutagenesis: past, present and future. Oncogene 24(52):7656–7672

    Article  PubMed  CAS  Google Scholar 

  • Valk PJ, Hol S et al (1997) The genes encoding the peripheral cannabinoid receptor and alpha-L-fucosidase are located near a newly identified common virus integration site, Evi11. J Virol 71(9):6796–6804

    PubMed  CAS  Google Scholar 

  • Valk PJ, Vankan Y et al (1999) Retroviral insertions in Evi12, a novel common virus integration site upstream of Tra1/Grp94, frequently coincide with insertions in the gene encoding the peripheral cannabinoid receptor Cnr2. J Virol 73(5):3595–3602

    PubMed  CAS  Google Scholar 

  • van der Lugt NM, Domen J et al (1995) Proviral tagging in E mu-myc transgenic mice lacking the Pim-1 proto-oncogene leads to compensatory activation of Pim-2. EMBO J 14(11):2536–2544

    PubMed  Google Scholar 

  • van Lohuizen M, Berns A (1990) Tumorigenesis by slow-transforming retroviruses – an update. Biochim Biophys Acta 1032(2–3):213–235

    PubMed  Google Scholar 

  • van Lohuizen M, Breuer M et al (1989) N-myc is frequently activated by proviral insertion in MuLV-induced T cell lymphomas. EMBO J 8(1):133–136

    PubMed  Google Scholar 

  • van Ooyen A, Kwee V et al (1985) The nucleotide sequence of the human int-1 mammary oncogene; evolutionary conservation of coding and non-coding sequences. EMBO J 4(11):2905–2909

    PubMed  Google Scholar 

  • Vandenbussche M, Janssen A et al (2008) Generation of a 3D indexed Petunia insertion database for reverse genetics. Plant J 54(6):1105–1114

    Article  PubMed  CAS  Google Scholar 

  • Varmus HE (1983) Using retroviruses as insertional mutagens to identify cellular oncogenes. Prog Clin Biol Res 119:23–35

    PubMed  CAS  Google Scholar 

  • Weiser KC, Justice MJ (2005) Cancer biology: Sleeping Beauty awakens. Nature 436(7048):184–186

    Article  PubMed  CAS  Google Scholar 

  • Wold WS, Green M (1979) Historic milestones in cancer virology. Semin Oncol 6(4):461–478

    PubMed  CAS  Google Scholar 

  • Wood LD, Parsons DW et al (2007) The genomic landscapes of human breast and colorectal cancers. Science 318(5853):1108–1113

    Article  PubMed  CAS  Google Scholar 

  • Wu S, Ying G et al (2007) Toward simpler and faster genome-wide mutagenesis in mice. Nat Genet 39(7):922–930

    Article  PubMed  CAS  Google Scholar 

  • Wu X, Burgess SM (2004) Integration target site selection for retroviruses and transposable elements. Cell Mol Life Sci 61(19–20):2588–2596

    Article  PubMed  CAS  Google Scholar 

  • Wu X, Li Y et al (2003) Transcription start regions in the human genome are favored targets for MLV integration. Science 300(5626):1749–1751

    Article  PubMed  CAS  Google Scholar 

  • Wu X, Luke BT et al (2006) Redefining the common insertion site. Virology 344(2):292–295

    Article  PubMed  CAS  Google Scholar 

  • Xing Y, Ouyang Z et al (2007) Assessing the conservation of mammalian gene expression using high-density exon arrays. Mol Biol Evol 24(6):1283–1285

    Article  PubMed  CAS  Google Scholar 

  • Yant SR, Wu X et al (2005) High-resolution genome-wide mapping of transposon integration in mammals. Mol Cell Biol 25(6):2085–2094

    Article  PubMed  CAS  Google Scholar 

  • Yin B, Largaespada DA (2007) PCR-based procedures to isolate insertion sites of DNA elements. Biotechniques 43(1):79–84

    Article  PubMed  CAS  Google Scholar 

  • York A (2005) Sleeping beauty offers new method to find cancer genes. Lancet Oncol 6(8):545

    Article  PubMed  Google Scholar 

  • Zagoraiou L, Drabek D et al (2001) In vivo transposition of Minos, a Drosophila mobile element, in mammalian tissues. Proc Natl Acad Sci USA 98(20):11474–11478

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

I apologize to colleagues whose work I could not discuss here due to space limitations. I thank the members of the Largaespada laboratory and the Center for Genome Engineering for constant support and helpful discussions. Research in the Largaespada laboratory is supported by the National Institutes of Health (R01 CA113636-01A1 and UO1 CA84221), the American Cancer Society (RPG LIB-106632), and the Leukemia and Lymphoma Society of America (LLS 7019).

Author information

Authors and Affiliations

  1. The Department of Genetics, Cell Biology and Development, The Center for Genome Engineering, Masonic Cancer Center, The University of Minnesota, Twin Cities; 6-160 Jackson Hall; 321 Church St. S.E., Minneapolis, MN, 55455, USA

    David A. Largaespada

Authors
  1. David A. Largaespada
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David A. Largaespada .

Editor information

Editors and Affiliations

  1. , Laboratory Of Cancer Biology and Genetic, National Cancer Institute, Convent Dr. 37, Bethesda, 20892, Maryland, USA

    Jeffrey E. Green

  2. National Cancer Institute, Center for Cancer Research, National Institutes of Health, South Drive 50, Bethesda, 20892, Maryland, USA

    Thomas Ried

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Largaespada, D.A. (2012). Insertional Mutagenesis for Generating Mouse Models of Cancer. In: Green, J., Ried, T. (eds) Genetically Engineered Mice for Cancer Research. Springer, New York, NY. https://doi.org/10.1007/978-0-387-69805-2_4

Download citation

Publish with us

Policies and ethics

Search

Navigation