Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Genome-wide SNP analysis of Tg.AC transgenic mice reveals an oncogenic collaboration between v-Ha-ras and Ink4a, which is absent in p53 deficiency

Oncogene volume 27, pages 2456–2465 (2008)Cite this article

Abstract

Oncogenesis is a progressive process often involving collaboration between various oncogenes and tumor suppressors. To identify those genes that collaborate with oncogenic ras, we took advantage of the Tg.AC transgenic mouse, a line that harbors the v-Ha-ras transgene and spontaneously develops an array of malignant tumors. By crossing Tg.AC mice on an inbred FVB background to other inbred strains, F1 mice were created that could be analysed using genome wide, single nucleotide polymorphism (SNP) screens. Loss of heterozygosity (LOH) in tumors and tumor cell lines marked a somatic event, possibly the inactivation of tumor suppressor gene(s). LOH could also represent DNA damage, a sign of genomic instability in the pretransformed cell. Nonetheless, the screens showed no evidence of such generalized genomic instability. Instead, they revealed a single region of LOH on chromosome 4 that occurred via somatic recombination/gene conversion, generating a region of isoparental disomy. This LOH provided a clue that linked v-Ha-ras to the inactivation of the Ink4a locus in 25 of 32 tumor cell lines. This collaboration is seen regardless of tumor type or genetic background. In contrast, tumors that develop in bitransgenic mice bearing both the v-Ha-ras gene and a heterozygous mutant p53 allele tend to retain the Ink4a locus and instead lose the p53 wild-type allele. This suggests that different strategies can be selected to collaborate with v-Ha-ras in tumorigenesis.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  • Aguirre AJ, Bardeesy N, Sinha M, Lopez L, Tuveson DA, Horner J et al. (2003). Activated Kras and Ink4a/Arf deficiency cooperate to produce metastatic pancreatic ductal adenocarcinoma. Genes Dev 17: 3112–3126.

    Article  CAS  Google Scholar 

  • Beausejour CM, Krtolica A, Galimi F, Narita M, Lowe SW, Yaswen P et al. (2003). Reversal of human cellular senescence: roles of the p53 and p16 pathways. EMBO J 22: 4212–4222.

    Article  CAS  Google Scholar 

  • Ben-Porath I, Weinberg RA . (2005). The signals and pathways activating cellular senescence. Int J Biochem Cell Biol 37: 961–976.

    Article  CAS  Google Scholar 

  • Berger JH, Bardeesy N . (2007). Modeling INK4/ARF tumor suppression in the mouse. Curr Mol Med 7: 63–75.

    Article  CAS  Google Scholar 

  • Campbell PM, Der CJ . (2004). Oncogenic Ras and its role in tumor cell invasion and metastasis. Semin Cancer Biol 14: 105–114.

    Article  CAS  Google Scholar 

  • Campisi J . (2005). Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell 120: 513–522.

    Article  CAS  Google Scholar 

  • Cardiff RD, Leder A, Kuo A, Pattengale PK, Leder P . (1993). Multiple tumor types appear in a transgenic mouse with the ras oncogene. Am J Pathol 142: 1199–1207.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chin L, Pomerantz J, Polsky D, Jacobson M, Cohen C, Cordon-Cardo C et al. (1997). Cooperative effects of INK4a and ras in melanoma susceptibility in vivo. Genes Dev 11: 2822–2834.

    Article  CAS  Google Scholar 

  • Chirgwin JM, Przybyla AE, MacDonald RJ, Rutter WJ . (1979). Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry 18: 5294–5299.

    Article  CAS  Google Scholar 

  • Donehower LA, Harvey M, Slagle BL, McArthur MJ, Montgomery Jr CA, Butel JS et al. (1992). Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 356: 215–221.

    Article  CAS  Google Scholar 

  • Dryja TP, Cavenee W, White R, Rapaport JM, Petersen R, Albert DM et al. (1984). Homozygosity of chromosome 13 in retinoblastoma. N Engl J Med 310: 550–553.

    Article  CAS  Google Scholar 

  • Gil J, Peters G . (2006). Regulation of the INK4b-ARF-INK4a tumour suppressor locus: all for one or one for all. Nat Rev Mol Cell Biol 7: 667–677.

    Article  CAS  Google Scholar 

  • Guan RJ, Fu Y, Holt PR, Pardee AB . (1999). Association of K-ras mutations with p16 methylation in human colon cancer. Gastroenterology 116: 1063–1071.

    Article  CAS  Google Scholar 

  • Humble MC, Trempus CS, Spalding JW, Cannon RE, Tennant RW . (2005). Biological, cellular, and molecular characteristics of an inducible transgenic skin tumor model: a review. Oncogene 24: 8217–8228.

    Article  CAS  Google Scholar 

  • Kamijo T, Weber JD, Zambetti G, Zindy F, Roussel MF, Sherr CJ . (1998). Functional and physical interactions of the ARF tumor suppressor with p53 and Mdm2. Proc Natl Acad Sci USA 95: 8292–8297.

    Article  CAS  Google Scholar 

  • Kamijo T, Zindy F, Roussel MF, Quelle DE, Downing JR, Ashmun RA et al. (1997). Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19ARF. Cell 91: 649–659.

    Article  CAS  Google Scholar 

  • Kelly-Spratt KS, Gurley KE, Yasui Y, Kemp CJ . (2004). p19Arf suppresses growth, progression, and metastasis of Hras-driven carcinomas through p53-dependent and -independent pathways. PLoS Biol 2: E242.

    Article  Google Scholar 

  • Krimpenfort P, Ijpenberg A, Song JY, van der Valk M, Nawijn M, Zevenhoven J et al. (2007). p15Ink4b is a critical tumour suppressor in the absence of p16Ink4a. Nature 448: 943–946.

    Article  CAS  Google Scholar 

  • Leder A, Daugherty C, Whitney B, Leder P . (1997). Mouse zeta- and alpha-globin genes: embryonic survival, alpha-thalassemia, and genetic background effects. Blood 90: 1275–1282.

    CAS  PubMed  Google Scholar 

  • Leder A, Kuo A, Cardiff RD, Sinn E, Leder P . (1990). v-Ha-ras transgene abrogates the initiation step in mouse skin tumorigenesis: effects of phorbol esters and retinoic acid. Proc Natl Acad Sci USA 87: 9178–9182.

    Article  CAS  Google Scholar 

  • Lin AW, Lowe SW . (2001). Oncogenic ras activates the ARF–p53 pathway to suppress epithelial cell transformation. Proc Natl Acad Sci USA 98: 5025–5030.

    Article  CAS  Google Scholar 

  • Linardopoulos S, Street AJ, Quelle DE, Parry D, Peters G, Sherr CJ et al. (1995). Deletion and altered regulation of p16INK4a and p15INK4b in undifferentiated mouse skin tumors. Cancer Res 55: 5168–5172.

    CAS  PubMed  Google Scholar 

  • Lukas J, Parry D, Aagaard L, Mann DJ, Bartkova J, Strauss M et al. (1995). Retinoblastoma-protein-dependent cell-cycle inhibition by the tumour suppressor p16. Nature 375: 503–506.

    Article  CAS  Google Scholar 

  • Moran JL, Bolton AD, Tran PV, Brown A, Dwyer ND, Manning DK et al. (2006). Utilization of a whole genome SNP panel for efficient genetic mapping in the mouse. Genome Res 16: 436–440.

    Article  CAS  Google Scholar 

  • Pomerantz J, Schreiber-Agus N, Liegeois NJ, Silverman A, Alland L, Chin L et al. (1998). The Ink4a tumor suppressor gene product, p19Arf, interacts with MDM2 and neutralizes MDM2's inhibition of p53. Cell 92: 713–723.

    Article  CAS  Google Scholar 

  • Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW . (1997). Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88: 593–602.

    Article  CAS  Google Scholar 

  • Sharpless NE . (2005). INK4a/ARF: a multifunctional tumor suppressor locus. Mutat Res 576: 22–38.

    Article  CAS  Google Scholar 

  • Sherr CJ . (2006). Divorcing ARF and p53: an unsettled case. Nat Rev Cancer 6: 663–673.

    Article  CAS  Google Scholar 

  • Sherr CJ, McCormick F . (2002). The RB and p53 pathways in cancer. Cancer Cell 2: 103–112.

    Article  CAS  Google Scholar 

  • Sinn E, Muller W, Pattengale P, Tepler I, Wallace R, Leder P . (1987). Coexpression of MMTV/v-Ha-ras and MMTV/c-myc genes in transgenic mice: synergistic action of oncogenes in vivo. Cell 49: 465–475.

    Article  CAS  Google Scholar 

  • Tannapfel A, Benicke M, Katalinic A, Uhlmann D, Kockerling F, Hauss J et al. (2000). Frequency of p16(INK4A) alterations and K-ras mutations in intrahepatic cholangiocarcinoma of the liver. Gut 47: 721–727.

    Article  CAS  Google Scholar 

  • Uhrbom L, Dai C, Celestino JC, Rosenblum MK, Fuller GN, Holland EC . (2002). Ink4a-Arf loss cooperates with KRas activation in astrocytes and neural progenitors to generate glioblastomas of various morphologies depending on activated Akt. Cancer Res 62: 5551–5558.

    CAS  Google Scholar 

Download references

Acknowledgements

We thank Professors Cynthia Morton and Michelle Kelliher for helpful discussions.

Author information

Authors and Affiliations

  1. Department of Genetics, Harvard Medical School, Boston, MA, USA

    A Leder, J McMenamin, F Zhou & P Leder

  2. Genetics Division, Brigham and Women's Hospital, Boston, MA, USA

    J L Moran & D R Beier

Authors
  1. A Leder
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J McMenamin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. F Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J L Moran
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. D R Beier
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. P Leder
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to P Leder.

Additional information

Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Leder, A., McMenamin, J., Zhou, F. et al. Genome-wide SNP analysis of Tg.AC transgenic mice reveals an oncogenic collaboration between v-Ha-ras and Ink4a, which is absent in p53 deficiency. Oncogene 27, 2456–2465 (2008). https://doi.org/10.1038/sj.onc.1210866

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1210866

Keywords

This article is cited by

Search

Advanced search

Quick links