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 Paper
  • Published:

Additive effect of p53, p21 and Rb deletion in triple knockout primary hepatocytes

Oncogene volume 23, pages 1489–1497 (2004)Cite this article

Abstract

Using Cre-Lox technology to inducibly delete Rb from wild-type, p21- and/or p53-deficient primary hepatocytes, we investigated the role of p53, p21 and pRb in the regulation of liver cell proliferation, polyploidization and death. These cellular decisions are critical to maintaining liver cell replacement in disease, and in determining the likelihood of carcinogenesis in chronic liver injury. Clearly, the present study shows a complex interplay between p53, p21 and pRb, which regulates the likelihood of hepatocytes stimulated from quiescence, to proliferate, undergo polyploidy or die. It reveals that these proteins act both in concert and independently, demonstrating that a small set of key cellular players is common to diverse cell decisions of fundamental importance to disease.

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 7
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

Abbreviations

s.d.:

standard deviation

Rb-floxed:

homozygote for floxed Rb

wt:

wild-type or Rb-floxed cells treated with control adenovirus, or untreated

p21−/−:

knockout for p21

p53−/−:

knockout for p53

Rb−/−:

Rb-floxed cells infected by Cre-recombinase

p14/p19ARF:

human p14ARF or mouse p19ARF

References

  • Bargonetti J and Manfredi JJ . (2002). Curr. Opin. Oncol., 14, 86–91.

  • Bates S and Vousden KH . (1999). Cell Mol. Life Sci., 55, 28–37.

  • Bellamy CO, Clarke AR, Wyllie AH and Harrison DJ . (1997). FASEB J., 11, 591–599.

  • Borel F, Lohez OD, Lacroix FB and Margolis RL . (2002). Proc. Natl. Acad. Sci. USA, 99, 9819–9824.

  • Brodsky WY and Uryvaeva IV . (1977). Int. Rev. Cytol., 50, 275–332.

  • Brugarolas J, Bronson RT and Jacks T . (1998). J. Cell Biol., 141, 503–514.

  • Bulavin DV, Tararova ND, Aksenov ND, Pospelov VA and Pospelova TV . (1999). Oncogene, 18, 5611–5619.

  • Chan TA, Hermeking H, Lengauer C, Kinzler KW and Vogelstein B . (1999). Nature, 401, 616–620.

  • Chang BD, Watanabe K, Broude EV, Fang J, Poole JC, Kalinichenko TV and Roninson IB . (2000). Proc. Natl. Acad. Sci. USA, 97, 4291–4296.

  • Chau BN, Borges HL, Chen TT, Masselli A, Hunton IC and Wang JY . (2002). Nat. Cell Biol., 4, 757–765.

  • Clarke AR, Maandag ER, van R, Vander Lugt NM, Hooper ML, Berns A and te R . (1992). Nature, 359, 328–330.

  • DeGregori J, Leone G, Miron A, Jakoi L and Nevins JR . (1997). Proc. Natl. Acad. Sci. USA, 94, 7245–7250.

  • Deng C, Zhang P, Harper JW, Elledge SJ and Leder P . (1995). Cell, 82, 675–684.

  • Dimri GP, Nakanishi M, Desprez PY, Smith JR and Campisi J . (1996). Mol. Cell. Biol., 16, 2987–2997.

  • Dotto GP . (2000). Biochim. Biophys. Acta, 1471, M43–M56.

  • Fotedar R, Brickner H, Saadatmandi N, Rousselle T, Diederich L, Munshi A, Jung B, Reed JC and Fotedar A . (1999). Oncogene, 18, 3652–3658.

  • Goke R, Goke A, Goke B, El Deiry WS and Chen Y . (2001). Digestion, 64, 75–80.

  • Gupta S . (2000). Semin. Cancer Biol., 10, 161–171.

  • Harbour JW and Dean DC . (2000a). Nat. Cell Biol., 2, E65–E67.

  • Harbour JW and Dean DC . (2000b). Genes Dev., 14, 2393–2409.

  • Hengst L, Gopfert U, Lashuel HA and Reed SI . (1998). Genes Dev., 12, 3882–3888.

  • Herrera RE, Sah VP, Williams BO, Makela TP, Weinberg RA and Jacks T . (1996). Mol. Cell. Biol., 16, 2402–2407.

  • Hickman ES, Moroni MC and Helin K . (2002). Curr. Opin. Genet. Dev., 12, 60–66.

  • Javelaud D and Besancon F . (2002). J. Biol. Chem., 277, 37949–37954.

  • Jin YH, Yoo KJ, Lee YH and Lee SK . (2000). J. Biol. Chem., 275, 30256–30263.

  • Kreamer BL, Staecker JL, Sawada N, Sattler GL, Hsia MT and Pitot HC . (1986). In vitro Cell Dev. Biol., 22, 201–211.

  • Lukas J, Herzinger T, Hansen K, Moroni MC, Resnitzky D, Helin K, Reed SI and Bartek J . (1997). Genes Dev., 11, 1479–1492.

  • Macleod KF, Hu Y and Jacks T . (1996). EMBO J., 15, 6178–6188.

  • Meraldi P, Lukas J, Fry AM, Bartek J and Nigg EA . (1999). Nat. Cell Biol., 1, 88–93.

  • Mussman JG, Horn HF, Carroll PE, Okuda M, Tarapore P, Donehower LA and Fukasawa K . (2000). Oncogene, 19, 1635–1646.

  • Niculescu AB, Chen X, Smeets M, Hengst L, Prives C and Reed SI . (1998). Mol. Cell. Biol., 18, 629–643.

  • Nigg EA . (2002). Nat. Rev. Cancer, 2, 815–825.

  • Nurse P . (1991). Nature, 354, 356–358.

  • Paunesku T, Mittal S, Protic M, Oryhon J, Korolev SV, Joachimiak A and Woloschak GE . (2001). Int. J. Radiat. Biol., 77, 1007–1021.

  • Prost S, Ford JM, Taylor C, Doig J and Harrison DJ . (1998). J. Biol. Chem., 273, 33327–33332.

  • Prost S, Sheahan S, Rannie D and Harrison DJ . (2001). Nucleic Acids Res., 29, E80.1–E80.7.

  • Purdie CA, Harrison DJ, Peter A, Dobbie L, White S, Howie SE, Salter DM, Bird CC, Wyllie AH and Hooper ML . (1994). Oncogene, 9, 603–609.

  • Renton KW, Deloria LB and Mannering GJ . (1978). Mol. Pharmacol., 14, 672–681.

  • Rogoff HA, Pickering MT, Debatis ME, Jones S and Kowalik TF . (2002). Mol. Cell. Biol., 22, 5308–5318.

  • Roninson IB . (2002). Cancer Lett., 179, 1–14.

  • Russell JL, Powers JT, Rounbehler RJ, Rogers PM, Conti CJ and Johnson DG . (2002). Mol. Cell. Biol., 22, 1360–1368.

  • Silver DP and Livingston DM . (2001). Mol. Cell, 8, 233–243.

  • Smits VA, Klompmaker R, Vallenius T, Rijksen G, Makela TP and Medema RH . (2000). J. Biol. Chem., 275, 30638–30643.

  • Spruck CH, Won KA and Reed SI . (1999). Nature, 401, 297–300.

  • Tang HY, Zhao K, Pizzolato JF, Fonarev M, Langer JC and Manfredi JJ . (1998). J. Biol. Chem., 273, 29156–29163.

  • Tarapore P and Fukasawa K . (2000). Cancer Invest., 18, 148–155.

  • Tarapore P and Fukasawa K . (2002). Oncogene, 21, 6234–6240.

  • Taylor WR and Stark GR . (2001). Oncogene, 20, 1803–1815.

  • Tsai KY, MacPherson D, Rubinson DA, Crowley D and Jacks T . (2002). Curr. Biol., 12, 159–163.

  • Tsao YP, Huang SJ, Chang JL, Hsieh JT, Pong RC and Chen SL . (1999). J. Virol., 73, 4983–4990.

  • Vindelov LL, Christensen IJ and Nissen NI . (1983). Cytometry, 3, 323–327.

  • Vooijs M, Jonkers J, Lyons S and Berns A . (2002). Cancer Res., 62, 1862–1867.

  • Wang XW, Zhan Q, Coursen JD, Khan MA, Kontny HU, Yu L, Hollander MC, Connor PM, Fornace AJ and Harris CC . (1999). Proc. Natl. Acad. Sci. USA, 96, 3706–3711.

  • Wu H, Wade M, Krall L, Grisham J, Xiong Y and Van D . (1996). Genes Dev., 10, 245–260.

  • Zhang Y and Xiong Y . (2001). Cell Growth Differ., 12, 175–186.

  • Zhu JW, DeRyckere D, Li FX, Wan YY and DeGregori J . (1999). Cell Growth Differ., 10, 829–838.

Download references

Acknowledgements

The Rb-floxed (Rblox/lox) mice and the p21−/− mice were a kind gift from Anton Berns (Netherlands Cancer Institute, Amsterdam) and Philip Leder (Harvard Medical School, Boston, MA), to whom we are very grateful. We wish to thank Helen Caldwell for technical assistance. This work was supported by a grant from the Melville Trust for the Care and Cure of Cancer to SP.

Author information

Authors and Affiliations

  1. School of Molecular & Clinical Medicine, University of Edinburgh, Teviot Place, Edinburgh, EH8 9AG, UK

    Sharon Sheahan, Christopher OC Bellamy, Louise Treanor, David J Harrison & Sandrine Prost

Authors
  1. Sharon Sheahan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christopher OC Bellamy
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Louise Treanor
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. David J Harrison
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sandrine Prost
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sandrine Prost.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sheahan, S., Bellamy, C., Treanor, L. et al. Additive effect of p53, p21 and Rb deletion in triple knockout primary hepatocytes. Oncogene 23, 1489–1497 (2004). https://doi.org/10.1038/sj.onc.1207280

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1207280

Keywords

This article is cited by

Search

Advanced search

Quick links