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.

  • Letter
  • Published:

Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas

Nature volume 445, pages 656–660 (2007)Cite this article

A Corrigendum to this article was published on 26 May 2011

Abstract

Although cancer arises from a combination of mutations in oncogenes and tumour suppressor genes, the extent to which tumour suppressor gene loss is required for maintaining established tumours is poorly understood. p53 is an important tumour suppressor that acts to restrict proliferation in response to DNA damage or deregulation of mitogenic oncogenes, by leading to the induction of various cell cycle checkpoints, apoptosis or cellular senescence1,2. Consequently, p53 mutations increase cell proliferation and survival, and in some settings promote genomic instability and resistance to certain chemotherapies3. To determine the consequences of reactivating the p53 pathway in tumours, we used RNA interference (RNAi) to conditionally regulate endogenous p53 expression in a mosaic mouse model of liver carcinoma4,5. We show that even brief reactivation of endogenous p53 in p53-deficient tumours can produce complete tumour regressions. The primary response to p53 was not apoptosis, but instead involved the induction of a cellular senescence program that was associated with differentiation and the upregulation of inflammatory cytokines. This program, although producing only cell cycle arrest in vitro, also triggered an innate immune response that targeted the tumour cells in vivo, thereby contributing to tumour clearance. Our study indicates that p53 loss can be required for the maintenance of aggressive carcinomas, and illustrates how the cellular senescence program can act together with the innate immune system to potently limit tumour growth.

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: Reactivation of p53 results in liver tumour regression.
Figure 2: The primary response to p53 reactivation is not apoptosis.
Figure 3: p53 reactivation induces cellular senescence.
Figure 4: Clearance of liver tumours by an innate immune response.

Similar content being viewed by others

References

  1. Harris, S. L. & Levine, A. J. The p53 pathway: positive and negative feedback loops. Oncogene 24, 2899–2908 (2005)

    Article  CAS  Google Scholar 

  2. Sherr, C. J. Principles of tumor suppression. Cell 116, 235–246 (2004)

    Article  CAS  Google Scholar 

  3. Lowe, S. W., Cepero, E. & Evan, G. Intrinsic tumour suppression. Nature 432, 307–315 (2004)

    Article  ADS  CAS  Google Scholar 

  4. Zender, L. et al. Generation and analysis of genetically defined liver carcinomas derived from bipotential liver progenitors. Cold Spring Harb. Symp. Quant. Biol. 70, 251–261 (2005)

    Article  CAS  Google Scholar 

  5. Zender, L. et al. Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach. Cell 125, 1253–1267 (2006)

    Article  CAS  Google Scholar 

  6. Staib, F., Hussain, S. P., Hofseth, L. J., Wang, X. W. & Harris, C. C. TP53 and liver carcinogenesis. Hum. Mutat. 21, 201–216 (2003)

    Article  CAS  Google Scholar 

  7. Dickins, R. A. et al. Probing tumor phenotypes using stable and regulated synthetic microRNA precursors. Nature Genet. 37, 1289–1295 (2005)

    Article  CAS  Google Scholar 

  8. Silva, J. M. et al. Second-generation shRNA libraries covering the mouse and human genomes. Nature Genet. 37, 1281–1288 (2005)

    Article  CAS  Google Scholar 

  9. Chin, L. et al. Essential role for oncogenic Ras in tumour maintenance. Nature 400, 468–472 (1999)

    Article  ADS  CAS  Google Scholar 

  10. Jain, M. et al. Sustained loss of a neoplastic phenotype by brief inactivation of MYC. Science 297, 102–104 (2002)

    Article  ADS  CAS  Google Scholar 

  11. Braig, M. et al. Oncogene-induced senescence as an initial barrier in lymphoma development. Nature 436, 660–665 (2005)

    Article  ADS  CAS  Google Scholar 

  12. Chen, Z. et al. Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 436, 725–730 (2005)

    Article  ADS  CAS  Google Scholar 

  13. Collado, M. et al. Tumour biology: senescence in premalignant tumours. Nature 436, 642 (2005)

    Article  ADS  CAS  Google Scholar 

  14. Michaloglou, C. et al. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 436, 720–724 (2005)

    Article  ADS  CAS  Google Scholar 

  15. Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D. & Lowe, S. W. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88, 593–602 (1997)

    Article  CAS  Google Scholar 

  16. Minamino, T. et al. Ras induces vascular smooth muscle cell senescence and inflammation in human atherosclerosis. Circulation 108, 2264–2269 (2003)

    Article  CAS  Google Scholar 

  17. Shelton, D. N., Chang, E., Whittier, P. S., Choi, D. & Funk, W. D. Microarray analysis of replicative senescence. Curr. Biol. 9, 939–945 (1999)

    Article  CAS  Google Scholar 

  18. Gorgoulis, V. G. et al. p53-dependent ICAM-1 overexpression in senescent human cells identified in atherosclerotic lesions. Lab. Invest. 85, 502–511 (2005)

    Article  CAS  Google Scholar 

  19. Maeda, S., Kamata, H., Luo, J. L., Leffert, H. & Karin, M. IKKβ couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell 121, 977–990 (2005)

    Article  CAS  Google Scholar 

  20. Mundt, B. et al. Involvement of TRAIL and its receptors in viral hepatitis. FASEB J. 17, 94–96 (2003)

    Article  CAS  Google Scholar 

  21. Hong, F. et al. β-glucan functions as an adjuvant for monoclonal antibody immunotherapy by recruiting tumoricidal granulocytes as killer cells. Cancer Res. 63, 9023–9031 (2003)

    CAS  PubMed  Google Scholar 

  22. Shultz, L. D. et al. Multiple defects in innate and adaptive immunologic function in NOD/LtSz-scid mice. J. Immunol. 154, 180–191 (1995)

    CAS  PubMed  Google Scholar 

  23. Ghiringhelli, F., Menard, C., Martin, F. & Zitvogel, L. The role of regulatory T cells in the control of natural killer cells: relevance during tumor progression. Immunol. Rev. 214, 229–238 (2006)

    Article  CAS  Google Scholar 

  24. Ventura, A. et al. Restoration of p53 function leads to tumour regression in vivo. Nature advance online publication, doi:10.1038/nature05541 (24 January 2007)

  25. Christophorou, M. A., Ringshausen, I., Finch, A. J., Swigart, L. B. & Evan, G. I. The pathological response to DNA damage does not contribute to p53-mediated tumour suppression. Nature 443, 214–217 (2006)

    Article  ADS  CAS  Google Scholar 

  26. Bykov, V. J. et al. Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound. Nature Med. 8, 282–288 (2002)

    Article  CAS  Google Scholar 

  27. Vassilev, L. T. et al. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 303, 844–848 (2004)

    Article  ADS  CAS  Google Scholar 

  28. Gray-Schopfer, V. C. et al. Cellular senescence in naevi and immortalisation in melanoma: a role for p16?. Br. J. Cancer 95, 496–505 (2006)

    Article  CAS  Google Scholar 

  29. Roninson, I. B. Tumor cell senescence in cancer treatment. Cancer Res. 63, 2705–2715 (2003)

    CAS  PubMed  Google Scholar 

  30. Krtolica, A., Parrinello, S., Lockett, S., Desprez, P. Y. & Campisi, J. Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging. Proc. Natl Acad. Sci. USA 98, 12072–12077 (2001)

    Article  ADS  CAS  Google Scholar 

Download references

Acknowledgements

We thank L. Bianco and M. Jiao for technical assistance. We also thank G. Evan, T. Jacks, A. Ventura, M. Narita, A. Chicas, M. Yon, G. Hannon and other members of the Lowe and Hannon laboratories for advice and discussions. We thank M. McCurrach for editorial assistance. W.X. is in the MCB graduate program at Stony Brook University. This work was generously supported by the Emmy Noether Programme of the German Research Foundation, Alan and Edith Seligson, the Don Monti Foundation, and grants from the National Institutes of Health (C.C.C, S.W.L.). This work is dedicated to our friend and colleague Dr. Enrique (Henry) Cepero.

Author Contributions W.X.: study design and conduction of experiments; L.Z.: study design and conduction of experiments; C.M.: design and conduction of flow cytometry experiments; R.A.D.: vector development; E.H.: histopathological analyses; V.K.: microarray analysis; C.C.C: histopathological analyses; S.W.L.: study design, principal investigator.

Author information

Author notes

  1. Wen Xue and Lars Zender: These authors contributed equally to this work.

Authors and Affiliations

  1. Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, 11724, USA

    Wen Xue, Lars Zender, Cornelius Miething, Ross A. Dickins, Valery Krizhanovsky & Scott W. Lowe

  2. Howard Hughes Medical Institute, Cold Spring Harbor, New York, 11724, USA

    Ross A. Dickins & Scott W. Lowe

  3. Division of Molecular Pathology, Memorial Sloan-Kettering Cancer Center, New York, 10021, USA

    Eva Hernando & Carlos Cordon-Cardo

Authors
  1. Wen Xue
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lars Zender
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Cornelius Miething
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ross A. Dickins
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Eva Hernando
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Valery Krizhanovsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Carlos Cordon-Cardo
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Scott W. Lowe
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Scott W. Lowe.

Ethics declarations

Competing interests

Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.

Supplementary information

Supplementary information

This file contains Supplementary Methods , Supplementary figures S1-S9 with legends and additional references. (PDF 5545 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Xue, W., Zender, L., Miething, C. et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 445, 656–660 (2007). https://doi.org/10.1038/nature05529

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature05529

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing