Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis (original) (raw)

• Letter
• Published: 04 August 2005
• Lloyd C. Trotman1,2,
• David Shaffer1,3,
• Hui-Kuan Lin1,2,
• Zohar A. Dotan1,2,
• Masaru Niki1,2,
• Jason A. Koutcher3,
• Howard I. Scher3,
• Thomas Ludwig4,
• William Gerald2,
• Carlos Cordon-Cardo2 &
• …
• Pier Paolo Pandolfi1,2

Nature volume 436, pages 725–730 (2005)Cite this article

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Abstract

Cellular senescence has been theorized to oppose neoplastic transformation triggered by activation of oncogenic pathways in vitro1,2,3, but the relevance of senescence in vivo has not been established. The PTEN and p53 tumour suppressors are among the most commonly inactivated or mutated genes in human cancer including prostate cancer4,5. Although they are functionally distinct, reciprocal cooperation has been proposed, as PTEN is thought to regulate p53 stability, and p53 to enhance PTEN transcription6,7,8,9,10. Here we show that conditional inactivation of Trp53 in the mouse prostate fails to produce a tumour phenotype, whereas complete Pten inactivation in the prostate triggers non-lethal invasive prostate cancer after long latency. Strikingly, combined inactivation of Pten and Trp53 elicits invasive prostate cancer as early as 2 weeks after puberty and is invariably lethal by 7 months of age. Importantly, acute Pten inactivation induces growth arrest through the p53-dependent cellular senescence pathway both in vitro and in vivo, which can be fully rescued by combined loss of Trp53. Furthermore, we detected evidence of cellular senescence in specimens from early-stage human prostate cancer. Our results demonstrate the relevance of cellular senescence in restricting tumorigenesis in vivo and support a model for cooperative tumour suppression in which p53 is an essential failsafe protein of _Pten_-deficient tumours.

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References

1. Lowe, S. W., Cepero, E. & Evan, G. Intrinsic tumour suppression. Nature 432, 307–315 (2004)
   Article ADS CAS Google Scholar
2. Serrano, M. & Blasco, M. A. Putting the stress on senescence. Curr. Opin. Cell Biol. 13, 748–753 (2001)
   Article CAS Google Scholar
3. Campisi, J. Cellular senescence as a tumour-suppressor mechanism. Trends Cell Biol. 11, S27–S31 (2001)
   Article CAS Google Scholar
4. Vogelstein, B., Lane, D. & Levine, A. J. Surfing the p53 network. Nature 408, 307–310 (2000)
   Article ADS CAS Google Scholar
5. Di Cristofano, A. & Pandolfi, P. P. The multiple roles of PTEN in tumour suppression. Cell 100, 387–390 (2000)
   Article CAS Google Scholar
6. Stambolic, V. et al. Regulation of PTEN transcription by p53. Mol. Cell 8, 317–325 (2001)
   Article CAS Google Scholar
7. Mayo, L. D. & Donner, D. B. A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus. Proc. Natl Acad. Sci. USA 98, 11598–11603 (2001)
   Article ADS CAS Google Scholar
8. Zhou, B. P. et al. HER-2/neu induces p53 ubiquitination via Akt-mediated MDM2 phosphorylation. Nature Cell Biol. 3, 973–982 (2001)
   Article CAS Google Scholar
9. Freeman, D. J. et al. PTEN tumour suppressor regulates p53 protein levels and activity through phosphatase-dependent and -independent mechanisms. Cancer Cell 3, 117–130 (2003)
   Article CAS Google Scholar
10. Trotman, L. C. & Pandolfi, P. P. PTEN and p53: who will get the upper hand? Cancer Cell 3, 97–99 (2003)
    Article CAS Google Scholar
11. Schmitt, C. A. et al. A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy. Cell 109, 335–346 (2002)
    Article CAS Google Scholar
12. Suzuki, H. et al. Interfocal heterogeneity of PTEN/MMAC1 gene alterations in multiple metastatic prostate cancer tissues. Cancer Res. 58, 204–209 (1998)
    CAS PubMed Google Scholar
13. Feilotter, H. E., Nagai, M. A., Boag, A. H., Eng, C. & Mulligan, L. M. Analysis of PTEN and the 10q23 region in primary prostate carcinomas. Oncogene 16, 1743–1748 (1998)
    Article CAS Google Scholar
14. Muller, M., Rink, K., Krause, H. & Miller, K. PTEN/MMAC1 mutations in prostate cancer. Prostate Cancer Prostatic Dis. 3, S32 (2000)
    Article CAS Google Scholar
15. Hermans, K. G. et al. Loss of a small region around the PTEN locus is a major chromosome 10 alteration in prostate cancer xenografts and cell lines. Genes Chromosom. Cancer 39, 171–184 (2004)
    Article CAS Google Scholar
16. Qian, J. et al. Loss of p53 and c-myc overrepresentation in stage T(2–3)N(1–3)M(0) prostate cancer are potential markers for cancer progression. Mod. Pathol. 15, 35–44 (2002)
    Article Google Scholar
17. Navone, N. M. et al. p53 mutations in prostate cancer bone metastases suggest that selected p53 mutants in the primary site define foci with metastatic potential. J. Urol. 161, 304–308 (1999)
    Article CAS Google Scholar
18. Di Cristofano, A., De Acetis, M., Koff, A., Cordon-Cardo, C. & Pandolfi, P. P. Pten and p27KIP1 cooperate in prostate cancer tumour suppression in the mouse. Nature Genet. 27, 222–224 (2001)
    Article CAS Google Scholar
19. Trotman, L. C. et al. Pten dose dictates cancer progression in the prostate. PLoS Biol. 1, 385–396 (2003)
    Article CAS Google Scholar
20. Jonkers, J. & Berns, A. Conditional mouse models of sporadic cancer. Nature Rev. Cancer 2, 251–265 (2002)
    Article CAS Google Scholar
21. Wu, X. et al. Generation of a prostate epithelial cell-specific Cre transgenic mouse model for tissue-specific gene ablation. Mech. Dev. 101, 61–69 (2001)
    Article CAS Google Scholar
22. Dimri, G. P. et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc. Natl Acad. Sci. USA 92, 9363–9367 (1995)
    Article ADS CAS Google Scholar
23. Weinberg, R. A. The cat and mouse games that genes, viruses, and cells play. Cell 88, 573–575 (1997)
    Article CAS Google Scholar
24. Miyauchi, H. et al. Akt negatively regulates the in vitro lifespan of human endothelial cells via a p53/p21-dependent pathway. EMBO J. 23, 212–220 (2004)
    Article CAS Google Scholar
25. Stewart, S. L., King, J. B., Thompson, T. D., Friedman, C. & Wingo, P. A. Cancer mortality surveillance—United States, 1990–2000. MMWR Surveill. Summ. 53, 1–108 (2004)
    PubMed Google Scholar
26. Levi, F., Lucchini, F., Negri, E., Boyle, P. & La Vecchia, C. Leveling of prostate cancer mortality in Western Europe. Prostate 60, 46–52 (2004)
    Article Google Scholar
27. Abate-Shen, C. & Shen, M. M. Molecular genetics of prostate cancer. Genes Dev. 14, 2410–2434 (2000)
    Article CAS Google Scholar
28. Bykov, V. J. et al. Restoration of the tumour suppressor function to mutant p53 by a low-molecular-weight compound. Nature Med. 8, 282–288 (2002)
    Article CAS Google Scholar
29. 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
30. Maeda, T. et al. Role of the proto-oncogene Pokemon in cellular transformation and ARF repression. Nature 433, 278–285 (2005)
    Article ADS CAS Google Scholar

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Acknowledgements

We thank T. Maeda and T. Jacks for helpful suggestions; D. Peeper, C. Schmitt and M. Serrano for exchanging unpublished data and coordinating the submission of manuscripts; N. Hay, U. Greber and S. Hemmi for reagents; L. Cai and L. DiSantis for critical reading and editing of the manuscript; other members of the Pandolfi lab for advice and discussion; K. Manova and C. Farrell from the Molecular Cytology Core Facility for assistance with IHC analysis; and C. Le, C. Matei, D. Procissi and I. Buchanan for MRI analysis. This work was supported by NIH grants to P.P.P.

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Authors and Affiliations

1. Cancer Biology and Genetics Program,
   Zhenbang Chen, Lloyd C. Trotman, David Shaffer, Hui-Kuan Lin, Zohar A. Dotan, Masaru Niki & Pier Paolo Pandolfi
2. Department of Pathology,
   Zhenbang Chen, Lloyd C. Trotman, Hui-Kuan Lin, Zohar A. Dotan, Masaru Niki, William Gerald, Carlos Cordon-Cardo & Pier Paolo Pandolfi
3. Departments of Medicine, Radiology and Medical Physics, Memorial Sloan-Kettering Cancer Center, Sloan-Kettering Institute, 1275 York Avenue, New York, 10021, New York, USA
   David Shaffer, Jason A. Koutcher & Howard I. Scher
4. Department of Anatomy and Cell Biology, Institute of Cancer Genetics, Columbia University, 1150 St Nicholas Avenue, New York, 10032, New York, USA
   Thomas Ludwig

Authors

1. Zhenbang Chen
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2. Lloyd C. Trotman
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3. David Shaffer
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4. Hui-Kuan Lin
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5. Zohar A. Dotan
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6. Masaru Niki
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7. Jason A. Koutcher
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8. Howard I. Scher
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9. Thomas Ludwig
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10. William Gerald
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11. Carlos Cordon-Cardo
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12. Pier Paolo Pandolfi
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Correspondence toPier Paolo Pandolfi.

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Supplementary information

Supplementary Methods

This file contains the experimental methods mentioned in the text, but data obtained are presented as the supplementary figures. The methods detailed include adenovirus for the infection of MEFs with Adenovirus expressing Cre, and autopsy and histopathology for the standard procedures of slide preparation from paraffin-embedded tissues. (DOC 32 kb)

Supplementary Figure Legends

This file contains figure legends for Supplementary Figure S1-S6 and Supplementary Table S1. This text will help readers to understand the experimental procedures and the conclusions in the text. (DOC 40 kb)

Supplementary Figure S1

Scheme of Pten and Trp53 conditional knockout alleles. (PDF 70 kb)

Supplementary Figure S2

Specificity of recombination. (PDF 5004 kb)

Supplementary Figure S3

In vitro modelling of acute loss of Pten in MEFs. (PDF 1181 kb)

Supplementary Figure S4

In vivo status of proliferation and signalling markers in the prostates of the indicated mutants and wt mice. (PDF 5017 kb)

Supplementary Figure S5

In vitro senescence analysis. (PDF 4291 kb)

Supplementary Figure S6

a, AP lobes of indicated genotypes reveal necessity for complete Pten loss for induction of senescence as measured by β-gal activity. Bars, 50µm. b, low magnifications of AP stained for β-gal activity from wt, Pten null and Pten-Trp53 double null mice. Bar, 10µm. (PDF 3920 kb)

Supplementary Table S1

Cryosections prepared from twelve different human radical prostatectomy specimens (collected under IRB approval) were analyzed for senescence with β-gal staining. (PDF 26 kb)

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Chen, Z., Trotman, L., Shaffer, D. et al. Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis.Nature 436, 725–730 (2005). https://doi.org/10.1038/nature03918

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• Received: 23 February 2005
• Accepted: 15 June 2005
• Issue Date: 04 August 2005
• DOI: https://doi.org/10.1038/nature03918

Editorial Summary

Cell senescence and cancer

Cellular senescence, a growth-arrest program that limits the lifespan of mammalian cells and prevents unlimited cell proliferation, is attracting considerable interest because of its links to tumour suppression. Using a mouse model in which the oncogene Ras is activated in the haematopoietic compartment of bone marrow, Braig et al. show that cellular senescence can block lymphoma development. Genetic inactivation of the histone methyltransferase Suv39h1 that controls senescence by ‘epigenetic’ modification of DNA-associated proteins, or a pharmacological approach that mimics loss of this enzyme, allow the formation of malignant lymphomas in response to oncogenic Ras. This work has important implications for both tumour development and tumour therapy. Michaloglou et al. report that oncogene-induced senescence may be a physiologically important process in humans, keeping moles in a benign state for many years: unchecked they develop into malignant melanomas. Chen et al. also find that cellular senescence blocks tumorigenesis in vivo: they show that acting together, the p53 tumour suppressor and the cellular senescence system can prevent prostate cancer induction in mice by the PTEN mutation. Collado et al. show that cellular senescence is a defining feature of Ras-initiated premalignant tumours; this could prove valuable in the diagnosis and prognosis of cancer.

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