Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Loss of Trp53 does not initiate prostate tumours but renders Pten -deficient carcinomas lethal.
Figure 2: Acute loss of Pten triggers the p53-dependent senescence pathway in primary mouse embryonic fibroblasts (MEFs).
Figure 3: Acute loss of Pten results in ARF upregulation and p53/p21 stabilization in primary MEFs.
Figure 4: The p53-dependent cellular senescence pathway restricts tumorigenesis in Pten -deficient prostates.

References

  1. 1

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

    ADS  CAS  Article  Google Scholar 

  2. 2

    Serrano, M. & Blasco, M. A. Putting the stress on senescence. Curr. Opin. Cell Biol. 13, 748–753 (2001)

    CAS  Article  Google Scholar 

  3. 3

    Campisi, J. Cellular senescence as a tumour-suppressor mechanism. Trends Cell Biol. 11, S27–S31 (2001)

    CAS  Article  Google Scholar 

  4. 4

    Vogelstein, B., Lane, D. & Levine, A. J. Surfing the p53 network. Nature 408, 307–310 (2000)

    ADS  CAS  Article  Google Scholar 

  5. 5

    Di Cristofano, A. & Pandolfi, P. P. The multiple roles of PTEN in tumour suppression. Cell 100, 387–390 (2000)

    CAS  Article  Google Scholar 

  6. 6

    Stambolic, V. et al. Regulation of PTEN transcription by p53. Mol. Cell 8, 317–325 (2001)

    CAS  Article  Google Scholar 

  7. 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)

    ADS  CAS  Article  Google Scholar 

  8. 8

    Zhou, B. P. et al. HER-2/neu induces p53 ubiquitination via Akt-mediated MDM2 phosphorylation. Nature Cell Biol. 3, 973–982 (2001)

    CAS  Article  Google Scholar 

  9. 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)

    CAS  Article  Google Scholar 

  10. 10

    Trotman, L. C. & Pandolfi, P. P. PTEN and p53: who will get the upper hand? Cancer Cell 3, 97–99 (2003)

    CAS  Article  Google Scholar 

  11. 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)

    CAS  Article  Google Scholar 

  12. 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. 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)

    CAS  Article  Google Scholar 

  14. 14

    Muller, M., Rink, K., Krause, H. & Miller, K. PTEN/MMAC1 mutations in prostate cancer. Prostate Cancer Prostatic Dis. 3, S32 (2000)

    CAS  Article  Google Scholar 

  15. 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)

    CAS  Article  Google Scholar 

  16. 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. 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)

    CAS  Article  Google Scholar 

  18. 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)

    CAS  Article  Google Scholar 

  19. 19

    Trotman, L. C. et al. Pten dose dictates cancer progression in the prostate. PLoS Biol. 1, 385–396 (2003)

    CAS  Article  Google Scholar 

  20. 20

    Jonkers, J. & Berns, A. Conditional mouse models of sporadic cancer. Nature Rev. Cancer 2, 251–265 (2002)

    CAS  Article  Google Scholar 

  21. 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)

    CAS  Article  Google Scholar 

  22. 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)

    ADS  CAS  Article  Google Scholar 

  23. 23

    Weinberg, R. A. The cat and mouse games that genes, viruses, and cells play. Cell 88, 573–575 (1997)

    CAS  Article  Google Scholar 

  24. 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)

    CAS  Article  Google Scholar 

  25. 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. 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. 27

    Abate-Shen, C. & Shen, M. M. Molecular genetics of prostate cancer. Genes Dev. 14, 2410–2434 (2000)

    CAS  Article  Google Scholar 

  28. 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)

    CAS  Article  Google Scholar 

  29. 29

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

    ADS  CAS  Article  Google Scholar 

  30. 30

    Maeda, T. et al. Role of the proto-oncogene Pokemon in cellular transformation and ARF repression. Nature 433, 278–285 (2005)

    ADS  CAS  Article  Google Scholar 

Download references

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.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Pier Paolo Pandolfi.

Ethics declarations

Competing interests

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

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)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

Further reading

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

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