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:

PML regulates p53 acetylation and premature senescence induced by oncogenic Ras

Nature volume 406, pages 207–210 (2000)Cite this article

Abstract

The tumour suppressor p53 induces cellular senescence in response to oncogenic signals1. p53 activity is modulated by protein stability and post-translational modification, including phosphorylation and acetylation2. The mechanism of p53 activation by oncogenes remains largely unknown. Here we report that the tumour suppressor PML regulates the p53 response to oncogenic signals. We found that oncogenic Ras upregulates PML expression, and overexpression of PML induces senescence in a p53-dependent manner. p53 is acetylated at lysine 382 upon Ras expression, an event that is essential for its biological function. Ras induces re-localization of p53 and the CBP acetyltransferase within the PML nuclear bodies and induces the formation of a trimeric p53–PML–CBP complex. Lastly, Ras-induced p53 acetylation, p53–CBP complex stabilization and senescence are lost in PML-/-fibroblasts. Our data establish a link between PML and p53 and indicate that integrity of the PML bodies is required for p53 acetylation and senescence upon oncogene expression.

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: PML is required for Ras-induced senescence in primary cells.
Figure 2: PML-induced senescence is dependent on p53.
Figure 3: p53 acetylation accompanies sensenance and is downregulated in PML —/- fibroblasts
Figure 4: RasV12 induces complex formation between p53, PML and CBP.
Figure 5: Colocalization of PML, CBP and p53 after expression of PML or RasV12.

Similar content being viewed by others

References

  1. 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 

  2. Giaccia, A. J. & Kastan, M. B. The complexity of p53 modulation: emerging patterns from divergent signals. Genes Dev. 12, 2973–2983 (1998).

    Article  CAS  Google Scholar 

  3. de The, H., Chomienne, C., Lanotte, M., Degos, L. & Dejean, A. The t(15;17) translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor alpha gene to a novel transcribed locus. Nature 347, 558– 561 (1990).

    Article  ADS  CAS  Google Scholar 

  4. Borrow, J., Goddard, A. D., Sheer, D. & Solomon, E. Molecular analysis of acute promyelocytic leukemia breakpoint cluster region on chromosome 17. Science 249, 1577– 1580 (1990).

    Article  ADS  CAS  Google Scholar 

  5. Fagioli, M. et al. Cooperation between the RING + B1-B2 and coiled-coil domains of PML is necessary for its effects on cell survival. Oncogene 16, 2905–2913 ( 1998).

    Article  CAS  Google Scholar 

  6. Le, X. F., Yang, P. & Chang, K. S. Analysis of the growth and transformation suppressor domains of promyelocytic leukemia gene, PML. J. Biol. Chem. 271, 130–135 (1996).

    Article  CAS  Google Scholar 

  7. Liu, J. H., Mu, Z. M. & Chang, K. S. PML suppresses oncogenic transformation of NIH/3T3 cells by activated neu. J. Exp. Med. 181, 1965 –1973 (1995).

    Article  CAS  Google Scholar 

  8. Wang, Z. G. et al. Role of PML in cell growth and the retinoic acid pathway. Science 279, 1547–1551 (1998).

    Article  ADS  CAS  Google Scholar 

  9. 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 

  10. Dyck, J. A. et al. A novel macromolecular structure is a target of the promyelocyte-retinoic acid receptor oncoprotein. Cell 76, 333– 343 (1994).

    Article  CAS  Google Scholar 

  11. Metz, T., Harris, A. W. & Adams, J. M. Absence of p53 allows direct immortalization of hematopoietic cells by the myc and raf oncogenes. Cell 82, 29–36 (1995).

    Article  CAS  Google Scholar 

  12. Harvey, M. et al. In vitro growth characteristics of embryo fibroblasts isolated from p53- deficient mice. Oncogene 8, 2457–2467 (1993).

    CAS  PubMed  Google Scholar 

  13. Alcorta, D. A. et al. Involvement of the cyclin-dependent kinase inhibitor p16 (INK4a) in replicative senescence of normal human fibroblasts. Proc. Natl Acad. Sci. USA 93, 13742–13747 (1996).

    Article  ADS  CAS  Google Scholar 

  14. el-Deiry, W. S. et al. WAF1, a potential mediator of p53 tumor suppression. Cell 75, 817–825 ( 1993).

    Article  CAS  Google Scholar 

  15. Sherr, C. J. & Weber, J. D. The ARF/p53 pathway. Curr. Opin. Genet. Dev. 10, 94–99 (2000).

    Article  CAS  Google Scholar 

  16. Sakaguchi, K. et al. DNA damage activates p53 through a phosphorylation-acetylation cascade. Genes Dev. 12, 2831– 2841 (1998).

    Article  CAS  Google Scholar 

  17. Liu, L. et al. p53 sites acetylated in vitro by PCAF and p300 are acetylated in vivo in response to DNA damage. Mol. Cell. Biol. 19, 1202–1209 (1999).

    Article  CAS  Google Scholar 

  18. Doucas, V., Tini, M., Egan, D. A. & Evans, R. M. Modulation of CREB binding protein function by the promyelocytic (PML) oncoprotein suggests a role for nuclear bodies in hormone signaling. Proc. Natl Acad. Sci. USA 96, 2627–2632 ( 1999).

    Article  ADS  CAS  Google Scholar 

  19. Grignani, F. et al. High-efficiency gene transfer and selection of human hematopoietic progenitor cells with a hybrid EBV/retroviral vector expressing the green fluorescence protein. Cancer Res. 58, 14 –19 (1998).

    CAS  PubMed  Google Scholar 

  20. Gu, W. & Roeder, R. G. Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain. Cell 90, 595–606 (1997).

    Article  CAS  Google Scholar 

  21. Lill, N. L., Grossman, S. R., Ginsberg, D., DeCaprio, J. & Livingston, D. M. Binding and modulation of p53 by p300/CBP coactivators. Nature 387, 823–827 (1997).

    Article  ADS  CAS  Google Scholar 

  22. LaMorte, V. J., Dyck, J. A., Ochs, R. L. & Evans, R. M. Localization of nascent RNA and CREB binding protein with the PML- containing nuclear body. Proc. Natl Acad. Sci. USA 95, 4991– 4996 (1998).

    Article  ADS  CAS  Google Scholar 

  23. Ishov, A. M. et al. PML is critical for ND10 formation and recruits the PML-interacting protein daxx to this nuclear structure when modified by SUMO-1. J. Cell Biol. 147, 221–234 (1999).

    Article  CAS  Google Scholar 

  24. Zhong, S. et al. Role of SUMO-1 modified PML in nuclear body formation. Blood 95, 2748–2752 ( 2000).

    CAS  PubMed  Google Scholar 

  25. Quignon, F. et al. PML induces a novel caspase-independent death process. Nature Genet. 20, 259–265 (1998).

    Article  CAS  Google Scholar 

  26. Sherr, C. J. Tumor surveillance via the ARF-p53 pathway. Genes Dev. 12, 2984–2991 (1998).

    Article  CAS  Google Scholar 

  27. Livingstone, L. R. et al. Altered cell cycle arrest and gene amplification potential accompany loss of wild-type p53. Cell 70, 923–935 (1992).

    Article  CAS  Google Scholar 

  28. Yin, Y., Tainsky, M. A., Bischoff, F. Z., Strong, L. C. & Wahl, G. M. Wild-type p53 restores cell-cycle control and inhibits gene amplification in cells with mutant p53 alleles. Cell 70, 937–948 (1992).

    Article  CAS  Google Scholar 

  29. Zhong, S. et al. A role for PML and the nuclear body in genomic stability. Oncogene 18, 7941–7947 ( 1999).

    Article  CAS  Google Scholar 

  30. Grignani, F. et al. Fusion proteins of the retinoic acid receptor-alpha recruit histone deacetylase in promyelocytic leukaemia. Nature 391, 815–818 (1998).

    Article  ADS  CAS  Google Scholar 

Download references

Acknowledgements

We thank Y. Nakatani, M. Sciurpi and A. Ariesi for reagents, discussion and technical help. This work was supported by grants from MURST, AIRC and the EC.

Author information

Authors and Affiliations

  1. European Institute of Oncology Department of Experimental Oncology, Milan, 20141, Italy

    Mark Pearson, Roberta Carbone, Mario Cioce, Saverio Minucci & Pier Giuseppe Pelicci

  2. Istituto di Medicina Interna e Scienze Oncologiche, Perugia University, Perugia, 06100, Italy

    Carla Sebastiani, Marta Fagioli & Pier Giuseppe Pelicci

  3. Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Shin’ichi Saito, Yuichiro Higashimoto & Ettore Appella

  4. Department of Human Genetics and Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, Cornell University, New York, 10021, USA

    Pier Paolo Pandolfi

Authors
  1. Mark Pearson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Roberta Carbone
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Carla Sebastiani
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mario Cioce
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Marta Fagioli
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shin’ichi Saito
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yuichiro Higashimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ettore Appella
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Saverio Minucci
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Pier Paolo Pandolfi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Pier Giuseppe Pelicci
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Pier Giuseppe Pelicci.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pearson, M., Carbone, R., Sebastiani, C. et al. PML regulates p53 acetylation and premature senescence induced by oncogenic Ras. Nature 406, 207–210 (2000). https://doi.org/10.1038/35018127

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/35018127

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