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:

Deacetylation of p53 modulates its effect on cell growth and apoptosis

Nature volume 408, pages 377–381 (2000)Cite this article

Abstract

The p53 tumour suppressor is a transcriptional factor whose activity is modulated by protein stability and post-translational modifications including acetylation1,2,3,4. The mechanism by which acetylated p53 is maintained in vivo remains unclear. Here we show that the deacetylation of p53 is mediated by an histone deacetylase-1 (HDAC1)-containing complex. We have also purified a p53 target protein in the deacetylase complexes (designated PID; but identical to metastasis-associated protein 2 (MTA2)), which has been identified as a component of the NuRD complex5,6,7. PID specifically interacts with p53 both in vitro and in vivo, and its expression reduces significantly the steady-state levels of acetylated p53. PID expression strongly represses p53-dependent transcriptional activation, and, notably, it modulates p53-mediated cell growth arrest and apoptosis. These results show that deacetylation and functional interactions by the PID/MTA2-associated NuRD complex may represent an important pathway to regulate p53 function.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Indirect interactions between p53 and HDAC1, and purification of PID.
Figure 2: PID interacts with p53 both in vitro and in vivo.
Figure 3: PID is involved in p53 deacetylation.
Figure 4: PID repression of transcription activation mediated by wild-type p53, Gal–VP16, or p53(K–R) mutant in cells.
Figure 5: The effects of PID on p53-mediated cell growth arrest, endogenous p21 activation and apopotosis.

Similar content being viewed by others

References

  1. Levine, A. J. p53, the cellular gatekeeper for growth and division. Cell 88, 323–331 (1997).

    Article  CAS  Google Scholar 

  2. Prives, C. & Hall, P. A. The p53 pathway. J. Pathol. 187, 112–126 ( 1999).

    Article  CAS  Google Scholar 

  3. 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 

  4. Yu, J. et al. Identification and classification of p53-regulated genes. Proc. Natl Acad. Sci. USA 96, 14517– 14522 (1999).

    Article  ADS  CAS  Google Scholar 

  5. Zhang, Y. et al. Analysis of NuRD subunits reveals a histone deacetylase core complex and connection with DNA methylation. Genes Dev. 13, 1924–1935 (1999).

    Article  CAS  Google Scholar 

  6. Wade, P. A. et al. Mi-2 complex couples DNA methylation to chromatin remodeling and histone deacetylation. Nature Genet. 23, 62–66 (1999).

    Article  CAS  Google Scholar 

  7. Futamara, M. et al. Molecular cloning, mapping, and characterization of a novel human gene MTA-L1, showing homology to a metastasis associated gene, MTA1. J. Hum. Genet. 44, 52– 56 (1999).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  10. 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 

  11. Gu, W., Shi, X. L. & Roeder, R. G. Synergistic activation of transcription by CBP and p53. Nature 387, 819–823 (1997).

    Article  ADS  CAS  Google Scholar 

  12. Zhang, Y., LeRoy, G., Seelig, H. P., Lane, W. S. & Reinberg, D. The dermatomyositis-specific autoantigen Mi2 is a component of a complex containing histone deacetylase and nucleosome remodeling activities. Cell 95, 279–289 (1998).

    Article  CAS  Google Scholar 

  13. Xue, Y. et al. NURD, a novel complex with both ATP-dependent chromatin-remodeling and histone deacetylase activities. Mol. Cell 2, 851–861 (1998).

    Article  CAS  Google Scholar 

  14. Tong, J. K., Hassig, C. A., Schnitzler, G. R., Kingston, R. E. & Schreiber, S. L. Chromatin deacetylation by an ATP-dependent nucleosome remodelling complex. Nature 395, 917–921 ( 1998).

    Article  ADS  CAS  Google Scholar 

  15. Taunton, J., Hassig, C. A. & Schreiber, S. L. A mammalian histone deacetylase related to the yeast transcriptional regulator RPD3p. Science 272, 408–411 (1996).

    Article  ADS  CAS  Google Scholar 

  16. Hassig, C. A. et al. A role for histone deacetylase activity in HDAC1-mediated transcriptional repression. Proc. Natl Acad. Sci. USA 95, 3519–3524 (1998).

    Article  ADS  CAS  Google Scholar 

  17. Gu, W. et al. A novel human SRB/MED-containing cofactor complex (SMCC) involved in transcription regulation. Mol. Cell 3, 97–108 (1999).

    Article  CAS  Google Scholar 

  18. Ito, M. et al. Identity between TRAP and SMCC complexes indicates novel pathways for the function of nuclear receptors and diverse mammalian activators. Mol. Cell 3, 361–370 ( 1999).

    Article  CAS  Google Scholar 

  19. Toh, Y., Pencil, S. D. & Nicolson, G. L. A novel candidate metastasis-associated gene, mta1, differentially expressed in highly metatastic mammary adenocarcinoma cell lines. cDNA cloning, expression, and protein analyses. J. Biol. Chem. 269, 22958–22963 ( 1994).

    CAS  PubMed  Google Scholar 

  20. Toh, Y. et al. Overexpression of MTA1 gene in gastrointerstinal carcinomas: correlation with invasion and metastasis. Int. J. Cancer 74, 459–463 (1997).

    Article  CAS  Google Scholar 

  21. Toh, Y., Kuwano, H., Mori, M., Nicolson, G. L. & Sugimachi, K. Overexpression of metastasis-associated MTA1 mRNA in invasive oesophagal carcinomas. Br. J. Cancer 79, 1723–1726 (1999).

    Article  CAS  Google Scholar 

  22. Lin, J., Chen, J., Elenbaas, X. & Levine, A. J. Several hydrophobic amino acids in the p53 amino-terminal domain are required for transcriptional activation, binding to mdm-2 and the adenovirus 5 E1b 55-kD protein. Genes Dev. 8, 1235–1246 (1994).

    Article  CAS  Google Scholar 

  23. Jimenez, G. S. et al. A transactivation-deficient mouse model provides insights into Trp53 regulation and function. Nature Genet. 26 , 37–43 (2000).

    Article  CAS  Google Scholar 

  24. Yoshida, M., Horinouchi, S. & Beppu, T. Trichostatin A and trapoxin: Novel chemical probes for the role of histone acetylation in chromatin structure and function. BioEssays 5, 423–430 ( 1995).

    Article  Google Scholar 

  25. Pearson, M. et al. PML regulates p53 acetylation and premature senescence induced by oncogenic Ras. Nature 406, 207– 210 (2000).

    Article  ADS  CAS  Google Scholar 

  26. Yu, A., Fan, H., Lao, D., Bailey, A. D. & Weiner, A. M. Activation of p53 or loss of the Cockayne syndrome group B repair protein causes metaphase fragility of human U1, U2, and 5S genes. Mol. Cell 5, 801– 810 (2000).

    Article  CAS  Google Scholar 

  27. Amundson, S. A., Nyers, T. G. & Flornace, A. J. Roles for p53 in growth arrest and apoptosis: putting on the brakes after genotoxic stress. Oncogene 17, 3287–3299 (1998).

    Article  Google Scholar 

  28. Attardi, L. D. . Lowe, S. W., Brugarolas, J. & Jacks, T. Transcriptional activation by p53, but not induction of the p21 gene, is essential for oncogene-mediated apoptosis. EMBO J. 15, 3693–3701 (1996).

    Article  CAS  Google Scholar 

  29. Haupt, Y., Rowan, S., Shaulian, E., Vousden, K. H. & Oren, M. Induction of apoptosis in HeLa cells by trans-activation deficient p53. Genes Dev. 9, 2170– 2183 (1995).

    Article  CAS  Google Scholar 

  30. Murphy, M. et al. Transcriptional repression by wild-type p53 utilizes histone deacetylase, mediated by interaction with mSin3a. Genes Dev. 13, 2490–2501 (1999).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank R. Dalla-Favera, R. Baer and B. Tycko for critical discussions, and use of laboratory space and reagents; K. Vousden, B. Vogelstein, A. Levine, M. Oren, Y. Xiong, C. Hassig, S. L. Schreiber, S. Chellappan, G. Lozano and P. P. Pandolfi for antibodies, cell lines and plasmids; J. Qin, W. Wang and Y. Zhang for help; G. Cattoretti and H. Niu for suggestions in apoptosis assays; the sequencing facility of Columbia University Cancer Center for sequencing; F. Huang, M. Li, A. Nikolaev and N. A. Papanikolaou for sharing unpublished data and critical comment; and R.G. Roeder for continuous support and encouragement. This work was supported in part by grants from the NIH/NCI, the American Cancer Society and the Herbert Irving Comprehensive Cancer Center to W.G.

Author information

Author notes

  1. Jianyuan Luo and Fei Su: These two authors contributed equally to this work

Authors and Affiliations

  1. Institute of Cancer Genetics, and Department of Pathology, College of Physicians & Surgeons, Columbia University, 1150 St. Nicholas Avenue, New York, 10032 , New York, USA

    Jianyuan Luo, Fei Su, Delin Chen, Ariel Shiloh & Wei Gu

Author notes

  1. Correspondence and requests for material should be addressed to W.G. (e-mail: wg8@columbia.edu). The GenBank accession number for the PID sequence is AF295807.

    • Wei Gu
Authors
  1. Jianyuan Luo
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Fei Su
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Delin Chen
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Ariel Shiloh
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Wei Gu
    View author publications

    You can also search for this author inPubMed Google Scholar

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Luo, J., Su, F., Chen, D. et al. Deacetylation of p53 modulates its effect on cell growth and apoptosis . Nature 408, 377–381 (2000). https://doi.org/10.1038/35042612

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/35042612

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