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.

  • Original Article
  • Published:

PML enhances the regulation of p53 by CK1 in response to DNA damage

Oncogene volume 27, pages 3653–3661 (2008)Cite this article

Abstract

In response to stress, p53 is accumulated and activated to induce appropriate growth inhibitory responses. This requires the release of p53 from the constraints of its negative regulators Mdm2 and Mdm4. A key event in this dissociation is the phosphorylation of p53 at threonine residue (Thr18) within the Mdm2/4-binding domain. Casein kinase 1 (CK1) plays a major role in this phosphorylation. The promyelocytic leukemia protein (PML) regulates certain modifications of p53 in response to DNA damage. Here, we investigated the role of PML in the regulation of Thr18 phosphorylation. We found that PML enhances Thr18 phosphorylation of endogenous p53 in response to stress. On DNA damage, CK1 accumulates in the cell, with a proportion concentrated in the nucleus together with p53 and PML. Furthermore, CK1 interacts with endogenous p53 and PML, and this interaction is enhanced by genotoxic stress. Inhibition of CK1 impairs the protection of p53 by PML from Mdm2-mediated degradation. Our findings support a role for PML in the regulation of p53 by CK1. We propose that following DNA damage, PML facilitates Thr18 phosphorylation by recruiting p53 and CK1 into PML nuclear bodies, thereby protecting p53 from inhibition by Mdm2, leading to p53 activation.

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
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  • Behrend L, Milne DM, Stöter M, Deppert W, Campbell LE, Meek DW et al. (2000). IC261, a specific inhibitor of the protein kinases casein kinase 1-delta and -epsilon, triggers the mitotic checkpoint and induces p53-dependent postmitotic effects. Oncogene 19: 5303–5313.

    Article  CAS  PubMed  Google Scholar 

  • Craig AL, Burch L, Vojtesek B, Mikutowska J, Thompson A, Hupp TR . (1999). Novel phosphorylation sites of human tumour suppressor protein p53 at Ser20 and Thr18 that disrupt the binding of mdm2 (mouse double minute 2) protein are modified in human cancers. Biochem J 342 (Pt 1): 133–141.

    CAS  PubMed  PubMed Central  Google Scholar 

  • de Stanchina E, Querido E, Narita M, Davuluri RV, Pandolfi PP, Ferbeyre G et al. (2004). PML is a direct p53 target that modulates p53 effector functions. Mol Cell 13: 523–535.

    Article  CAS  PubMed  Google Scholar 

  • Dumaz N, Milne DM, Meek DW . (1999). Protein kinase CK1 is a p53-threonine 18 kinase which requires prior phosphorylation of serine 15. FEBS Lett 463: 312–316.

    Article  CAS  PubMed  Google Scholar 

  • Gurrieri C, Capodieci P, Bernardi R, Scaglioni PP, Nafa K, Rush LJ et al. (2004). Loss of the tumor suppressor PML in human cancers of multiple histologic origins. J Natl Cancer Inst 96: 269–279.

    Article  CAS  PubMed  Google Scholar 

  • Hoekstra MF, Dhillon N, Carmel G, DeMaggio AJ, Lindberg RA, Hunter T et al. (1994). Budding and fission yeast casein kinase I isoforms have dual-specificity protein kinase activity. Mol Biol Cell 5: 877–886.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Iwakuma T, Lozano G . (2003). MDM2, an introduction. Mol Cancer Res 1: 993–1000.

    CAS  PubMed  Google Scholar 

  • Knippschild U, Gocht A, Wolff S, Huber N, Löhler J, Stöter M . (2005). The casein kinase 1 family: participation in multiple cellular processes in eukaryotes. Cell Signal 17: 675–689.

    Article  CAS  PubMed  Google Scholar 

  • Knippschild U, Milne DM, Campbell LE, DeMaggio AJ, Christenson E, Hoekstra MF et al. (1997). p53 is phosphorylated in vitro and in vivo by the delta and epsilon isoforms of casein kinase 1 and enhances the level of casein kinase 1 delta in response to topoisomerase-directed drugs. Oncogene 15: 1727–1736.

    Article  CAS  PubMed  Google Scholar 

  • Lai Z, Auger KR, Manubay CM, Copeland RA . (2000). Thermodynamics of p53 binding to hdm2 (1–126): effects of phosphorylation and p53 peptide length. Arch Biochem Biophys 381: 278–284.

    Article  CAS  PubMed  Google Scholar 

  • Langley E, Pearson M, Faretta M, Bauer UM, Frye RA, Minucci S et al. (2002). Human SIR2 deacetylates p53 and antagonizes PML/p53-induced cellular senescence. EMBO J 21: 2383–2396.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lavin MF, Gueven N . (2006). The complexity of p53 stabilization and activation. Cell Death Differ 13: 941–950.

    Article  CAS  PubMed  Google Scholar 

  • Louria-Hayon I, Grossman T, Sionov RV, Alsheich O, Pandolfi PP, Haupt Y . (2003). The promyelocytic leukemia protein protects p53 from Mdm2-mediated inhibition and degradation. J Biol Chem 278: 33134–33141.

    Article  CAS  PubMed  Google Scholar 

  • Marine JC, Dyer MA, Jochemsen AG . (2007). MDMX: from bench to bedside. J Cell Sci 120: 371–378.

    Article  CAS  PubMed  Google Scholar 

  • Maritzen T, Lohler J, Deppert W, Knippschild U . (2003). Casein kinase I delta (CKIdelta) is involved in lymphocyte physiology. Eur J Cell Biol 82: 369–378.

    Article  CAS  PubMed  Google Scholar 

  • Mashhoon N, DeMaggio AJ, Tereshko V, Bergmeier SC, Egli M, Hoekstra MF et al. (2000). Crystal structure of a conformation-selective casein kinase-1 inhibitor. J Biol Chem 275: 20052–20060.

    Article  CAS  PubMed  Google Scholar 

  • Meek DW . (2004). The p53 response to DNA damage. DNA Repair (Amst) 3: 1049–1056.

    Article  CAS  Google Scholar 

  • Muller S, Miller Jr WH, Dejean A . (1998). Trivalent antimonials induce degradation of the PML-RAR oncoprotein and reorganization of the promyelocytic leukemia nuclear bodies in acute promyelocytic leukemia NB4 cells. Blood 92: 4308–4316.

    CAS  PubMed  Google Scholar 

  • Rizzo MG, Zepparoni A, Cristofanelli B, Scardigli R, Crescenzi M, Blandino G et al. (1998). Wt-p53 action in human leukaemia cell lines corresponding to different stages of differentiation. Br J Cancer 77: 1429–1438.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Saito S, Yamaguchi H, Higashimoto Y, Chao C, Xu Y, Fornace Jr AJ et al. (2003). Phosphorylation site interdependence of human p53 post-translational modifications in response to stress. J Biol Chem 278: 37536–37544.

    Article  CAS  PubMed  Google Scholar 

  • Sakaguchi K, Saito S, Higashimoto Y, Roy S, Anderson CW, Appella E . (2000). Damage-mediated phosphorylation of human p53 threonine 18 through a cascade mediated by a casein 1-like kinase. Effect on Mdm2 binding. J Biol Chem 275: 9278–9283.

    Article  CAS  PubMed  Google Scholar 

  • Salomoni P, Pandolfi PP . (2002). p53 De-ubiquitination: at the edge between life and death. Nat Cell Biol 4: E152–E153.

    Article  CAS  PubMed  Google Scholar 

  • Schon O, Friedler A, Bycroft M, Freund SM, Fersht AR . (2002). Molecular mechanism of the interaction between MDM2 and p53. J Mol Biol 323: 491–501.

    Article  CAS  PubMed  Google Scholar 

  • Sionov RV, Coen S, Goldberg Z, Berger M, Bercovich B, Ben-Neriah Y et al. (2001). c-Abl regulates p53 levels under normal and stress conditions by preventing its nuclear export and ubiquitination. Mol Cell Biol 21: 5869–5878.

    Article  CAS  PubMed  Google Scholar 

  • Soubeyrand S, Schild-Poulter C, Haché RJ . (2004). Structured DNA promotes phosphorylation of p53 by DNA-dependent protein kinase at serine 9 and threonine 18. Eur J Biochem 271: 3776–3784.

    Article  CAS  PubMed  Google Scholar 

  • Trotman LC, Alimonti A, Scaglioni PP, Koutcher JA, Cordon-Cardo C, Pandolfi PP . (2006). Identification of a tumour suppressor network opposing nuclear Akt function. Nature 441: 523–527.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang ZG, Delva L, Gaboli M, Rivi R, Giorgio M, Cordon-Cardo C et al. (1998). Role of PML in cell growth and the retinoic acid pathway. Science 279: 1547–1551.

    Article  CAS  PubMed  Google Scholar 

  • Wolff S, Stoter M, Giamas G, Piesche M, Henne-Bruns D, Banting G et al. (2006). Casein kinase 1 delta (CK1delta) interacts with the SNARE associated protein snapin. FEBS Lett 580: 6477–6484.

    Article  CAS  PubMed  Google Scholar 

  • Zhu J, Koken MH, Quignon F, Chelbi-Alix MK, Degos L, Wang ZY et al. (1997). Arsenic-induced PML targeting onto nuclear bodies: implications for the treatment of acute promyelocytic leukemia. Proc Natl Acad Sci USA 94: 3978–3983.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zimber A, Nguyen QD, Gespach C . (2004). Nuclear bodies and compartments: functional roles and cellular signaling in health and disease. Cell Signal 16: 1085–1104.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Stefan Muller and PP Pandolfi for their generous gifts of expression plasmids, Anthony DeMaggio and Dan Eilat for antibodies. PML-knockout MEFs were a kind gift from PP Pandolfi. This work was supported by grants from the Association for International Cancer Research, the German-Israeli Foundation for Scientific Research and Development, the Israel Science Foundation (Grant No. 1341/05), in part, by the Intramural Research Program of the NIH, NCI, CCR and by EC FP6 funding of the European Commission (contract 503576). This publication reflects only the authors' views. The European Commission is not liable for any use that may be made of the information here.

Author information

Authors and Affiliations

  1. Department of Immunology, The Hebrew University Hadassah Medical School, Jerusalem, Israel

    O Alsheich-Bartok, S Haupt, I Alkalay-Snir & Y Haupt

  2. The Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    S Saito & E Appella

Authors
  1. O Alsheich-Bartok
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S Haupt
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. I Alkalay-Snir
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S Saito
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. E Appella
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Y Haupt
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Y Haupt.

Additional information

Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Alsheich-Bartok, O., Haupt, S., Alkalay-Snir, I. et al. PML enhances the regulation of p53 by CK1 in response to DNA damage. Oncogene 27, 3653–3661 (2008). https://doi.org/10.1038/sj.onc.1211036

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1211036

Keywords

This article is cited by

Search

Advanced search

Quick links