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.

  • Short Communication
  • Published:

Doxorubicin promotes transcriptional upregulation of Cdc25B in cancer cells by releasing Sp1 from the promoter

Oncogene volume 32, pages 5123–5128 (2013)Cite this article

Subjects

Abstract

Cdc25B phosphatases have a key role in G2/M cell-cycle progression by activating the CDK1-cyclinB1 complexes and functioning as important targets of checkpoints. Overexpression of Cdc25B results in a bypass of the G2/M checkpoint and illegitimate entry into mitosis. It can also cause replicative stress, which leads to genomic instability. Thus, fine-tuning of the Cdc25B expression level is critical for correct cell-cycle arrest in response to DNA damage. In response to genotoxic stress, Cdc25B is mainly regulated by post-transcriptional mechanisms affecting either Cdc25B protein stability or translation. Here, we show that upon DNA damage Cdc25B can be regulated at the transcriptional level. Although ionizing radiation downregulates Cdc25B in a p53-dependent pathway, doxorubicin transcriptionally upregulates Cdc25B in p53-proficient cancer cells. We show that in the presence of wild-type p53, doxorubicin activates the Cdc25B promoter by preventing the binding of Sp1 and increasing the binding of NF-Y on the Cdc25B promoter, thus preventing p53 from downregulating this promoter. Our results highlight the mechanistically distinct regulation of the three Cdc25 phosphatases by checkpoint signalling following doxorubicin treatment.

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

Similar content being viewed by others

References

  1. Boutros R, Dozier C, Ducommun B . The when and wheres of CDC25 phosphatases. Curr Opin Cell Biol 2006; 18: 185–191.

    Article  CAS  PubMed  Google Scholar 

  2. Lindqvist A, Kallstrom H, Lundgren A, Barsoum E, Rosenthal CK . Cdc25B cooperates with Cdc25A to induce mitosis but has a unique role in activating cyclin B1-Cdk1 at the centrosome. J Cell Biol 2005; 171: 35–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Galaktionov K, Lee AK, Eckstein J, Draetta G, Meckler J, Loda M et al. CDC25 phosphatases as potential human oncogenes. Science 1995; 269: 1575–1577.

    Article  CAS  PubMed  Google Scholar 

  4. Kang CM, Cho HN, Ahn JM, Lee SS, Jeoung DI, Cho CK et al. Alteration of gene expression during radiation-induced resistance and tumorigenesis in NIH3T3 cells revealed by cDNA microarrays: involvement of MDM2 and CDC25B. Carcinogenesis 2004; 25: 123–132.

    Article  PubMed  Google Scholar 

  5. Yao Y, Slosberg ED, Wang L, Hibshoosh H, Zhang YJ, Xing WQ et al. Increased susceptibility to carcinogen-induced mammary tumors in MMTV-Cdc25B transgenic mice. Oncogene 1999; 18: 5159–5166.

    Article  CAS  PubMed  Google Scholar 

  6. Boutros R, Lobjois V, Ducommun B . CDC25 phosphatases in cancer cells: key players? Good targets? Nat Rev Cancer 2007; 7: 495–507.

    Article  CAS  PubMed  Google Scholar 

  7. Karlsson-Rosenthal C, Millar JB . Cdc25: mechanisms of checkpoint inhibition and recovery. Trends Cell Biol 2006; 16: 285–292.

    Article  CAS  PubMed  Google Scholar 

  8. Aressy B, Bugler B, Valette A, Biard D, Ducommun B . Moderate variations in CDC25B protein levels modulate the response to DNA damaging agents. Cell Cycle 2008; 7: 2234–2240.

    Article  CAS  PubMed  Google Scholar 

  9. Bugler B, Quaranta M, Aressy B, Brezak MC, Prevost G, Ducommun B . Genotoxic-activated G2-M checkpoint exit is dependent on CDC25B phosphatase expression. Mol Cancer Ther 2006; 5: 1446–1451.

    Article  CAS  PubMed  Google Scholar 

  10. Miyata H, Doki Y, Yamamoto H, Kishi K, Takemoto H, Fujiwara Y et al. Overexpression of CDC25B overrides radiation-induced G2-M arrest and results in increased apoptosis in esophageal cancer cells. Cancer Res 2001; 61: 3188–3193.

    CAS  PubMed  Google Scholar 

  11. Bansal P, Lazo JS . Induction of Cdc25B regulates cell cycle resumption after genotoxic stress. Cancer Res 2007; 67: 3356–3363.

    Article  CAS  PubMed  Google Scholar 

  12. Jullien D, Bugler B, Dozier C, Cazales M, Ducommun B . Identification of N-terminally truncated stable nuclear isoforms of CDC25B that are specifically involved in G2/M checkpoint recovery. Cancer Res 2011; 71: 1968–1977.

    Article  CAS  PubMed  Google Scholar 

  13. Lemaire M, Froment C, Boutros R, Mondesert O, Nebreda AR, Monsarrat B et al. CDC25B phosphorylation by p38 and MK-2. Cell Cycle 2006; 5: 1649–1653.

    Article  CAS  PubMed  Google Scholar 

  14. Dalvai M, Mondesert O, Bourdon JC, Ducommun B, Dozier C . Cdc25B is negatively regulated by p53 through Sp1 and NF-Y transcription factors. Oncogene 2011; 30: 2282–2288.

    Article  CAS  PubMed  Google Scholar 

  15. Korner K, Jerome V, Schmidt T, Muller R . Cell cycle regulation of the murine cdc25B promoter: essential role for nuclear factor-Y and a proximal repressor element. J Biol Chem 2001; 276: 9662–9669.

    Article  CAS  PubMed  Google Scholar 

  16. Scian MJ, Carchman EH, Mohanraj L, Stagliano KE, Anderson MA, Deb D et al. Wild-type p53 and p73 negatively regulate expression of proliferation related genes. Oncogene 2008; 27: 2583–2593.

    Article  CAS  PubMed  Google Scholar 

  17. Zhao H, Watkins JL, Piwnica-Worms H . Disruption of the checkpoint kinase 1/cell division cycle 25A pathway abrogates ionizing radiation-induced S and G2 checkpoints. Proc Natl Acad Sci USA 2002; 99: 14795–14800.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Wang B, Xiao Z, Ko HL, Ren EC . The p53 response element and transcriptional repression. Cell Cycle 2010; 9: 870–879.

    Article  CAS  PubMed  Google Scholar 

  19. Rashi-Elkeles S, Elkon R, Shavit S, Lerenthal Y, Linhart C, Kupershtein A et al. Transcriptional modulation induced by ionizing radiation: p53 remains a central player. Mol Oncol 2011; 5: 336–348.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. St Clair S, Giono L, Varmeh-Ziaie S, Resnick-Silverman L, Liu WJ, Padi A et al. DNA damage-induced downregulation of Cdc25C is mediated by p53 via two independent mechanisms: one involves direct binding to the cdc25C promoter. Mol Cell 2004; 16: 725–736.

    Article  PubMed  Google Scholar 

  21. Xiao Z, Chen Z, Gunasekera AH, Sowin TJ, Rosenberg SH, Fesik S et al. Chk1 mediates S and G2 arrests through Cdc25A degradation in response to DNA-damaging agents. J Biol Chem 2003; 278: 21767–21773.

    Article  CAS  PubMed  Google Scholar 

  22. Baldin V, Cans C, Knibiehler M, Ducommun B . Phosphorylation of human CDC25B phosphatase by CDK1-cyclin A triggers its proteasome-dependent degradation. J Biol Chem 1997; 272: 32731–32734.

    Article  CAS  PubMed  Google Scholar 

  23. Bu Y, Suenaga Y, Ono S, Koda T, Song F, Nakagawara A et al. Sp1-mediated transcriptional regulation of NFBD1/MDC1 plays a critical role in DNA damage response pathway. Genes Cells 2008; 13: 53–66.

    Article  CAS  PubMed  Google Scholar 

  24. Uchida Y, Itoh M, Taguchi Y, Yamaoka S, Umehara H, Ichikawa S et al. Ceramide reduction and transcriptional up-regulation of glucosylceramide synthase through doxorubicin-activated Sp1 in drug-resistant HL-60/ADR cells. Cancer Res 2004; 64: 6271–6279.

    Article  CAS  PubMed  Google Scholar 

  25. Xu J, Zhou JY, Wei WZ, Philipsen S, Wu GS . Sp1-mediated TRAIL induction in chemosensitization. Cancer Res 2008; 68: 6718–6726.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Chu S . Transcriptional regulation by post-transcriptional modification-Role of phosphorylation in Sp1 transcriptional activity. Gene 508: 1–8.

    Article  CAS  PubMed  Google Scholar 

  27. Beishline K, Kelly CM, Olofsson BA, Koduri S, Emrich J, Greenberg RA et al. Sp1 facilitates DNA double-strand break repair through a nontranscriptional mechanism. Mol Cell Biol 2012; 32: 3790–3799.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Iwahori S, Yasui Y, Kudoh A, Sato Y, Nakayama S, Murata T et al. Identification of phosphorylation sites on transcription factor Sp1 in response to DNA damage and its accumulation at damaged sites. Cell Signal 2008; 20: 1795–1803.

    Article  CAS  PubMed  Google Scholar 

  29. Olofsson BA, Kelly CM, Kim J, Hornsby SM, Azizkhan-Clifford J . Phosphorylation of Sp1 in response to DNA damage by ataxia telangiectasia-mutated kinase. Mol Cancer Res 2007; 5: 1319–1330.

    Article  CAS  PubMed  Google Scholar 

  30. Bocangel D, Sengupta S, Mitra S, Bhakat KK . p53-Mediated down-regulation of the human DNA repair gene O6-methylguanine-DNA methyltransferase (MGMT) via interaction with Sp1 transcription factor. Anticancer Res 2009; 29: 3741–3750.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Cuesta A, Zambrano A, Royo M, Pascual A . The tumour suppressor p53 regulates the expression of amyloid precursor protein (APP). Biochem J 2009; 418: 643–650.

    Article  CAS  PubMed  Google Scholar 

  32. Thompson T, Tovar C, Yang H, Carvajal D, Vu BT, Xu Q et al. Phosphorylation of p53 on key serines is dispensable for transcriptional activation and apoptosis. J Biol Chem 2004; 279: 53015–53022.

    Article  CAS  PubMed  Google Scholar 

  33. Szulawska A, Gniazdowski M, Czyz M . Sequence specificity of formaldehyde-mediated covalent binding of anthracycline derivatives to DNA. Biochem Pharmacol 2005; 69: 7–18.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank Dr Bert Vogelstein (Howard Hughes Medical Institute, Baltimore USA) for providing the WT and p53−/− HCT116 cells. MD was a recipient of a post-doctoral fellowship from Fondation de la Recherche Medicale. This work was supported by C.N.R.S, Université Paul Sabatier, la région Midi-Pyrénées, l’Institut National du Cancer (PL2008), the Cancéropôle Grand Sud-Ouest, le conseil de radioprotection d’EDF et la Ligue Nationale Contre le Cancer (Equipe labellisée 2008).

Author information

Authors and Affiliations

  1. CNRS, LBME-UMR5099, Toulouse, France

    M Dalvai

  2. Université de Toulouse, Toulouse, France

    M Dalvai, O Mondesert, B Bugler, S Manenti, B Ducommun & C Dozier

  3. CNRS, ITAV UMS 3039, Toulouse, France

    O Mondesert & B Ducommun

  4. CNRS, LBCMCP-UMR5088, Toulouse, France

    B Bugler

  5. Department of Hematology and Immunology, INSERM UMR1037/CNRS ERL 5294- Cancer Research Center of Toulouse, Toulouse, France

    S Manenti & C Dozier

  6. CNRS ERL 5294, Toulouse, France

    S Manenti & C Dozier

  7. CHU de Toulouse, Toulouse, France

    B Ducommun

Authors
  1. M Dalvai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. O Mondesert
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. B Bugler
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S Manenti
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. B Ducommun
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. C Dozier
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C Dozier.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dalvai, M., Mondesert, O., Bugler, B. et al. Doxorubicin promotes transcriptional upregulation of Cdc25B in cancer cells by releasing Sp1 from the promoter. Oncogene 32, 5123–5128 (2013). https://doi.org/10.1038/onc.2012.524

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2012.524

Keywords

This article is cited by

Search

Advanced search

Quick links