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