Journal
ONCOGENE
Volume 32, Issue 42, Pages 5123-5128Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2012.524
Keywords
Cdc25B; doxorubicin; p53; Sp1
Funding
- Fondation de la Recherche Medicale
- C.N.R.S
- Universite Paul Sabatier
- la region Midi-Pyrenees
- l'Institut National du Cancer [PL2008]
- Canceropole Grand Sud-Ouest, le conseil de radioprotection d'EDF et la Ligue Nationale Contre le Cancer (Equipe labellisee)
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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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