title: Doxorubicin promotes transcriptional upregulation of Cdc25B in cancer cells by releasing Sp1 from the promoter.
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.
authors.affiliation: 1] CNRS, LBME-UMR5099, Toulouse, France [2] Université de Toulouse, Toulouse, France.
authors.forename: M
authors.initials: M
authors.lastname: Dalvai
authors.forename: O
authors.initials: O
authors.lastname: Mondesert
authors.forename: B
authors.initials: B
authors.lastname: Bugler
authors.forename: S
authors.initials: S
authors.lastname: Manenti
authors.forename: B
authors.initials: B
authors.lastname: Ducommun
authors.forename: C
authors.initials: C
authors.lastname: Dozier
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D023081:CCAAT-Binding Factor / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics; D004317:Doxorubicin / Q000494:pharmacology* / Q000528:radiation effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D016158:Genes, p53; D045325:HCT116 Cells / Q000187:drug effects; D006801:Humans; D011401:Promoter Regions, Genetic; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D020687:cdc25 Phosphatases / Q000235:genetics* / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D023081:CCAAT-Binding Factor; D016329:Sp1 Transcription Factor; D004317:Doxorubicin; C517008:CDC25B protein, human; D020687:cdc25 Phosphatases