Cdc25B is negatively regulated by p53 through Sp1 and NF-Y transcription factors.
Cdc25B phosphatases function as key players in G2/M cell cycle progression by activating the CDK1-cyclinB1 complexes. They also have an essential role in recovery from the G2/M checkpoint activated in response to DNA damage. Overexpression of Cdc25B results in bypass of the G2/M checkpoint and illegitimate entry into mitosis, and also causes replicative stress, leading to genomic instability. Thus, fine-tuning of Cdc25B expression level is critical for correct cell cycle progression and G2 checkpoint recovery. However, the transcriptional regulation of Cdc25B remains largely unknown. Earlier studies have shown that the tumor suppressor p53 overexpression transcriptionally represses Cdc25B; however, the molecular mechanism of this repression has not yet been elucidated, although it was suggested to occur through the induction of p21. Here we show that Cdc25B is downregulated by the basal level of p53 in multiple cell types. This downregulation also occurs in p21-/- cell lines, indicating that p21 is not required for p53-mediated regulation of Cdc25B. Deletion and mutation analyses of the Cdc25B promoter revealed that downregulation by p53 is dependent on the presence of functional Sp1/Sp3 and NF-Y binding sites. Furthermore, chromatin immunoprecipitation analyses show that p53 binds to the Cdc25B promoter and mediates transcriptional attenuation through the Sp1 and NF-Y transcription factors. Our results suggest that the inability to downregulate Cdc25B after loss of p53 might contribute to tumorigenesis.
Université de Toulouse, LBCMCP, Toulouse, France.
M
M
Dalvai
O
O
Mondesert
J-C
JC
Bourdon
B
B
Ducommun
C
C
Dozier
D023081:CCAAT-Binding Factor / Q000502:physiology*; D045744:Cell Line, Tumor; D006801:Humans; D016329:Sp1 Transcription Factor / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D020687:cdc25 Phosphatases / Q000502:physiology*
D023081:CCAAT-Binding Factor; D016329:Sp1 Transcription Factor; D016159:Tumor Suppressor Protein p53; C517008:CDC25B protein, human; D020687:cdc25 Phosphatases