Cdc25B is negatively regulated by p53 through Sp1 and NF-Y transcription factors
Cdc25B is negatively regulated by p53 through Sp1 and NF-Y transcription factors
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DOI：
10.1038/onc.2010.588
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发表时间：
2011-05-01
期刊：
影响因子：
8
通讯作者：
Dozier, C.
中科院分区：
文献类型：
--
作者：
Dalvai, M.;Mondesert, O.;Dozier, C.
CDC25B磷酸酶通过激活CDK1-cyClinB1复合体，在G2/M细胞周期进程中发挥关键作用。它们在从因DNA损伤而激活的G2/M检查点恢复过程中也起着至关重要的作用。过表达CDC25B会绕过G2/M检查点，非法进入有丝分裂，也会导致复制压力，导致基因组不稳定。因此，微调CDC25B的表达水平对于正确的细胞周期进程和G2检查点恢复至关重要。然而，CDC25B的转录调控在很大程度上仍不清楚。早期的研究表明，肿瘤抑制因子P53的过度表达在转录水平上抑制了CDc25B；然而，这种抑制的分子机制尚未阐明，尽管有人认为它是通过诱导p21发生的。在这里，我们表明，在多种细胞类型中，CDC25B受到P53基础水平的下调。这种下调也发生在p21-/-细胞系中，表明p21不是P53介导的CDC25B调节所必需的。对CDC25B启动子的缺失和突变分析表明，P53的下调依赖于功能Sp1/SP3和NF-Y结合位点的存在。此外，染色质免疫沉淀分析表明，p53与CDc25B启动子结合，并通过Sp1和NF-Y转录因子介导转录减弱。我们的结果表明，在P53丢失后，无法下调CDC25B的表达可能与肿瘤的发生有关。Oncogene(2011)30,2282-2288；doi：10.1038/onc.2010.588；2011年1月17日在线发布
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 immuno-precipitation 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. Oncogene (2011) 30, 2282-2288; doi:10.1038/onc.2010.588; published online 17 January 2011