Abstract
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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Baldin V, Cans C, Knibiehler M, Ducommun B . (1997a). Phosphorylation of human CDC25B phosphatase by CDK1-cyclin A triggers its proteasome-dependent degradation. J Biol Chem 272: 32731–32734.
Baldin V, Cans C, Superti-Furga G, Ducommun B . (1997b). Alternative splicing of the human CDC25B tyrosine phosphatase. Possible implications for growth control? Oncogene 14: 2485–2495.
Benatti P, Basile V, Merico D, Fantoni LI, Tagliafico E, Imbriano C . (2008). A balance between NF-Y and p53 governs the pro- and anti-apoptotic transcriptional response. Nucleic Acids Res 36: 1415–1428.
Bocangel D, Sengupta S, Mitra S, Bhakat KK . (2009). p53-Mediated down-regulation of the human DNA repair gene O6-methylguanine-DNA methyltransferase (MGMT) via interaction with Sp1 transcription factor. Anticancer Res 29: 3741–3750.
Boutros R, Dozier C, Ducommun B . (2006). The when and wheres of Cdc25 phosphatases. Curr Opin Cell Biol 18: 185–191.
Boutros R, Lobjois V, Ducommun B . (2007). CDC25 phosphatases in cancer cells: key players? Good targets? Nat Rev Cancer 7: 495–507.
Brosh R, Rotter V . (2010). Transcriptional control of the proliferation cluster by the tumor suppressor p53. Mol Biosyst 6: 17–29.
Brummelkamp TR, Bernards R, Agami R . (2002). A system for stable expression of short interfering RNAs in mammalian cells. Science 296: 550–553.
Bugler B, Quaranta M, Aressy B, Brezak MC, Prevost G, Ducommun B . (2006). Genotoxic-activated G2-M checkpoint exit is dependent on CDC25B phosphatase expression. Mol Cancer Ther 5: 1446–1451.
Bugler B, Schmitt E, Aressy B, Ducommun B . (2010). Unscheduled expression of CDC25B in S-phase leads to replicative stress and DNA damage. Mol Cancer 9: 29.
Di Agostino S, Strano S, Emiliozzi V, Zerbini V, Mottolese M, Sacchi A et al. (2006). Gain of function of mutant p53: the mutant p53/NF-Y protein complex reveals an aberrant transcriptional mechanism of cell cycle regulation. Cancer Cell 10: 191–202.
Essafi-Benkhadir K, Grosso S, Puissant A, Robert G, Essafi M, Deckert M et al. (2009). Dual role of Sp3 transcription factor as an inducer of apoptosis and a marker of tumour aggressiveness. PLoS One 4: e4478.
Iacovoni JS, Caron P, Lassadi I, Nicolas E, Massip L, Trouche D et al. (2010). High-resolution profiling of gamma H2AX around DNA double strand breaks in the mammalian genome. EMBO J 29: 1446–1457.
Imbriano C, Gurtner A, Cocchiarella F, Di Agostino S, Basile V, Gostissa M et al. (2005). Direct p53 transcriptional repression: in vivo analysis of CCAAT-containing G2/M promoters. Mol Cell Biol 25: 3737–3751.
Innocente SA, Lee JM . (2005). p53 is a NF-Y- and p21-independent, Sp1-dependent repressor of cyclin B1 transcription. FEBS Lett 579: 1001–1007.
Jin W, Chen Y, Di GH, Miron P, Hou YF, Gao H et al. (2008). Estrogen receptor (ER) beta or p53 attenuates ER alpha-mediated transcriptional activation on the BRCA2 promoter. J Biol Chem 283: 29671–29680.
Jung MS, Yun J, Chae HD, Kim JM, Kim SC, Choi TS et al. (2001). p53 and its homologues, p63 and p73, induce a replicative senescence through inactivation of NF-Y transcription factor. Oncogene 20: 5818–5825.
Karlsson C, Katich S, Hagting A, Hoffmann I, Pines J . (1999). Cdc25B and Cdc25C differ markedly in their properties as initiators of mitosis. J Cell Biol 146: 573–584.
Korner K, Jerome V, Schmidt T, Muller R . (2001). Cell cycle regulation of the murine cdc25B promoter: essential role for nuclear factor-Y and a proximal repressor element. J Biol Chem 276: 9662–9669.
Koutsodontis G, Vasilaki E, Chou WC, Papakosta P, Kardassis D . (2005). Physical and functional interactions between members of the tumour suppressor p53 and the Sp families of transcription factors: importance for the regulation of genes involved in cell-cycle arrest and apoptosis. Biochem J 389: 443–455.
Lambertini C, Pantano S, Dotto GP . (2010). Differential control of Notch1 gene transcription by Klf4 and Sp3 transcription factors in normal versus cancer-derived keratinocytes. PLoS One 5: e10369.
Langerod A, Zhao H, Borgan O, Nesland JM, Bukholm IR, Ikdahl T et al. (2007). TP53 mutation status and gene expression profiles are powerful prognostic markers of breast cancer. Breast Cancer Res 9: R30.
Lin RK, Wu CY, Chang JW, Juan LJ, Hsu HS, Chen CY et al. (2010). Dysregulation of p53/Sp1 control leads to DNA methyltransferase-1 overexpression in lung cancer. Cancer Res 70: 5807–5817.
Lindqvist A, Kallstrom H, Lundgren A, Barsoum E, Rosenthal CK . (2005). Cdc25B cooperates with Cdc25A to induce mitosis but has a unique role in activating cyclin B1-Cdk1 at the centrosome. J Cell Biol 171: 35–45.
Mantovani R . (1999). The molecular biology of the CCAAT-binding factor NF-Y. Gene 239: 15–27.
Miyata H, Doki Y, Yamamoto H, Kishi K, Takemoto H, Fujiwara Y et al. (2001). Overexpression of CDC25B overrides radiation-induced G2-M arrest and results in increased apoptosis in esophageal cancer cells. Cancer Res 61: 3188–3193.
Muller GA, Engeland K . (2009). The central role of CDE/CHR promoter elements in the regulation of cell cycle-dependent gene transcription. FEBS J 277: 877–893.
Riley T, Sontag E, Chen P, Levine A . (2008). Transcriptional control of human p53-regulated genes. Nat Rev Mol Cell Biol 9: 402–412.
Scian MJ, Carchman EH, Mohanraj L, Stagliano KE, Anderson MA, Deb D et al. (2008). Wild-type p53 and p73 negatively regulate expression of proliferation related genes. Oncogene 27: 2583–2593.
Sugrue MM, Shin DY, Lee SW, Aaronson SA . (1997). Wild-type p53 triggers a rapid senescence program in human tumor cells lacking functional p53. Proc Natl Acad Sci USA 94: 9648–9653.
Thompson T, Tovar C, Yang H, Carvajal D, Vu BT, Xu Q et al. (2004). Phosphorylation of p53 on key serines is dispensable for transcriptional activation and apoptosis. J Biol Chem 279: 53015–53022.
Torgeman A, Mor-Vaknin N, Zelin E, Ben-Aroya Z, Lochelt M, Flugel RM et al. (2001). Sp1-p53 heterocomplex mediates activation of HTLV-I long terminal repeat by 12-O-tetradecanoylphorbol-13-acetate that is antagonized by protein kinase C. Virology 281: 10–20.
Troester MA, Herschkowitz JI, Oh DS, He X, Hoadley KA, Barbier CS et al. (2006). Gene expression patterns associated with p53 status in breast cancer. BMC Cancer 6: 276.
Varmeh S, Manfredi JJ . (2009). Inappropriate activation of cyclin-dependent kinases by the phosphatase Cdc25b results in premature mitotic entry and triggers a p53-dependent checkpoint. J Biol Chem 284: 9475–9488.
Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z et al. (2004). in vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science 303: 844–848.
Vousden KH, Prives C . (2009). Blinded by the light: the growing complexity of p53. Cell 137: 413–431.
Wang B, Xiao Z, Ko HL, Ren EC . (2010). The p53 response element and transcriptional repression. Cell Cycle 9: 870–879.
Wierstra I . (2008). Sp1: emerging roles--beyond constitutive activation of TATA-less housekeeping genes. Biochem Biophys Res Commun 372: 1–13.
Zhou Y, Mehta KR, Choi AP, Scolavino S, Zhang X . (2003). DNA damage-induced inhibition of securin expression is mediated by p53. J Biol Chem 278: 462–470.
Acknowledgements
We thank Dr Bert Vogelstein (Howard Hughes Medical Institute, Baltimore USA) for providing the WT, p53−/− and p21−/− HCT116 cells. MD was a recipient of a post-doctoral fellowship from the CNRS (Centre National de la Recherche Scientifique). This work was supported by CNRS, Université Paul Sabatier, la région Midi-Pyrénées, l’Institut National du Cancer, the Cancéropôle Grand Sud-Ouest and la Ligue Nationale Contre le Cancer (Equipe labellisée 2008).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies the paper on the Oncogene website
Rights and permissions
About this article
Cite this article
Dalvai, M., Mondesert, O., Bourdon, JC. et al. Cdc25B is negatively regulated by p53 through Sp1 and NF-Y transcription factors. Oncogene 30, 2282–2288 (2011). https://doi.org/10.1038/onc.2010.588
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/onc.2010.588
Keywords
This article is cited by
-
Mutant P53 induces MELK expression by release of wild-type P53-dependent suppression of FOXM1
npj Breast Cancer (2020)
-
Census and evaluation of p53 target genes
Oncogene (2017)
-
p53-dependent gene repression through p21 is mediated by recruitment of E2F4 repression complexes
Oncogene (2014)
-
Association of p21 with NF-YA suppresses the expression of Polo-like kinase 1 and prevents mitotic death in response to DNA damage
Cell Death & Disease (2014)
-
Cell-type and transcription factor specific enrichment of transcriptional cofactor motifs in ENCODE ChIP-seq data
BMC Genomics (2013)