CDC25B induces cellular senescence and correlates with tumor suppression in a p53-dependent manner

Abstract

The phosphatase cell division cycle 25B (Cdc25B) regulates cell cycle progression. Increased Cdc25B levels are often detected in cancer cell lines and human cancers and have been implicated in contributing to tumor growth, potentially by providing cancer cells with the ability to bypass checkpoint controls. However, the specific mechanism by which increased Cdc25B impacts tumor progression is not clear. Here we analyzed The Cancer Genome Atlas (TCGA) database and found that patients with high CDC25B expression had the expected poor survival. However, we also found that high CDC25B expression had a p53-dependent tumor suppressive effect in lung cancer and possibly several other cancer types. Looking in more detail at the tumor suppressive function of Cdc25B, we found that increased Cdc25B expression caused inhibition of cell growth in human normal fibroblasts. This effect was not due to alteration of specific cell cycle stage or inhibition of apoptosis, nor by induction of the DNA damage response. Instead, increased CDC25B expression led cells into senescence. We also found that p53 was required to induce senescence, which might explain the p53-dependent tumor suppressive function of Cdc25B. Mechanistically, we found that the Cdc25B phosphatase activity was required to induce senescence. Further analysis also found that Cdc25B stabilized p53 through binding and dephosphorylating p53. Together, this study identified a tumor-suppressive function of Cdc25B that is mediated through a p53-dependent senescence pathway. The phosphatase cell division cycle 25B (Cdc25B) regulates cell cycle progression. Increased Cdc25B levels are often detected in cancer cell lines and human cancers and have been implicated in contributing to tumor growth, potentially by providing cancer cells with the ability to bypass checkpoint controls. However, the specific mechanism by which increased Cdc25B impacts tumor progression is not clear. Here we analyzed The Cancer Genome Atlas (TCGA) database and found that patients with high CDC25B expression had the expected poor survival. However, we also found that high CDC25B expression had a p53-dependent tumor suppressive effect in lung cancer and possibly several other cancer types. Looking in more detail at the tumor suppressive function of Cdc25B, we found that increased Cdc25B expression caused inhibition of cell growth in human normal fibroblasts. This effect was not due to alteration of specific cell cycle stage or inhibition of apoptosis, nor by induction of the DNA damage response. Instead, increased CDC25B expression led cells into senescence. We also found that p53 was required to induce senescence, which might explain the p53-dependent tumor suppressive function of Cdc25B. Mechanistically, we found that the Cdc25B phosphatase activity was required to induce senescence. Further analysis also found that Cdc25B stabilized p53 through binding and dephosphorylating p53. Together, this study identified a tumor-suppressive function of Cdc25B that is mediated through a p53-dependent senescence pathway. Cell division cycle 25B (Cdc25B) phosphatase is a key player in G2/M cell cycle progression (1Boutros R. Dozier C. Ducommun B. The when and wheres of CDC25 phosphatases.Curr. Opin. Cell Biol. 2006; 18: 185-191Crossref PubMed Scopus (342) Google Scholar). The Cdc25B protein level begins to increase from mid S-phase and peaks during the G2/M phase (2Gabrielli B.G. De Souza C.P. Tonks I.D. Clark J.M. Hayward N.K. Ellem K.A. Cytoplasmic accumulation of CDC25B phosphatase in mitosis triggers centrosomal microtubule nucleation in HeLa cells.J. Cell Sci. 1996; 109: 1081-1093Crossref PubMed Google Scholar). It then activates the Cdk1-cyclinB1 complexes during the G2 to M phase transition of the cell cycle (3Lindqvist A. Kallstrom H. Lundgren A. Barsoum E. Rosenthal C.K. Cdc25B cooperates with Cdc25A to induce mitosis but has a unique role in activating cyclin B1-Cdk1 at the centrosome.J. Cell Biol. 2005; 171: 35-45Crossref PubMed Scopus (148) Google Scholar, 4De Souza C.P. Ellem K.A. Gabrielli B.G. Centrosomal and cytoplasmic Cdc2/cyclin B1 activation precedes nuclear mitotic events.Exp. Cell Res. 2000; 257: 11-21Crossref PubMed Scopus (126) Google Scholar). The Cdc25B protein level is rapidly decreased by the proteasome pathway after M phase of the cell cycle (2Gabrielli B.G. De Souza C.P. Tonks I.D. Clark J.M. Hayward N.K. Ellem K.A. Cytoplasmic accumulation of CDC25B phosphatase in mitosis triggers centrosomal microtubule nucleation in HeLa cells.J. Cell Sci. 1996; 109: 1081-1093Crossref PubMed Google Scholar, 5Baldin V. Cans C. Knibiehler M. Ducommun B. Phosphorylation of human CDC25B phosphatase by CDK1/cyclin A triggers its proteasome-dependent degradation.J. Biol. Chem. 1997; 272: 32731-32735Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar). Cdc25B protein level was also found to be increased after DNA damages such as UV radiation, ionizing radiation, or genotoxic agents. The increased Cdc25B level has a role in recovery from the G2/M checkpoint activated in response to DNA damages (6Bugler B. Quaranta M. Aressy B. Brezak M.C. Prevost G. Ducommun B. Genotoxic-activated G2-M checkpoint exit is dependent on CDC25B phosphatase expression.Mol. Cancer Ther. 2006; 5: 1446-1451Crossref PubMed Scopus (44) Google Scholar, 7Bansal P. Lazo J.S. Induction of Cdc25B regulates cell cycle resumption after genotoxic stress.Cancer Res. 2007; 67: 3356-3363Crossref PubMed Scopus (34) Google Scholar). It leads to bypass of genotoxic-induced G2/M checkpoint arrest. In addition to cell cycle deregulation, CDC25B overexpression also has an oncogenic property. It was shown that Cdc25B cooperated with either oncogenic HRAS or Rb inactivation to transform mouse embryonic fibroblasts in vitro and to form tumors in vivo (8Galaktionov K. Lee A.K. Eckstein J. Draetta G. Meckler J. Loda M. Beach D. CDC25 phosphatases as potential human oncogenes.Science. 1995; 269: 1575-1577Crossref PubMed Scopus (498) Google Scholar). It was also reported that targeted overexpression of CDC25B in mammary glands of mice induced hyperplasia and promoted proliferation (9Ma Z.Q. Chua S.S. DeMayo F.J. Tsai S.Y. Induction of mammary gland hyperplasia in transgenic mice over- expressing human cdc25B.Oncogene. 1999; 18: 4564-4576Crossref PubMed Scopus (79) Google Scholar). Tumor growth could then be induced with additional challenge by carcinogen (10Yao Y. Slosberg E.D. Wang L. Hibshoosh H. Zhang Y.J. Xing W.Q. Santella R.M. Weinstein I.B. Increased susceptibility to carcinogen-induced mammary tumors in MMTV-Cdc25B transgenic mice.Oncogene. 1999; 18: 5159-5166Crossref PubMed Scopus (71) Google Scholar). Thus, although CDC25B overexpression is not sufficient to induce tumor growth, it impacts positively toward tumorigenesis. CDC25B has been reported to be overexpressed in various cancer cell lines and human cancers (11Nagata A. Igarashi M. Jinno S. Suto K. Okayama H. An additional homolog of the fission yeast cdc25 gene occurs in humans and is highly expressed in some cancer cells.New Biol. 1991; 3: 959-968PubMed Google Scholar, 12Boutros R. Lobjois V. Ducommun B. CDC25 phosphatases in cancer cells: Key players? Good targets?.Nat. Rev. Cancer. 2007; 7: 495-507Crossref PubMed Scopus (542) Google Scholar). Although the mechanism of how CDC25B expression is increased in cancer cells is still unclear, several lines of evidence showed that it might be related to oncogene activation and/or p53 inactivation. For example, it was shown that CDC25B mRNA level was increased in SV40- or HPV E6 and E7-transformed fibroblasts (11Nagata A. Igarashi M. Jinno S. Suto K. Okayama H. An additional homolog of the fission yeast cdc25 gene occurs in humans and is highly expressed in some cancer cells.New Biol. 1991; 3: 959-968PubMed Google Scholar). CDC25B was also shown to be a target of both oncogene c-myc and tumor suppressor gene p53 (13Galaktionov K. Chen X. Beach D. Cdc25 cell-cycle phosphatase as a target of c-myc.Nature. 1996; 382: 511-517Crossref PubMed Scopus (642) Google Scholar, 14Dalvai M. Mondesert O. Bourdon J.C. Ducommun B. Dozier C. Cdc25B is negatively regulated by p53 through Sp1 and NF-Y transcription factors.Oncogene. 2011; 30: 2282-2288Crossref PubMed Scopus (36) Google Scholar, 15Scian M.J. Carchman E.H. Mohanraj L. Stagliano K.E. Anderson M.A. Deb D. Crane B.M. Kiyono T. Windle B. Deb S.P. Deb S. Wild-type p53 and p73 negatively regulate expression of proliferation related genes.Oncogene. 2008; 27: 2583-2593Crossref PubMed Scopus (59) Google Scholar). With its role in checkpoint control, Cdc25B overexpression might contribute to tumorigenic pathway by rapidly pushing cells into mitosis with incompletely replicated DNA, thus providing cancer cells with the ability to bypass checkpoint control to enhance their proliferation. To reveal the impact of increased Cdc25B in tumorigenesis, we first analyzed the association of CDC25B expression to survival of cancer patients. To our surprise, we found that high CDC25B expression significantly associated with survival patients p53 in lung cancer and possibly several other cancer patients. The that Cdc25B has a p53-dependent tumor-suppressive To the of increased Cdc25B, we normal human fibroblasts in our We found CDC25B overexpression induced senescence in a p53-dependent The not to be to normal lung as and several cancer cells also showed We showed that Cdc25B stabilized p53 protein through with p53 and p53. Thus, our evidence to a role of Cdc25B in senescence induction that is related to tumor CDC25B has been reported in various cancer cell lines and human cancers (11Nagata A. Igarashi M. Jinno S. Suto K. Okayama H. An additional homolog of the fission yeast cdc25 gene occurs in humans and is highly expressed in some cancer cells.New Biol. 1991; 3: 959-968PubMed Google Scholar, 12Boutros R. Lobjois V. Ducommun B. CDC25 phosphatases in cancer cells: Key players? Good targets?.Nat. Rev. Cancer. 2007; 7: 495-507Crossref PubMed Scopus (542) Google Scholar). To the role of increased Cdc25B in tumorigenesis, the association of CDC25B expression by analysis to the survival of cancer patients was by the of Cancer was in the The The survival the was first into high and The showed that high CDC25B expression associated with poor With the association p53 and CDC25B the p53 was also to the We found high CDC25B expression associated with poor of the p53 and The that high CDC25B expression impacts negatively to the survival of cancer with the expected oncogenic role of the impact of CDC25B expression and p53 on cancer was we found that CDC25B expression not to have an impact on the survival of lung cancer patients when lung cancer patients on their p53 high CDC25B expression significantly associated with survival in patients p53 and CDC25B expression level also showed survival in patients p53 and association could be in several other cancer although the analysis not due to the of patients. For example, a could be and cancer patients CDC25B expression levels might also to the of and and cancer patients and Thus, in addition to the oncogenic the analysis identified a p53-dependent tumor-suppressive role of Cdc25B in several cancer types. The mechanism of how increased Cdc25B its tumor-suppressive effect was had shown that increased Cdc25B caused and in cancer cells H. Y. H. K. H. Y. T. M. M. H. Weinstein I.B. M. of CDC25B G2-M and in increased in cancer Res. Google Scholar, J. CDC25B and overexpression in cancer cell PubMed Scopus Google Scholar). To the of cancer human normal lung cell was in this The Cdc25B level in cells was or to the of gene into normal expression was to CDC25B into high required to Cdc25B The of to was as this expressed CDC25B or The expressed CDC25B was as it the at and level Thus, CDC25B was into normal human cells the of cells was first by the cell after CDC25B shown in the growth of cells was that high Cdc25B level the proliferation of normal With the role of Cdc25B in cell cycle the effect of increased Cdc25B on cell cycle progression was analysis showed that of Cdc25B not to a in the of cell cycle It was also that the of cells was not increased CDC25B that increased Cdc25B not in normal fibroblasts. The of the cells to be and a to that of cells Thus, the in cells then Lee X. G. M. G. C. M. O. M. J. A that human cells in and in in Sci. S. A. 1995; PubMed Scopus Google Scholar, J.M. senescence and in human Cell Res. 1999; PubMed Scopus Google Scholar). The cells showed an increase of the activity The of cells was increased from in normal or cells to in with this the of cells was from in normal or cells to in cells The and not to normal lung as human normal also showed growth inhibition and activation of the activity CDC25B overexpression Together, the that a is in response to CDC25B overexpression in normal fibroblasts. It was reported that cells often that the and and to senescence in an and a of in vivo Rev. Cancer. PubMed Scopus Google Scholar). The might through of cells and thus has on the through alteration of and the and not to be induced in cells The that although a is it is from senescence. Cdc25B is a protein to the activity is senescence, a both and was It was reported that Cdc25B of its phosphatase activity J. M.J. cdc25 is a specific phosphatase that activates 1991; 67: Full Text PDF PubMed Scopus Google Scholar). this was and into shown in the CDC25B both the and protein level of the The Cdc25B phosphatase activity cells was also cell from or with and then analyzed the phosphatase shown in although the phosphatase activity was increased in of phosphatase activity was in that the its phosphatase The proliferation and activity then analyzed in shown in and cells expressing the showed growth inhibition and not The that the phosphatase activity is senescence. To into the of senescence, the of several In CDC25B overexpression increased both p53 and levels and decreased Rb protein To the of p53 in senescence, we to p53 level P. P. R. G. V. of a of in Ther. Full Text Full Text PDF PubMed Scopus Google Scholar). The cells first with expressing p53 or and then with shown in the level of p53 was The growth and activity of cells also In p53 the activity of Cdc25B was and the of cells was also decreased and The that p53 is required senescence. The p53-dependent effect of Cdc25B was also in cancer cancer cell and its in our C. T. S. J.M. B. p53 and to G2 after DNA PubMed Scopus Google Scholar). CDC25B or was into cells and their growth We found that the growth of p53 cells was CDC25B but not in the cells We also found that CDC25B not cell growth in lung cancer cell that p53 and Thus, the p53-dependent growth effect of Cdc25B is not to normal fibroblasts. CDC25B overexpression was reported to through R. Lobjois V. Ducommun B. CDC25B in the cycle and in microtubule Res. 2007; 67: PubMed Scopus Google Scholar, R. Mondesert O. C. P. G. M. Ducommun B. Gabrielli B. CDC25B overexpression and the of PubMed Scopus Google Scholar). then DNA damage response in the DNA damage the Res. PubMed Scopus (36) Google Scholar). p53 is a key of Cdc25B p53 through To this the was in CDC25B expressing Phosphorylation of and several and as shown in CDC25B overexpression not accumulation of DNA damage nor activated that the increased p53 level was not due to of p53 could be caused by p53 expression and/or p53 The expression of p53 at the transcription level was first We found that not the mRNA level of p53 The effect of Cdc25B on the of p53 protein was The p53 is a protein with a We found that Cdc25B stabilized p53 by its to The of p53 was also in cells the We found that the not the of p53 protein that the phosphatase activity of Cdc25B is required p53 The protein of both and the was also We found that the of was that of p53 was not due to of the of p53 is regulated by the pathway of p53 Full Text Full Text PDF PubMed Scopus Google Scholar). is the p53 The of Cdc25B in with p53 pathway was We first analyzed the of Cdc25B to p53 and showed that Cdc25B was detected in the of both p53 and that Cdc25B with both p53 and of the also showed that Cdc25B not to the p53 and the levels in the of both p53 and that the binding of to p53 and was The is with an that the of Cdc25B is J. J.M. G. P. K. A. H. J. of the of Cdc25 with its protein 2005; PubMed Scopus Google and implicated that Cdc25B might target p53 Phosphorylation of p53 has a role in protein of p53 Full Text Full Text PDF PubMed Scopus Google Scholar). To Cdc25B regulates p53 through dephosphorylating the of p53 on several and was K. S. Y. S. Anderson E. of human p53 through a mediated by a on Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google A. X. Phosphorylation of human p53 on 2000; PubMed Scopus Google Scholar, p53 at in response to Res. PubMed Scopus Google Scholar, X. Phosphorylation on by of A role in cell Full Text Full Text PDF PubMed Scopus Google T. O. A. S.Y. S. T. D. Y. of p53 on is p53 and in response to Biol. PubMed Scopus Google and D. R. X. P. B. C. p53 to by the J. PubMed Scopus Google this analysis their in p53 and the of specific was reported to be the of was also analyzed K. S. Y. S. Anderson E. of human p53 through a mediated by a on Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, is a which of 1999; PubMed Scopus Google Scholar). shown in of p53 was on and in cells In the not have an impact on p53 The that the phosphatase activity of Cdc25B is required p53 at more showed the also that Cdc25B not on a specific Together, evidence the function of Cdc25B in senescence that it and thus p53 of p53 then activates the senescence pathway. Cdc25B has been implicated in a function as an oncogene that impacts positively to cancer cell progression during (8Galaktionov K. Lee A.K. Eckstein J. Draetta G. Meckler J. Loda M. Beach D. CDC25 phosphatases as potential human oncogenes.Science. 1995; 269: 1575-1577Crossref PubMed Scopus (498) Google Scholar, 12Boutros R. Lobjois V. Ducommun B. CDC25 phosphatases in cancer cells: Key players? Good targets?.Nat. Rev. Cancer. 2007; 7: 495-507Crossref PubMed Scopus (542) Google Scholar). database analysis the expected role of high CDC25B in tumorigenesis. However, the analysis also that high Cdc25B levels have in lung and several other a tumor-suppressive function of Cdc25B. The of senescence induction by increased CDC25B expression an to the tumor-suppressive role of Cdc25B. However, this not explain the mechanism of how the tumor-suppressive effect was in a of cancer types. It has been that the of and the tumor types. have their specific effect on C. K. B. C. M. Zhang M.A. J.S. M.J. M.C. and cancer PubMed Scopus Google Scholar). Thus, although the is still to it is that more is required this tumor suppressive function of Cdc25B. is as a J. tumor and Good 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). of senescence is to be required tumor progression. Cdc25B level could be induced by normal fibroblasts with or HPV E6 and (11Nagata A. Igarashi M. Jinno S. Suto K. Okayama H. An additional homolog of the fission yeast cdc25 gene occurs in humans and is highly expressed in some cancer cells.New Biol. 1991; 3: 959-968PubMed Google Scholar, K. Chen X. Beach D. Cdc25 cell-cycle phosphatase as a target of c-myc.Nature. 1996; 382: 511-517Crossref PubMed Scopus (642) Google the increased Cdc25B might the senescence pathway to of normal cells in stage of tumorigenesis. Thus, of Cdc25B in tumor is to be tumor senescence during tumor progression be as it the inactivation of p53. However, in cells might increase the of p53 inactivation to tumor progression. p53 was reported to be a of CDC25B M. Mondesert O. Bourdon J.C. Ducommun B. Dozier C. Cdc25B is negatively regulated by p53 through Sp1 and NF-Y transcription factors.Oncogene. 2011; 30: 2282-2288Crossref PubMed Scopus (36) Google Scholar, 15Scian M.J. Carchman E.H. Mohanraj L. Stagliano K.E. Anderson M.A. Deb D. Crane B.M. Kiyono T. Windle B. Deb S.P. Deb S. Wild-type p53 and p73 negatively regulate expression of proliferation related genes.Oncogene. 2008; 27: 2583-2593Crossref PubMed Scopus (59) Google inactivation of p53 might increase the expression of CDC25B tumor The increased Cdc25B is then oncogenic that it cancer cell proliferation through checkpoint The might explain the function of Cdc25B during tumor With the role of Cdc25B in cell cycle increased CDC25B in and It is thus that response be induced in to to cell cycle progression. However, the response CDC25B overexpression to be in For example, overexpression of CDC25B was shown to increase after in cancer cells H. Y. H. K. H. Y. T. M. M. H. Weinstein I.B. M. of CDC25B G2-M and in increased in cancer Res. Google in cell overexpression of CDC25B to J. CDC25B and overexpression in cancer cell PubMed Scopus Google Scholar). in cancer cells that have the of CDC25B overexpression might on specific of cancer Thus, the role of Cdc25B on not be cancer cell In this we found that Cdc25B induced senescence in the of normal The is from the in cancer Thus, of normal fibroblasts could additional the of CDC25B during tumor of in normal fibroblasts was shown to induce senescence S. K. to 2008; 27: PubMed Scopus Google Scholar). This is senescence A is the induction of senescence by oncogenic in both human and normal fibroblasts M. Beach D. cell senescence associated with accumulation of p53 and 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). Although could be induced by various of p53 to be a mechanism to activation of the pathway G. The DNA damage pathway is a of 2007; PubMed Scopus Google Scholar). as an example, it was reported that overexpression and/or DNA to a p53-dependent H. K. T. T. induce senescence by the levels of Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, R. M. A. S. P. C. C. M G. A. R. senescence is a DNA damage response by DNA 2006; PubMed Scopus Google Scholar). Thus, the of p53 in senescence that a pathway might be However, we found increased Cdc25B not cell nor it Instead, we found that Cdc25B to p53 to and p53. evidence that the Cdc25B might on p53 to senescence pathway. We also that the was not identified in cells with increased Cdc25B. Thus, senescence induced by CDC25B overexpression is from The of p53 is regulated by pathway The of p53 and 2006; PubMed Scopus Google Scholar). the binding to specific p53 is and by the Phosphorylation also role in the of p53 of p53 Full Text Full Text PDF PubMed Scopus Google Scholar). For example, of at or was reported to target p53 to X. Phosphorylation on by of A role in cell Full Text Full Text PDF PubMed Scopus Google Scholar, D. R. X. P. B. C. p53 to by the J. PubMed Scopus Google Scholar, S. O. R. R. P. D. X. M. J. R. and protein are associated with the J. PubMed Scopus Google Scholar). the of at or p53 K. S. Y. S. Anderson E. of human p53 through a mediated by a on Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, T. O. A. S.Y. S. T. D. Y. of p53 on is p53 and in response to Biol. PubMed Scopus Google Scholar, of the accumulation and function of p53 by of the that to Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). In this we found that Cdc25B with p53 and the of several on p53. and p53 to be dephosphorylating p53 as of the to p53 to p53. Thus, our that binding of Cdc25B to p53 p53 and by the Cdc25B not to target specific of as of at decreased by Cdc25B. Thus, Cdc25B might from p53 It was reported that DNA damage induced the of and on p53 K. S. Y. S. Anderson E. of human p53 through a mediated by a on Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). Phosphorylation of then its with to by the pathway the p53-dependent checkpoint by p53 at Biol. PubMed Scopus Google Scholar). Thus, of by Cdc25B p53 However, it was also reported that of p53 was sufficient to induce nuclear of the protein and its with in the of DNA damage and not X. X. of p53 nuclear and cancer cells to DNA Sci. S. A. 2008; PubMed Scopus Google Scholar, Y. X. A in lung cancer the p53-dependent function of protein phosphatase PubMed Scopus Google Scholar). of was reported to be sufficient p53 D. R. X. P. B. C. p53 to by the J. PubMed Scopus Google Scholar). Thus, it is that at and/or might to p53 by Cdc25B. Although the of to p53 is unclear, it is that the effect of p53 to the of p53. 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