Human Cdc25 A inactivation in response to S phase inhibition and its role in preventing premature mitosis

The Cdc25 A phosphatase is required for the G1–S transition of the cell cycle and is overexpressed in human cancers. We found that it is ubiquitylated and rapidly degraded by the proteasome and that its levels increase from G1 until mitosis. By treating cells with the DNA synthesis inhibitor hydroxyurea, Cdc25 A rapidly decreased in abundance, and this was accompanied by an increase in Cdk2 phosphotyrosine content and a decrease in Cdk2 kinase activity. Cdc25 A overexpression altered the ability of cells to arrest in the presence of hydroxyurea, and caused them to undergo premature chromosome condensation. Cdc25 A overexpression could render tumor cells less sensitive to DNA replication checkpoints, thereby contributing to their genomic instability.

[1]  I. Hoffmann,et al.  Ectopic Expression of Cdc25A Accelerates the G1/S Transition and Leads to Premature Activation of Cyclin E- and Cyclin A-Dependent Kinases , 1999, Molecular and Cellular Biology.

[2]  K. Helin,et al.  CDC25A Phosphatase Is a Target of E2F and Is Required for Efficient E2F-Induced S Phase , 1999, Molecular and Cellular Biology.

[3]  Ingrid Hoffmann,et al.  Cdc25b and Cdc25c Differ Markedly in Their Properties as Initiators of Mitosis , 1999, The Journal of cell biology.

[4]  S. Carr,et al.  Mammalian Chk2 is a downstream effector of the ATM-dependent DNA damage checkpoint pathway , 1999, Oncogene.

[5]  A. Kumagai,et al.  Binding of 14-3-3 proteins and nuclear export control the intracellular localization of the mitotic inducer Cdc25. , 1999, Genes & development.

[6]  C. Cans,et al.  Use of CDC2 from etoposide-treated cells as substrate to assay CDC25 phosphatase activity. , 1999, Anticancer research.

[7]  T. Maniatis,et al.  A ubiquitin ligase complex essential for the NF-kappaB, Wnt/Wingless, and Hedgehog signaling pathways. , 1999, Genes & development.

[8]  M. Roussel,et al.  A rate limiting function of cdc25A for S phase entry inversely correlates with tyrosine dephosphorylation of Cdk2 , 1999, Oncogene.

[9]  P. Russell,et al.  Nuclear localization of Cdc25 is regulated by DNA damage and a 14-3-3 protein , 1999, Nature.

[10]  M. Roussel,et al.  Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization. , 1998, Genes & development.

[11]  J. Diffley,et al.  A Mec1- and Rad53-dependent checkpoint controls late-firing origins of DNA replication , 1998, Nature.

[12]  K. Shirahige,et al.  Regulation of DNA-replication origins during cell-cycle progression , 1998, Nature.

[13]  L. Mao,et al.  Overexpression of cdc25A and cdc25B is frequent in primary non-small cell lung cancer but is not associated with overexpression of c-myc. , 1998, Cancer research.

[14]  A. Nepveu,et al.  The mammalian Cut homeodomain protein functions as a cell‐cycle‐dependent transcriptional repressor which downmodulates p21WAF1/CIP1/SDI1 in S phase , 1998, The EMBO journal.

[15]  W. Ansorge,et al.  The cdc25B phosphatase is essential for the G2/M phase transition in human cells. , 1998, Journal of cell science.

[16]  N. Nomura,et al.  UBPY: a growth‐regulated human ubiquitin isopeptidase , 1998, The EMBO journal.

[17]  T. Moyana,et al.  Elevated expression of the cdc25A protein phosphatase in colon cancer. , 1998, Experimental cell research.

[18]  E. Montserrat,et al.  cdc25 cell cycle-activating phosphatases and c-myc expression in human non-Hodgkin's lymphomas. , 1998, Cancer Research.

[19]  C. Cans,et al.  Phosphorylation of Human CDC25B Phosphatase by CDK1-Cyclin A Triggers Its Proteasome-dependent Degradation* , 1997, The Journal of Biological Chemistry.

[20]  H. Yokozaki,et al.  Overexpression of Cyclin‐dependent Kinase‐activating CDC25B Phosphatase in Human Gastric Carcinomas , 1997, Japanese journal of cancer research : Gann.

[21]  R. Maestro,et al.  Overexpression of CDC25A and CDC25B in head and neck cancers. , 1997, Cancer research.

[22]  J. Massagué,et al.  Repression of the CDK activator Cdc25A and cell-cycle arrest by cytokine TGF-β in cells lacking the CDK inhibitor p15 , 1997, Nature.

[23]  G. Draetta,et al.  Cdc25 protein phosphatases in cell proliferation. , 1997, Biochimica et biophysica acta.

[24]  D. Beach,et al.  Cdc25 cell-cycle phosphatase as a target of c-myc , 1996, Nature.

[25]  N. Hayward,et al.  Cytoplasmic accumulation of cdc25B phosphatase in mitosis triggers centrosomal microtubule nucleation in HeLa cells. , 1996, Journal of cell science.

[26]  D. Beach,et al.  Pub1 acts as an E6‐AP‐like protein ubiquitiin ligase in the degradation of cdc25. , 1996, The EMBO journal.

[27]  M. Loda,et al.  CDC25 phosphatases as potential human oncogenes. , 1995, Science.

[28]  L. Hartwell,et al.  A checkpoint regulates the rate of progression through S phase in S. cerevisiae in Response to DNA damage , 1995, Cell.

[29]  M. Tatsuka,et al.  Requirement for tyrosine phosphorylation of Cdk4 in Gl arrest induced by ultraviolet irradiation , 1995, Nature.

[30]  L. Staszewski,et al.  Ubiquitin-dependent c-Jun degradation in vivo is mediated by the δ domain , 1994, Cell.

[31]  E. Karsenti,et al.  Activation of the phosphatase activity of human cdc25A by a cdk2‐cyclin E dependent phosphorylation at the G1/S transition. , 1994, The EMBO journal.

[32]  H Nojima,et al.  Cdc25A is a novel phosphatase functioning early in the cell cycle. , 1994, The EMBO journal.

[33]  F. McKeon,et al.  Human wee1 maintains mitotic timing by protecting the nucleus from cytoplasmically activated cdc2 kinase , 1993, Cell.

[34]  D O Morgan,et al.  Cell cycle regulation of CDK2 activity by phosphorylation of Thr160 and Tyr15. , 1992, The EMBO journal.

[35]  J. Yarbro.  Mechanism of action of hydroxyurea. , 1992, Seminars in oncology.

[36]  R. Pepperkok,et al.  Cyclin A is required at two points in the human cell cycle. , 1992, The EMBO journal.

[37]  R. Hay,et al.  Recognition of the adenovirus type 2 origin of DNA replication by the virally encoded DNA polymerase and preterminal proteins. , 1992, The EMBO journal.

[38]  D. Beach,et al.  Specific activation of cdc25 tyrosine phosphatases by B-type cyclins: Evidence for multiple roles of mitotic cyclins , 1991, Cell.

[39]  K. Sadhu,et al.  p55CDC25 is a nuclear protein required for the initiation of mitosis in human cells. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[40]  A Nagata,et al.  An additional homolog of the fission yeast cdc25+ gene occurs in humans and is highly expressed in some cancer cells. , 1991, The New biologist.

[41]  K. Sadhu,et al.  Human homolog of fission yeast cdc25 mitotic inducer is predominantly expressed in G2. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[42]  P. Reichard,et al.  Inhibition of ribonucleoside diphosphate reductase by hydroxyurea. , 1968, Cancer research.

[43]  J. Bennett,et al.  Myelodysplastic syndromes: introduction. , 2001 .