The Experts below are selected from a list of 21350436 Experts worldwide ranked by ideXlab platform
Bernard Ducommun - One of the best experts on this subject based on the ideXlab platform.
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cell cycle control by the cdc25 phosphatases
Anti-cancer Agents in Medicinal Chemistry, 2008Co-Authors: Bernadette Aressy, Bernard DucommunAbstract:: Cell division cycle 25 (CDC25) phosphatases are key actors in eukaryotic cell cycle control. They are responsible for the dephosphorylations that activate the cyclin-dependent kinases (CDK) at specific stages of the cell cycle. Human CDC25A, CDC25B and CDC25C are also central targets and regulators of the G2/M checkpoint mechanisms activated in response to DNA injury. The expression and activity of these enzymes is finely regulated by multiple mechanisms including post-translational modifications, interactions with regulatory partners, control of their intracellular localization, and cell cycle-regulated degradation. Altered expression of these phosphatases is associated with checkpoint bypass and genetic instability. Accordingly, increased expression of CDC25A and CDC25B is found in many high-grade tumors and is correlated with poor prognosis in human cancers. This review summarizes our current knowledge within this domain and discusses the data that support therapeutic strategies targeting CDC25 activity in the treatment of cancer.
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receptor based virtual ligand screening for the identification of novel cdc25 phosphatase inhibitors
Journal of Chemical Information and Modeling, 2008Co-Authors: Matthieu Montes, Mariepriscille Brun, Odile Mondesert, Marylorene Goddard, Maria A Miteva, Stephanie Kolb, Emmanuelle Braud, Christiane Garbay, Bernard Ducommun, Bruno O VilloutreixAbstract:CDC25 phosphatases play critical roles in cell cycle regulation and are attractive targets for anticancer therapies. Several small non-peptide molecules are known to inhibit CDC25, but many of them appear to form a covalent bond with the enzyme or act through oxidation of the thiolate group of the catalytic cysteine. Structure-based virtual ligand screening computations were performed with FRED, Surflex, and LigandFit, a compound collection of over 310 000 druglike molecules and the crystal structure of CDC25B in order to identify novel classes of ligands. In vitro experiments carried out on a selected list of 1500 molecules led to the discovery of 99 compounds able to inhibit CDC25B activity at 100 μM. Further docking computations were applied, allowing us to propose a binding mode for the most potent molecule (IC50 = 13 μM). Our best compounds represent promising new classes of CDC25 inhibitors that also exhibit antiproliferative properties.
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The when and wheres of CDC25 phosphatases.
Current Opinion in Cell Biology, 2006Co-Authors: Rose Boutros, Christine Dozier, Bernard DucommunAbstract:The CDC25 phosphatases are key regulators of normal cell division and the cell's response to DNA damage. Earlier studies suggested non-overlapping roles for each isoform during a specific cell cycle phase. However, recent data suggest that multiple CDC25 isoforms cooperate to regulate each cell cycle transition. For instance, although CDC25A was initially thought to exclusively regulate the G(1)-S transition, recent data demonstrate a significant role for CDC25A in the G(2)-M transition. Further evidence demonstrates that in addition to the ATM/ATR-CHK pathway, a p38-MAPKAP pathway is also involved in controlling CDC25 activity during G(2)/M checkpoint activation. Together with the fact that CDC25 overexpression is reported in many cancers, these data highlight the significance of developing specific CDC25 inhibitors for cancer therapy.
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inhibition of human tumor cell growth in vivo by an orally bioavailable inhibitor of cdc25 phosphatases
Molecular Cancer Therapeutics, 2005Co-Authors: Mariechristine Brezak, Odile Mondesert, Muriel Quaranta, Marieodile Contourgalcera, Olivier Lavergne, Philip G. Kasprzyk, P. Auvray, Gregoire Prevost, Bernard DucommunAbstract:Cell cycle regulators, such as the CDC25 phosphatases, are potential targets for the development of new anticancer drugs. Here we report the identification and the characterization of BN82685, a quinone-based CDC25 inhibitor that is active in vitro and in vivo . BN82685 inhibits recombinant CDC25A, B, and C phosphatases in vitro . It inhibits the growth of human tumor cell lines with an IC50 in the submicromolar range, independently of their resistance to chemotherapeutic agents. This inhibitory effect is irreversible on both the purified CDC25 enzyme in vitro and on tumor cell proliferation. The specificity of BN82685 towards the CDC25 phosphatases is shown by an increase in cyclin-dependent kinase 1 tyrosine 15 phosphorylation, by the reversion of the mitosis-inducing effect of CDC25B overexpression in HeLa cells, and by the lack of a growth inhibitory effect in an assay based on the use of a CDC25-independent fission yeast model. Finally, when administered p.o., BN82685 is shown to inhibit the growth of the human pancreatic tumor Mia PaCa-2 xenografted in athymic nude mice. BN82685 is therefore a promising new compound targeting CDC25, which confirms the interest of the inhibition of these enzymes as an anticancer therapeutic strategy.
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design synthesis and biological evaluation of novel naphthoquinone derivatives with cdc25 phosphatase inhibitory activity
Bioorganic & Medicinal Chemistry, 2005Co-Authors: Mariepriscille Brun, Delphine Angotti, Odile Mondesert, Muriel Quaranta, Matthieu Montes, Nohad Gresh, Maria A Miteva, Emmanuelle Braud, Bernard Ducommun, Christiane GarbayAbstract:CDC25 dual-specificity phosphatases are essential key regulators of eukaryotic cell cycle progression and the CDC25A and B isoforms are over-expressed in different tumors and related cancer cell lines. CDC25s are now considered to be interesting targets in the search for novel anticancer agents. We describe new compounds derived from vitamin K3 that inhibit CDC25B activity with IC50 values in the low micromolar range. These naphthoquinone derivatives also display antiproliferative activity on HeLa cells as expected for CDC25 inhibitors and inhibit cell growth in a clonogenic assay at submicromolar concentrations. They increase inhibitory tyrosine 15 phosphorylation of CDK and induce the cleavage of PARP, a hallmark of apoptosis.
Odile Mondesert - One of the best experts on this subject based on the ideXlab platform.
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receptor based virtual ligand screening for the identification of novel cdc25 phosphatase inhibitors
Journal of Chemical Information and Modeling, 2008Co-Authors: Matthieu Montes, Mariepriscille Brun, Odile Mondesert, Marylorene Goddard, Maria A Miteva, Stephanie Kolb, Emmanuelle Braud, Christiane Garbay, Bernard Ducommun, Bruno O VilloutreixAbstract:CDC25 phosphatases play critical roles in cell cycle regulation and are attractive targets for anticancer therapies. Several small non-peptide molecules are known to inhibit CDC25, but many of them appear to form a covalent bond with the enzyme or act through oxidation of the thiolate group of the catalytic cysteine. Structure-based virtual ligand screening computations were performed with FRED, Surflex, and LigandFit, a compound collection of over 310 000 druglike molecules and the crystal structure of CDC25B in order to identify novel classes of ligands. In vitro experiments carried out on a selected list of 1500 molecules led to the discovery of 99 compounds able to inhibit CDC25B activity at 100 μM. Further docking computations were applied, allowing us to propose a binding mode for the most potent molecule (IC50 = 13 μM). Our best compounds represent promising new classes of CDC25 inhibitors that also exhibit antiproliferative properties.
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inhibition of human tumor cell growth in vivo by an orally bioavailable inhibitor of cdc25 phosphatases
Molecular Cancer Therapeutics, 2005Co-Authors: Mariechristine Brezak, Odile Mondesert, Muriel Quaranta, Marieodile Contourgalcera, Olivier Lavergne, Philip G. Kasprzyk, P. Auvray, Gregoire Prevost, Bernard DucommunAbstract:Cell cycle regulators, such as the CDC25 phosphatases, are potential targets for the development of new anticancer drugs. Here we report the identification and the characterization of BN82685, a quinone-based CDC25 inhibitor that is active in vitro and in vivo . BN82685 inhibits recombinant CDC25A, B, and C phosphatases in vitro . It inhibits the growth of human tumor cell lines with an IC50 in the submicromolar range, independently of their resistance to chemotherapeutic agents. This inhibitory effect is irreversible on both the purified CDC25 enzyme in vitro and on tumor cell proliferation. The specificity of BN82685 towards the CDC25 phosphatases is shown by an increase in cyclin-dependent kinase 1 tyrosine 15 phosphorylation, by the reversion of the mitosis-inducing effect of CDC25B overexpression in HeLa cells, and by the lack of a growth inhibitory effect in an assay based on the use of a CDC25-independent fission yeast model. Finally, when administered p.o., BN82685 is shown to inhibit the growth of the human pancreatic tumor Mia PaCa-2 xenografted in athymic nude mice. BN82685 is therefore a promising new compound targeting CDC25, which confirms the interest of the inhibition of these enzymes as an anticancer therapeutic strategy.
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design synthesis and biological evaluation of novel naphthoquinone derivatives with cdc25 phosphatase inhibitory activity
Bioorganic & Medicinal Chemistry, 2005Co-Authors: Mariepriscille Brun, Delphine Angotti, Odile Mondesert, Muriel Quaranta, Matthieu Montes, Nohad Gresh, Maria A Miteva, Emmanuelle Braud, Bernard Ducommun, Christiane GarbayAbstract:CDC25 dual-specificity phosphatases are essential key regulators of eukaryotic cell cycle progression and the CDC25A and B isoforms are over-expressed in different tumors and related cancer cell lines. CDC25s are now considered to be interesting targets in the search for novel anticancer agents. We describe new compounds derived from vitamin K3 that inhibit CDC25B activity with IC50 values in the low micromolar range. These naphthoquinone derivatives also display antiproliferative activity on HeLa cells as expected for CDC25 inhibitors and inhibit cell growth in a clonogenic assay at submicromolar concentrations. They increase inhibitory tyrosine 15 phosphorylation of CDK and induce the cleavage of PARP, a hallmark of apoptosis.
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Ability of human CDC25B phosphatase splice variants to replace the function of the fission yeast Cdc25 cell cycle regulator.
FEMS Yeast Research, 2004Co-Authors: Matthieu Lemaire, Odile Mondesert, Béatrix Bugler, Bernard DucommunAbstract:CDC25 phosphatases are essential and evolutionary-conserved actors of the eukaryotic cell cycle control. To examine and compare the properties of three splicing variants of human CDC25B, recombinant fission yeast strains expressing the human proteins in place of the endogenous Cdc25 were generated and characterized. We report, that the three CDC25B variants: (i) efficiently replace the yeast counterpart in vegetative growth, (ii) partly restore the gamma and UV radiation DNA damage-activated checkpoint, (iii) fail to restore the DNA replication checkpoint activated by hydroxyurea. Although these yeast strains do not reveal the specific functions of the human CDC25B variants, they should provide useful screening tools for the identification of new cell cycle regulators and pharmacological inhibitors of CDC25 phosphatase.
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a novel synthetic inhibitor of cdc25 phosphatases bn82002
Cancer Research, 2004Co-Authors: Mariechristine Brezak, Odile Mondesert, Muriel Quaranta, Olivier Lavergne, Marieodile Galcera, Martine Cazales, Veronique Baldin, Christophe Thurieau, Frederic Alby, Jeremiath HarnettAbstract:CDC25 dual-specificity phosphatases are essential regulators that dephosphorylate and activate cyclin-dependent kinase/cyclin complexes at key transitions of the cell cycle. CDC25 activity is currently considered to be an interesting target for the development of new antiproliferative agents. Here we report the identification of a new CDC25 inhibitor and the characterization of its effects at the molecular and cellular levels, and in animal models. BN82002 inhibits the phosphatase activity of recombinant human CDC25A, B, and C in vitro . It impairs the proliferation of tumoral cell lines and increases cyclin-dependent kinase 1 inhibitory tyrosine phosphorylation. In synchronized HeLa cells, BN82002 delays cell cycle progression at G 1 -S, in S phase and at the G 2 -M transition. In contrast, BN82002 arrests U2OS cell cycle mostly in the G 1 phase. Selectivity of this inhibitor is demonstrated: ( a ) by the reversion of the mitotic-inducing effect observed in HeLa cells upon CDC25B overexpression; and ( b ) by the partial reversion of cell cycle arrest in U2OS expressing CDC25. We also show that BN82002 reduces growth rate of human tumor xenografts in athymic nude mice. BN82002 is a original CDC25 inhibitor that is active both in cell and animal models. This greatly reinforces the interest in CDC25 as an anticancer target.
Helen Piwnicaworms - One of the best experts on this subject based on the ideXlab platform.
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contributions made by cdc25 phosphatases to proliferation of intestinal epithelial stem and progenitor cells
PLOS ONE, 2011Co-Authors: Sofia Origanti, Lynn S White, Thaddeus S Stappenbeck, Helen PiwnicawormsAbstract:The CDC25 protein phosphatases drive cell cycle advancement by activating cyclin-dependent protein kinases (CDKs). Humans and mice encode three family members denoted CDC25A, -B and -C and genes encoding these family members can be disrupted individually with minimal phenotypic consequences in adult mice. However, adult mice globally deleted for all three phosphatases die within one week after Cdc25 disruption. A severe loss of absorptive villi due to a failure of crypt epithelial cells to proliferate was observed in the small intestines of these mice. Because the Cdc25s were globally deleted, the small intestinal phenotype and loss of animal viability could not be solely attributed to an intrinsic defect in the inability of small intestinal stem and progenitor cells to divide. Here, we report the consequences of deleting different combinations of Cdc25s specifically in intestinal epithelial cells. The phenotypes arising in these mice were then compared with those arising in mice globally deleted for the Cdc25s and in mice treated with irinotecan, a chemotherapeutic agent commonly used to treat colorectal cancer. We report that the phenotypes arising in mice globally deleted for the Cdc25s are due to the failure of small intestinal stem and progenitor cells to proliferate and that blocking cell division by inhibiting the cell cycle engine (through Cdc25 loss) versus by inducing DNA damage (via irinotecan) provokes a markedly different response of small intestinal epithelial cells. Finally, we demonstrate that CDC25A and CDC25B but not CDC25C compensate for each other to maintain the proliferative capacity of intestinal epithelial stem and progenitor cells.
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response of small intestinal epithelial cells to acute disruption of cell division through cdc25 deletion
Proceedings of the National Academy of Sciences of the United States of America, 2009Co-Authors: Lynn S White, Thaddeus S Stappenbeck, Kristen E Hurov, Helen PiwnicawormsAbstract:The CDC25 protein phosphatases (CDC25A, B, and C) drive cell cycle transitions by activating key components of the cell cycle engine. CDC25A and CDC25B are frequently overproduced in human cancers. Disruption of Cdc25B or CDC25C individually or in combination has no effect on mouse viability. Here we report that CDC25A is the only family member to provide an essential function during early embryonic development, and that other family members compensate for its loss in adult mice. In contrast, conditional disruption of the entire family is lethal in adults due to a loss of small intestinal epithelial cell proliferation in crypts of Lieberkuhn. Cdc25 loss induced Wnt signaling, and overall crypt structures were preserved. In the face of continuous Wnt signaling, nearly all crypt epithelial progenitors differentiated into multiple cell lineages, including crypt base columnar cells, a proposed stem cell. A small population of Musashi/Dcamkl-1/nuclear β-catenin–positive epithelial cells was retained in these crypts. These findings have implications for the development of novel, less cytotoxic cancer chemotherapeutic drugs that specifically target the cell cycle.
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normal cell cycle and checkpoint responses in mice and cells lacking cdc25b and CDC25C protein phosphatases
Molecular and Cellular Biology, 2005Co-Authors: Angela M Ferguson, Peter J Donovan, Lynn S White, Helen PiwnicawormsAbstract:The Cdc25 family of protein phosphatases positively regulates cell division by activating cyclin-dependent protein kinases (CDKs). In humans and rodents, there are three Cdc25 family members—denoted Cdc25A, Cdc25B, and CDC25C—that can be distinguished based on their subcellular compartmentalizations, their abundances and/or activities throughout the cell cycle, the CDKs that they target for activation, and whether they are overexpressed in human cancers. In addition, murine forms of Cdc25 exhibit distinct patterns of expression throughout development and in adult tissues. These properties suggest that individual Cdc25 family members contribute distinct biological functions in embryonic and adult cell cycles of mammals. Interestingly, mice with CDC25C disrupted are healthy, and cells derived from these mice exhibit normal cell cycles and checkpoint responses. Cdc25B−/− mice are also generally normal (although females are sterile), and cells derived from Cdc25B−/− mice have normal cell cycles. Here we report that mice lacking both Cdc25B and CDC25C are obtained at the expected Mendelian ratios, indicating that Cdc25B and CDC25C are not required for mouse development or mitotic entry. Furthermore, cell cycles, DNA damage responses, and Cdc25A regulation are normal in cells lacking Cdc25B and CDC25C. These findings indicate that Cdc25A, or possibly other phosphatases, is able to functionally compensate for the loss of Cdc25B and CDC25C in mice.
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arsenite induced CDC25C degradation is through the ken box and ubiquitin proteasome pathway
Proceedings of the National Academy of Sciences of the United States of America, 2002Co-Authors: Fei Chen, Helen Piwnicaworms, Zhuo Zhang, Jacquelyn J. Bower, Stephen S. Leonard, Min Ding, Vince Castranova, Xianglin ShiAbstract:Arsenite is a known human carcinogen that induces tumorigenesis through either a genotoxic or an epigenetic mechanism. In this study, the effect of arsenite on cell cycle regulation and the mechanisms that contribute to this effect were investigated. Treatment of the cells with arsenite suppressed cell proliferation and reduced cell viability in a dose- or time-dependent manner. Analysis of cell cycle profile and cell cycle regulatory proteins indicated that arsenite arrested the cell cycle at G2/M phase, partially through induction of cell division cycle 25 (Cdc25) isoform C (CDC25C) degradation via ubiquitin–proteasome pathways. Mutation of the putative KEN box within the region 151 to 157 of human CDC25C or treatment of the cells with a peptide competitor encompassing the KEN box partially inhibited arsenite-induced ubiquitination of CDC25C. Thus, these results indicate that the regulated ubiquitination of CDC25C may be involved in the arsenite-induced proteolytic down-regulation of CDC25C activity in the G2/M phase of the cell cycle and suggest a link between cell cycle and the carcinogenic effects of arsenite.
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the chk1 protein kinase and the CDC25C regulatory pathways are targets of the anticancer agent ucn 01
Journal of Biological Chemistry, 2000Co-Authors: Paul R Graves, Julie K Schwarz, Janis Gales, Edward A Sausville, Patrick M Oconnor, Helen PiwnicawormsAbstract:Abstract A checkpoint operating in the G2 phase of the cell cycle prevents entry into mitosis in the presence of DNA damage. UCN-01, a protein kinase inhibitor currently undergoing clinical trials for cancer treatment, abrogates G2 checkpoint function and sensitizes p53-defective cancer cells to DNA-damaging agents. In most species, the G2 checkpoint prevents the Cdc25 phosphatase from removing inhibitory phosphate groups from the mitosis-promoting kinase Cdc2. This is accomplished by maintaining Cdc25 in a phosphorylated form that binds 14-3-3 proteins. The checkpoint kinases, Chk1 and Cds1, are proposed to regulate the interactions between human CDC25C and 14-3-3 proteins by phosphorylating CDC25C on serine 216. 14-3-3 proteins, in turn, function to keep CDC25C out of the nucleus. Here we report that UCN-01 caused loss of both serine 216 phosphorylation and 14-3-3 binding to CDC25C in DNA-damaged cells. In addition, UCN-01 potently inhibited the ability of Chk1 to phosphorylate CDC25C in vitro. In contrast, Cds1 was refractory to inhibition by UCN-01in vitro, and Cds1 was still phosphorylated in irradiated cells treated with UCN-01. Thus, neither Cds1 nor kinases upstream of Cds1, such as ataxia telangiectasia-mutated, are targets of UCN-01 action in vivo. Taken together our results identify the Chk1 kinase and the CDC25C pathway as potential targets of G2 checkpoint abrogation by UCN-01.
Ingrid Hoffmann - One of the best experts on this subject based on the ideXlab platform.
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cdc25 phosphatases are required for timely assembly of cdk1 cyclin b at the g2 m transition
Journal of Biological Chemistry, 2010Co-Authors: Oleg Timofeev, Florian Settele, Tore Kempf, Onur Cizmecioglu, Ingrid HoffmannAbstract:Abstract Progression through mitosis requires the coordinated regulation of Cdk1 kinase activity. Activation of Cdk1 is a multistep process comprising binding of Cdk1 to cyclin B, relocation of cyclin-kinase complexes to the nucleus, activating phosphorylation of Cdk1 on Thr161 by the Cdk-activating kinase (CAK; Cdk7 in metazoans), and removal of inhibitory Thr14 and Tyr15 phosphorylations. This dephosphorylation is catalyzed by the dual specific Cdc25 phosphatases, which occur in three isoforms in mammalian cells, Cdc25A, -B, and -C. We find that expression of Cdc25A leads to an accelerated G2/M phase transition. In Cdc25A-overexpressing cells, Cdk1 exhibits high kinase activity despite being phosphorylated on Tyr15. In addition, Tyr15-phosphorylated Cdk1 binds more cyclin B in Cdc25A-overexpressing cells compared with control cells. Consistent with this observation, we demonstrate that in human transformed cells, Cdc25A and Cdc25B, but not CDC25C phosphatases have an effect on timing and efficiency of cyclin-kinase complex formation. Overexpression of Cdc25A or Cdc25B promotes earlier assembly and activation of Cdk1-cyclin B complexes, whereas repression of these phosphatases by short hairpin RNA has a reverse effect, leading to a substantial decrease in amounts of cyclin B-bound Cdk1 in G2 and mitosis. Importantly, we find that Cdc25A overexpression leads to an activation of Cdk7 and increase in Thr161 phosphorylation of Cdk1. In conclusion, our data suggest that complex assembly and dephosphorylation of Cdk1 at G2/M is tightly coupled and regulated by Cdc25 phosphatases.
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the oncogenic serine threonine kinase pim 1 directly phosphorylates and activates the g2 m specific phosphatase CDC25C
The International Journal of Biochemistry & Cell Biology, 2006Co-Authors: Malte Bachmann, Ingrid Hoffmann, Christian Kosan, Pei Xiang Xing, Mathias Montenarh, Tarik MöröyAbstract:The proto-oncogene Pim-1 encodes a serine-threonine kinase which is a downstream effector of cytokine signaling and can enhance cell cycle progression by altering the activity of several cell cycle regulators among them the G1 specific inhibitor p21(Waf), the phosphatase Cdc25A and the kinase C-TAK1. Here, we demonstrate by using biochemical assays that Pim-1 can interact with the phosphatase CDC25C and is able to directly phosphorylate the N-terminal region of the protein. CDC25C is functionally related to Cdc25A but acts specifically at the G2/M cell cycle transition point and can be inactivated by C-TAK1-mediated phosphorylation. Immuno-fluorescence experiments showed that Pim-1 and CDC25C co-localize in the cytoplasm of both epithelial and myeloid cells. We find that phosphorylation by Pim-1 enhances the phosphatase activity of CDC25C and in transfected cells that are arrested in G2/M by bleomycin, Pim-1 can enhance progression into G1. Therefore, we propose that Pim-1 activates CDC25C by a direct phosphorylation and can thereby assume the function of a positive cell cycle regulator at the G2/M transition.
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The oncogenic serine/threonine kinase Pim-1 directly phosphorylates and activates the G2/M specific phosphatase CDC25C.
The international journal of biochemistry & cell biology, 2005Co-Authors: Malte Bachmann, Ingrid Hoffmann, Christian Kosan, Pei Xiang Xing, Mathias Montenarh, Tarik MöröyAbstract:The proto-oncogene Pim-1 encodes a serine-threonine kinase which is a downstream effector of cytokine signaling and can enhance cell cycle progression by altering the activity of several cell cycle regulators among them the G1 specific inhibitor p21(Waf), the phosphatase Cdc25A and the kinase C-TAK1. Here, we demonstrate by using biochemical assays that Pim-1 can interact with the phosphatase CDC25C and is able to directly phosphorylate the N-terminal region of the protein. CDC25C is functionally related to Cdc25A but acts specifically at the G2/M cell cycle transition point and can be inactivated by C-TAK1-mediated phosphorylation. Immuno-fluorescence experiments showed that Pim-1 and CDC25C co-localize in the cytoplasm of both epithelial and myeloid cells. We find that phosphorylation by Pim-1 enhances the phosphatase activity of CDC25C and in transfected cells that are arrested in G2/M by bleomycin, Pim-1 can enhance progression into G1. Therefore, we propose that Pim-1 activates CDC25C by a direct phosphorylation and can thereby assume the function of a positive cell cycle regulator at the G2/M transition.
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The role of Cdc25 phosphatases in cell cycle checkpoints
Protoplasma, 2000Co-Authors: Ingrid HoffmannAbstract:The major driving forces in the eukaryotic cell cycle are the cyclin-dependent kinases (Cdk). Cdks can be activated through dephosphorylation of inhibitory phosphorylations catalyzed by the Cdc25 phosphatase family. In higher-eukaryotic cells, there exist three Cdc25 family members, Cdc25A, Cdc25B, and CDC25C. While Cdc25A plays a major role at the G1-to-S phase transition, Cdc25B and C are required for entry into mitosis. The regulation of CDC25C is crucial for the operation of the DNA-damage checkpoint. Two protein kinases, Chk1 and Cds1, can be activated in response to DNA damage or in the presence of unreplicated DNA. Chk1 and Cds1 may phosphorylate CDC25C to prevent entry into mitosis through inhibition of Cdc2 (Cdk1) dephosphorylation.
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cell cycle regulation by the cdc25 phosphatase family
Progress in cell cycle research, 2000Co-Authors: Ida Nilsson, Ingrid HoffmannAbstract:Activation of cyclin-dependent kinases in higher eukaryotic cells can be achieved through dephosphorylation by members of the Cdc25 phosphatase family, Cdc25A, Cdc25B and CDC25C. Cdc25A plays an important role at the G1/S-phase transition. Cdc25B undergoes activation during S-phase and plays a role in activating the mitotic kinase Cdkl/cyclin B in the cytoplasm. Active Cdkl/cyclin B then phosphorylates and activates CDC25C leading to a positive feedback mechanism and to entry into mitosis. Cdc25A and B are potential human oncogenes. In addition, Cdc25 is a main player of the G2 arrest caused by DNA damage or in the presence of unreplicated DNA.
Johannes Rudolph - One of the best experts on this subject based on the ideXlab platform.
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Redox regulation of the Cdc25 phosphatases.
Antioxidants & Redox Signaling, 2005Co-Authors: Johannes RudolphAbstract:The Cdc25 phosphatases are essential for cell-cycle control in eukaryotes under normal conditions and in response to DNA damage via checkpoint controls. Recent evidence indicates direct control of the Cdc25s, and therefore the cell cycle, in response to changes in cellular redox status. These redox changes may originate intracellularly from mitochondrial leakage or in response to specific external triggers leading to production of reactive oxygen species (ROS). This review shows that the known chemistry and biology of the Cdc25s favor a direct role for these phosphatases in temporarily blocking cell-cycle progression until favorable reducing conditions are restored. First, the Cdc25s contain a highly reactive cysteine at the active site that can react directly with ROS, leading to enzyme inactivation. Second, the ROS-inactivated form of Cdc25 is expected to prevent cell-cycle progression based on precedent from cellular responses to DNA damage. Third, ROS-mediated oxidation of the Cdc25s leads to an intra...
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cdc25 phosphatases and cancer
Chemistry & Biology, 2004Co-Authors: Kolbrun Kristjansdottir, Johannes RudolphAbstract:The Cdc25 phosphatases function as key regulators of the cell cycle during normal eukaryotic cell division and as mediators of the checkpoint response in cells with DNA damage. The role of Cdc25s in cancer has become increasingly evident in recent years. More than 20 studies of patient samples from diverse cancers show significant overexpression of Cdc25 with frequent correlation to clinical outcome. Recent screening and design efforts have yielded novel classes of inhibitors that show specificity for the Cdc25s over other phosphatases and cause cell cycle arrest in vivo. Herein we provide a single source for those interested in the cellular functions of Cdc25 in cell cycle progression, its role in the progress of cancer and survival of cancer patients, and recent efforts in the design of specific inhibitors.
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Catalytic and chemical competence of regulation of cdc25 phosphatase by oxidation/reduction.
Biochemistry, 2003Co-Authors: Jungsan Sohn, Johannes RudolphAbstract:Cdc25 phosphatases belong to the family of protein tyrosine phosphatases (PTPs) that contain an active-site cysteine and form a phosphocysteine intermediate. Recently, oxidation/reduction of active-site cysteines of PTPs, including Cdc25, has been proposed to serve as a form of reversible regulation for this class of enzymes. Here we provide in vitro evidence that supports the chemical and kinetic competence for oxidation/reduction of the active-site cysteines of Cdc25B and CDC25C as a mechanism of regulation. Using kinetic measurements and mass spectrometry, we have found that the active-site cysteines of the Cdc25's are highly susceptible to oxidation. The rate of thiolate conversion to the sulfenic acid by hydrogen peroxide for Cdc25B is 15-fold and 400-fold faster than that for the protein tyrosine phosphatase PTP1B and the cellular reductant glutathione, respectively. If not for the presence of an adjacent (back-door) cysteine in proximity to the active-site cysteine in the Cdc25's, the sulfenic acid...
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catalytic and chemical competence of regulation of cdc25 phosphatase by oxidation reduction
Biochemistry, 2003Co-Authors: Jungsan Sohn, Johannes RudolphAbstract:Cdc25 phosphatases belong to the family of protein tyrosine phosphatases (PTPs) that contain an active-site cysteine and form a phosphocysteine intermediate. Recently, oxidation/reduction of active-site cysteines of PTPs, including Cdc25, has been proposed to serve as a form of reversible regulation for this class of enzymes. Here we provide in vitro evidence that supports the chemical and kinetic competence for oxidation/reduction of the active-site cysteines of Cdc25B and CDC25C as a mechanism of regulation. Using kinetic measurements and mass spectrometry, we have found that the active-site cysteines of the Cdc25's are highly susceptible to oxidation. The rate of thiolate conversion to the sulfenic acid by hydrogen peroxide for Cdc25B is 15-fold and 400-fold faster than that for the protein tyrosine phosphatase PTP1B and the cellular reductant glutathione, respectively. If not for the presence of an adjacent (back-door) cysteine in proximity to the active-site cysteine in the Cdc25's, the sulfenic acid...
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inhibition of cdc25 phosphatases by indolyldihydroxyquinones
Journal of Medicinal Chemistry, 2003Co-Authors: Jungsan Sohn, Brendan Kiburz, Zhitao Li, Alexias Safi, Liu Deng-pan, Michael C. Pirrung, Johannes RudolphAbstract:Overexpression of the Cdc25A and Cdc25B dual-specificity phosphatases correlates with a wide variety of cancers, making the Cdc25s attractive drug targets for anticancer therapies. However, the search for good lead molecules has been hampered by the reactivity of the active site thiolate anion and the flat solvent-exposed active site region. We describe here the indolyldihydroxyquinones, a new class of inhibitors of Cdc25 that bind reversibly to the active site with submicromolar potency. Structure−activity relationships in the 50 derivatives of the lead molecule 2,5-dihydroxy-3-(1H-indol-3-yl)[1,4]benzoquinone show interesting and consistent trends identifying features required for inhibition of all three isoforms of Cdc25. The compounds do not show time-dependent inhibition, indicating that they form neither covalent adducts with nor oxidize the active site thiol. Our best compounds, 2,5-dihydroxy-3-(7-farnesyl-1H-indol-3-yl)[1,4]benzoquinone and 2,5-dihydroxy-3-(4,6-dichloro-7-farnesyl-1H-indol-3-yl)[1...