CDC25 Phosphatase Inhibitors: An Update

Lavecchia, Antonio; Giovanni, Carmen Di; Novellino, Ettore

doi:10.2174/138955712798868940

Cited by 76 publications

(69 citation statements)

References 69 publications

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“…Cyclin A binds and activates CDK2, and thus promotes both cell cycle G1/S and G2/M transitions (Lim and Kaldis, 2013). In addition, Cdc25 phosphatases are also central targets and regulators of the G2/M checkpoint mechanisms (Lavecchia et al, 2012). The present results showed that protein expression of cyclin A and Cdc25A were down-regulated after the treatment of luteolin, supporting the arrest of cell cycle progression at the G2/M phase.…”

Section: Discussionsupporting

confidence: 61%

“…The pathway, therefore, is gaining attention as a molecular target for CCA treatment strategies.governed by the cell cycle, which is an order of events that is tightly regulated by a number of serine/threonine protein kinases known as cyclin-dependent kinase (CDK) and cyclins (Lim and Kaldis, 2013). In addition, the cell division cycle 25 (Cdc25) phosphatases are also a family of proteins that are vital to cell cycle regulation (Lavecchia et al, 2012). Furthermore, cancer cells acquire alternations for enhanced survival and become apoptosis-resistant to anticancer therapies.…”

Section: Introductionmentioning

confidence: 99%

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Luteolin Arrests Cell Cycling, Induces Apoptosis and Inhibits the JAK/STAT3 Pathway in Human Cholangiocarcinoma Cells

Aneknan

Kukongviriyapan²,

Prawan³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Section: Discussionsupporting

confidence: 61%

Section: Introductionmentioning

confidence: 99%

Luteolin Arrests Cell Cycling, Induces Apoptosis and Inhibits the JAK/STAT3 Pathway in Human Cholangiocarcinoma Cells

Aneknan

Kukongviriyapan²,

Prawan³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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“…Cdc25 inhibitors have been pursued as promising chemotherapeutic agents that could block cell-cycle progression in cancerous cells, but these compounds have had only limited clinical success (Lavecchia et al 2012 Figure S3. Purified phosphatases.…”

Section: Discussionmentioning

confidence: 99%

Redundant Regulation of Cdk1 Tyrosine Dephosphorylation in Saccharomyces cerevisiae

et al. 2015

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Cdk1 activity drives both mitotic entry and the metaphase-to-anaphase transition in all eukaryotes. The kinase Wee1 and the phosphatase Cdc25 regulate the mitotic activity of Cdk1 by the reversible phosphorylation of a conserved tyrosine residue. Mutation of cdc25 in Schizosaccharomyces pombe blocks Cdk1 dephosphorylation and causes cell cycle arrest. In contrast, deletion of MIH1, the cdc25 homolog in Saccharomyces cerevisiae, is viable. Although Cdk1-Y19 phosphorylation is elevated during mitosis in mih1D cells, Cdk1 is dephosphorylated as cells progress into G 1 , suggesting that additional phosphatases regulate Cdk1 dephosphorylation. Here we show that the phosphatase Ptp1 also regulates Cdk1 dephosphorylation in vivo and can directly dephosphorylate Cdk1 in vitro. Using a novel in vivo phosphatase assay, we also show that PP2A bound to Rts1, the budding yeast B56-regulatory subunit, regulates dephosphorylation of Cdk1 independently of a function regulating Swe1, Mih1, or Ptp1, suggesting that PP2A Rts1 either directly dephosphorylates Cdk1-Y19 or regulates an unidentified phosphatase.KEYWORDS Cdc25/Mih1; Cdk1; PP2A; Wee1/Swe1; mitosis M ITOTIC onset is regulated in all eukaryotes by an increase in Cdk1 activity caused by the dephosphorylation of Cdk1 on a conserved inhibitory tyrosine (tyrosine 19 in budding yeast) (Nurse 1990). The Wee1 kinase phosphorylates and inhibits Cdk1 (Gould and Nurse 1989; Parker et al. 1992), and the Cdc25 phosphatase acts as a mitotic inducer by dephosphorylating and activating Cdk1 (Dunphy and Kumagai 1991;Gautier et al. 1991). wee1 mutants in fission yeast shorten G 2 by prematurely activating Cdk1 (Nurse 1975;Russell and Nurse 1987), whereas cdc25 mutants cannot accumulate sufficient Cdk1 activity to enter mitosis and arrest (Russell and Nurse 1986). Both Wee1 and Cdc25 are the targets of numerous cell-cycle checkpoints, all of which delay mitotic entry by activating Wee1 or inhibiting Cdc25 (Kellogg 2003). In budding yeast, Swe1 (the Wee1 homolog) and Mih1 (the Cdc25 homolog) also function prior to mitosis (Russell et al. 1989;Harvey and Kellogg 2003;Pal et al. 2008), but our recent work revealed that overexpression of Swe1 or activation of a Swe1-dependent checkpoint arrests cells in metaphase .Deletion of cdc25 in fission yeast is lethal and arrests cells in G 2 , indicating the essential role of Cdk1-Y15 dephosphorylation in fission yeast (Russell and Nurse 1986). In contrast, although deletion of MIH1 exhibits high Cdk1-Y19 phosphorylation during mitosis, these cells have only mild delays in mitotic entry and anaphase onset and initiate Cdk1-Y19 dephosphorylation at anaphase onset (Russell et al. 1989;Pal et al. 2008;. This behavior argues that at least one additional phosphatase functions redundantly with Mih1.Russell and colleagues (Millar et al. 1992) identified the fission yeast Pyp3 as a phosphatase that functions redundantly with Cdc25. Increased expression of pyp3 or the budding yeast and mammalian homologs PTP1, PTP1B and TC-PTP1, respectively, suppress...

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“…Of note, the group of genes expressed Ag independently by OT1 but not AND T cells include cell cycle-associated Cdc25b, Cdc26, Cdc34, and Cdc37. Both Cdc25 and Cdc34 are regulators of proliferation for which specific inhibitors have identified that block cell cycle progression of tumor cells (57,58). Tbx21 encoding T-bet, the transcription factor regulating CTL differentiation, also falls into this category (Fig.…”

Section: Gene Expression Following Transient and Persistent Stimulationmentioning

confidence: 99%

Differential Kinetics of Antigen Dependency of CD4+ and CD8+ T Cells

Rabenstein

Ellwart

et al. 2014

The Journal of Immunology

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Ag recognition via the TCR is necessary for the expansion of specific T cells that then contribute to adaptive immunity as effector and memory cells. Because CD4+ and CD8+ T cells differ in terms of their priming APCs and MHC ligands we compared their requirements of Ag persistence during their expansion phase side by side. Proliferation and effector differentiation of TCR transgenic and polyclonal mouse T cells were thus analyzed after transient and continuous TCR signals. Following equally strong stimulation, CD4+ T cell proliferation depended on prolonged Ag presence, whereas CD8+ T cells were able to divide and differentiate into effector cells despite discontinued Ag presentation. CD4+ T cell proliferation was neither affected by Th lineage or memory differentiation nor blocked by coinhibitory signals or missing inflammatory stimuli. Continued CD8+ T cell proliferation was truly independent of self-peptide/MHC-derived signals. The subset divergence was also illustrated by surprisingly broad transcriptional differences supporting a stronger propensity of CD8+ T cells to programmed expansion. These T cell data indicate an intrinsic difference between CD4+ and CD8+ T cells regarding the processing of TCR signals for proliferation. We also found that the presentation of a MHC class II–restricted peptide is more efficiently prolonged by dendritic cell activation in vivo than a class I bound one. In summary, our data demonstrate that CD4+ T cells require continuous stimulation for clonal expansion, whereas CD8+ T cells can divide following a much shorter TCR signal.

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CDC25 Phosphatase Inhibitors: An Update

Cited by 76 publications

References 69 publications

Luteolin Arrests Cell Cycling, Induces Apoptosis and Inhibits the JAK/STAT3 Pathway in Human Cholangiocarcinoma Cells

Luteolin Arrests Cell Cycling, Induces Apoptosis and Inhibits the JAK/STAT3 Pathway in Human Cholangiocarcinoma Cells

Redundant Regulation of Cdk1 Tyrosine Dephosphorylation in Saccharomyces cerevisiae

Differential Kinetics of Antigen Dependency of CD4+ and CD8+ T Cells

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