Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.22 (cdc2)
 8,319 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two previously unidentified human cdc25 genes have been isolated, cdc25A and cdc25B. Both genes rescue a cdc25ts mutant of fission yeast. Microinjection of anti-cdc25A antibodies into HeLa cells causes their arrest in mitosis. cdc25A and cdc25B display endogenous tyrosine phosphatase activity that is stimulated several-fold, in the absence of cdc2, by stoichiometric addition of either cyclin B1 or B2 but not A or D1. Association between cdc25A and cyclin B1/cdc2 was detected in the HeLa cells. These findings indicate that B-type cyclins are multifunctional proteins that not only act as M phase regulatory subunits of the cdc2 protein kinase, but also activate the cdc25 tyrosine phosphatase, of which cdc2 is the physiological substrate. A region of amino acid similarity between cyclins and tyrosine PTPases has been detected. This region is absent in cdc25 phosphatases. The motif may represent an activating domain that has to be provided to cdc25 by intermolecular interaction with cyclin B.
 ...
PMID:Specific activation of cdc25 tyrosine phosphatases by B-type cyclins: evidence for multiple roles of mitotic cyclins. 183 78

The cdc25+ tyrosine phosphatase is a key mitotic inducer of the fission yeast Schizosaccharomyces pombe, controlling the timing of the initiation of mitosis. Mammals contain at least three cdc25+ homologues called cdc25A, cdc25B and cdc25C. In this study we investigate the biological function of cdc25A. Although very potent in rescuing the S.pombe cdc25 mutant, cdc25A is less structurally related to the S.pombe enzyme. Northern and Western blotting detection reveals that unlike cdc25B, cdc25C and cdc2, cdc25A is predominantly expressed in late G1. Moreover, immunodepletion of cdc25A in rat cells by microinjection of a specific antibody effectively blocks their cell cycle progression from G1 into the S phase, as determined by laser scanning single cell cytometry. These results indicate that cdc25A is not a mitotic regulator but a novel phosphatase that plays a crucial role in the start of the cell cycle. In view of its strong ability to activate cdc2 kinase and its specific expression in late G1, cdc2-related kinases functioning early in the cell cycle may be targets for this phosphatase.
 ...
PMID:Cdc25A is a novel phosphatase functioning early in the cell cycle. 815 93

The formation of the mitotic spindle is an essential prerequisite for successful mitosis. The dramatic changes in the level of microtubule (Mt) nucleation at the centrosomes and Mt dynamics that occur in prophase are presumed to be initiated through the activity of cdc2/cyclin B. Here we present data that the cdc25B isoform functions to activate the cytoplasmic pool of cdc2/cyclin B responsible for these events. In contrast to cdc25C, cdc25B is present at low levels in HeLa cells during interphase, but sharply increases in prophase, when cdc25B accumulation in the cytoplasm correlates with prophase spindle formation. Overexpression of wild type and dominant negative mutants of cdc25B and cdc25C shows that prophase Mt nucleation is a consequence of cytoplasmic cdc25B activity, and that cdc25C regulates nuclear G2/M events. Our data also suggest that the functional status of the centrosome can regulate nuclear mitotic events.
 ...
PMID:Cytoplasmic accumulation of cdc25B phosphatase in mitosis triggers centrosomal microtubule nucleation in HeLa cells. 874 55

The role of protein kinase C (PKC) in vascular endothelial cell proliferation was investigated using human umbilical vein endothelial cells released from the G1/S border. Phorbol 12-myristate 13-acetate (PMA) caused G2 arrest because 1) when added to G2 cells, PMA inhibited subsequent cell division; 2) these growth-arrested cells did not show morphological features of mitotic cells; and 3) PMA did not interrupt mitosis in cells released from nocodazole-induced M phase arrest. 1-Oleoyl-2-acetyl-sn-glycerol (OAG) added repeatedly from G2 also inhibited mitosis. The activation of cdc2 kinase around the G2/M transition was suppressed by PMA and OAG. Although cdc2 was expressed in the presence of PMA, dephosphorylation of its tyrosine residue was inhibited by PMA. In parallel, the expression of cdc25B was suppressed by PMA. The total and the cdc2-associated amount of cyclin B were both reduced by PMA. These data suggested that the PKC pathway negatively regulates the G2/M transition and that the inhibition of cdc2 kinase by the reduction in the levels of cdc25B and cyclin B may contribute to this effect.
 ...
PMID:Cell cycle arrest in the G2 phase induced by phorbol ester and diacylglycerol in vascular endothelial cells. 877 42

Endomitosis (polyploidization) is a distinctive feature of megakaryocyte differentiation. We examined this mechanism in an erythromegakaryocytic cell line, HEL, using a protein kinase inhibitor K252a or a phorbol-ester TPA. HEL cells treated with K252a showed a marked increase in the proportion of CD41 positive cells and polyploid cells as well as in cellular size and nuclear size. TPA showed similar results but induced multi-nucleation instead of enlargement of nuclear size. K252a added at the G1/S boundary phase did not inhibit the first and second round DNA synthesis, but inhibited cell division. K252a did not inhibit the expression of genes involved in mitosis such as cyclin B, cdc25B and cdc2, in the first round S phase. However, the cyclin B associated Cdc2 kinase activity needed for mitosis during the G2/M phase was reduced by K252a. TPA delayed DNA synthesis and expression of these genes, and suppressed Cdc2 kinase activity in the second round G2/M phase. These results suggest that the polyploidization induced by K252a results from inhibiting mitosis possibly caused by suppression of Cdc2 kinase activity. TPA may induce the multi-nucleation through a different mechanism.
 ...
PMID:Induction of polyploidization in the human erythroleukemia cell line (HEL) by protein kinase inhibitor (K252a) and the phorbol-ester TPA. 916 44

In response to low doses of ultraviolet (U.V.) radiation, cells undergo a G2 delay. In this study we have shown that the G2 delay results in the accumulation of inactive forms of cyclin B1/cdc2 and both the G2 and mitotic complexes of cyclin A/cdk. This appears to be through a block in the cdc25-dependent activation of these complexes. The expression and localisation of cyclin A and cyclin B1/cdk complexes are similar in U.V.-induced G2 delay and normal early G2 phase cells. Cdc25B and cdc25C also accumulate to normal G2 levels in U.V. irradiated cells, but the mitotic phosphorylation associated with increased activity of both cdc25B and cdc25C is absent. The cdc25B accumulates in the nucleus of U.V. irradiated cells and in normal G2 phase cells. Thus the block in cyclin B/cdc2 activation is in part due to the physical separation of cyclin B/cdc2, localised in the cytoplasm, from the cdc25B and cdc25C phosphatases localised in the nucleus. The data positions the U.V.-induced G2 checkpoint at either the S/G2 transition or early G2 phase, prior to the activation of cyclin A/cdk2.
 ...
PMID:Ultraviolet light-induced G2 phase cell cycle checkpoint blocks cdc25-dependent progression into mitosis. 926 61

Cdc25 regulates entry into mitosis by regulating the activation of cyclin B/cdc2. In humans, at least two cdc25 isoforms have roles in controlling the G2/M transition. Here we show, using bacterially expressed recombinant proteins, that two cdc25B splice variants, cdc25B2 and cdc25B3, are capable of activating cyclin A/cdk2 and cyclin B/cdc2, but that mitotic hyperphosphorylation of these proteins increases their activity toward only cyclin B1/cdc2. Cdc25C has only very low activity in its unphosphorylated form, and following hyperphosphorylation it will efficiently catalyze the activation of only cyclin B/cdc2. This was reflected by the in vivo activity of the immunoprecipitated cdc25B and cdc25C from interphase and mitotic HeLa cells. The increased activity of the hyperphosphorylated cdc25s toward cyclin B1/cdc2 was in large part due to increased binding of this substrate. The substrate specificity, activities, and timing of the hyperphosphorylation of cdc25B and cdc25C during G2 and M suggest that these two mitotic cdc25 isoforms are activated by different kinases and perform different functions during progression through G2 into mitosis.
 ...
PMID:Hyperphosphorylation of the N-terminal domain of Cdc25 regulates activity toward cyclin B1/Cdc2 but not cyclin A/Cdk2. 935 26

Cdc25 phosphatases play key roles in cell cycle progression by activating cyclin-dependent kinases. In human cells, cdc25 proteins are encoded by a multigene family, consisting of cdc25A, cdc25B and cdc25C. While cdc25A plays a crucial role at the G1/S phase transition, cdc25C is involved in the dephosphorylation and activation of the mitotic kinase, cdc2/cyclinB. In addition, cdc25C itself is regulated by cdc2/cyclinB which then creates a positive feedback loop that controls entry into mitosis. In this study we show that the activity of cdc25B appears during late S phase and peaks during G2 phase. Both in vitro and in vivo cdc25B is activated through phosphorylation during S-phase. Using a cell duplication, microinjection assay we show that ablation of cdc25B function by specific antibodies blocks cell cycle progression in Hs68 cells by inhibition of entry into mitosis. Cdc25B function neither plays a role in later stages of mitosis nor for the inititation of DNA replication. These results indicate that cdc25B is a mitotic regulator that might act as a 'starter phosphatase' to initiate the positive feedback loop at the entry into M phase.
 ...
PMID:The cdc25B phosphatase is essential for the G2/M phase transition in human cells. 968 38

The bovine papillomavirus E2 protein can inhibit the proliferation of HT-3 cells, a p53-negative cervical carcinoma cell line containing integrated human papillomavirus type 30 DNA. Here, we analyzed HT-3 cells to explore the mechanism of p53-independent E2-mediated growth inhibition. Expression of the E2 protein repressed expression of the endogenous human papillomavirus type 30 E6/E7 genes. This was accompanied by hypophosphorylation and increased accumulation of p105Rb and repression of E2F1 expression. The E2 protein also caused reduced cyclin-dependent kinase (cdk) 2 activity, but this did not appear to be due to increased expression of cdk inhibitors. Rather, expression of cyclin A, which regulates cdk2 activity, and the cdc25A and cdc25B phosphatases, which are thought to activate cdk2, was significantly reduced at both the RNA and protein levels in response to E2 expression. The E2 protein reduced expression of cdc25A and cdc25B in both HT-3 and HeLa cells, but not in cells that were not growth-inhibited by the E2 protein. E2 point mutants unable to inhibit cell growth did not repress cdc25A and cdc25B expression, nor did the cell cycle inhibitors hydroxyurea and mimosine. Based on these results and the known properties of cell cycle components, we propose a model to account for E2-induced growth inhibition of cervical carcinoma cell lines.
 ...
PMID:Bovine papillomavirus E2 protein activates a complex growth-inhibitory program in p53-negative HT-3 cervical carcinoma cells that includes repression of cyclin A and cdc25A phosphatase genes and accumulation of hypophosphorylated retinoblastoma protein. 1039 3

Glutathione S-transferase (GST)-cdc25B(31-566) induced germinal vesicle breakdown (GVBD) when microinjected into Xenopus oocytes. Purified, N-terminally truncated forms of cdc25B did not induce GVBD, even though many had phosphatase activity and activated cdc2 in vitro. N-terminally truncated forms of cdc25B inhibited induction of GVBD by longer forms of the enzyme suggesting a direct interaction in vivo. cdc25B(356-556), but not cdc25B(364-529), inhibited GVBD induction by GST-cdc25B(31-566) suggesting that a region of cdc25B near to the C-terminus was responsible for the inhibition. To determine the region of peptide sequence that was inhibitory, cdc25B(356-556) was subjected to proteolysis with endoproteinase lys-C. Following a demonstration that the resulting peptide mixture inhibited GST-cdc25B-dependent GVBD, a series of peptides spanning amino acids at the C-terminus were synthesized. The peptide TRSWAGERSR inhibited GVBD induced by GST-cdc25B. An alanine scan of the peptide revealed residues critical for GVBD inhibition, and site-directed mutagenesis of the corresponding residues in GST-cdc25B(31-566) eliminated its ability to induce GVBD. These results demonstrate that a cdc25B C-terminal domain, involved in dominant-negative inhibition of GVBD-competent cdc25B, is required for induction of GVBD following microinjection into oocytes.
 ...
PMID:Identification of a C-terminal cdc25 sequence required for promotion of germinal vesicle breakdown. 1076 67


1 2 3 Next >>