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)

Short-term exposure to okadaic acid (OA), a specific inhibitor of protein phosphatases 1 and 2A, induced resumption of meiosis, including metaphase spindle formation, in mouse oocytes treated with a phosphodiesterase inhibitor, while long incubations with OA arrested oocyte maturation at a step prior to spindle formation. To explore the basis for this difference, the overall patterns of protein synthesis and phosphorylation and the production of tissue-type plasminogen activator (tPA), the synthesis of which is induced after germinal vesicle breakdown (GVBD), were analyzed under various OA treatments. Short-term exposure to OA led to tPA production and did not greatly affect the maturation-associated changes in protein phosphorylation. By contrast, a long application of OA did not result in tPA production and induced more marked changes in protein phosphorylation. Microinjection into prophase oocytes of the product of the fission yeast gene p13suc1, known to inhibit p34cdc2 kinase activation and/or activity, prevented meiotic reinitiation. This effect was overcome by microinjection of OA, at concentrations higher than those required for induction of maturation in the absence of p13suc1. These observations suggest that inhibition of phosphatase 1 or 2A or both triggers meiotic resumption by acting at the same site or at a site proximal to the p13suc1-sensitive step of cdc2 kinase activation.
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PMID:Okadaic acid and p13suc1 modulate the reinitiation of meiosis in mouse oocytes. 133 41

Numerous investigators have studied the reproductive and genetic toxicity of caffeine. Caffeine has also been reported to retard meiotic progression and induce aneuploidy in hamster oocytes in vitro. However, the ability of caffeine to induce aneuploidy in mammalian oocytes in vivo has not been reported. The objective of this study was to test the hypothesis that chemical-induced perturbations during in vivo oocyte meiotic maturation (OM) predispose oocytes to chromosome missegregation. Caffeine inhibits cAMP phosphodiesterase, which is needed for dephosphorylating p34(cdc2) kinase and initiating OM. Following superovulation, a dose of 150 mg/kg caffeine was administered to Institute of Cancer Research (ICR) female mice at various times prior to metaphase I (MI). Ovulated oocytes were collected from the oviducts and processed for cytogenetic analysis. Statistical analyses of the frequencies of hyperploid, MI, diploid, premature centromere separation and single chromatids revealed nonsignificant (P > 0.05) differences between the controls and each of the caffeine groups. Structural chromosome aberrations were not found. Under our experimental conditions, we rejected the hypothesis and concluded that caffeine neither retarded the rate of OM nor increased the incidence of aneuploidy in mouse oocytes. The factors responsible for the different in vivo and in vitro responses require investigation.
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PMID:Cytogenetic effects of caffeine during in vivo mouse oocyte maturation. 867 64

The stimulation of thyroid cell proliferation by TSH through cAMP depends on permissive comitogenic factors, generally the insulin-like growth factors and insulin. In dog thyroid primary cultures, the use of the phosphodiesterase-resistant analog of cAMP (Bu)(2)cAMP instead of TSH allowed to unveil a potent comitogenic activity of carbamylcholine, which can substitute for insulin and was shown to mimic insulin action on cell cycle regulatory proteins. Like insulin, carbamylcholine induced the accumulation of cyclin D3 and overcame the repression by cAMP of this protein, which was shown 1) to be essential for cell cycle progression by means of microinjections of a neutralizing antibody; and 2) to be rate limiting for the cAMP-dependent assembly of cyclin D3-cdk4 complexes, their nuclear translocation and the phosphorylation of pRb. Relative to insulin, carbamylcholine offers the significant experimental advantage that its signaling cascades can be immediately deactivated by the muscarinic antagonist atropine. In the presence of carbamylcholine, the elimination of (Bu)(2)cAMP blocked within 2 h the entry of cells into DNA synthesis phase, but the addition of atropine still permitted the entry of cells in S phase. These data support our view that the progression in G1 phase stimulated by cAMP consists of at least two essential actions that are clearly dissociated: in a first stage, depending on the supportive activity of an agent that stimulates the required cyclin D3 accumulation, cAMP induces the assembly and nuclear translocation of cyclin D3-cdk4 complexes, and then cAMP can exert alone the last crucial control that determines the cell commitment toward DNA replication.
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PMID:Respective roles of carbamylcholine and cyclic adenosine monophosphate in their synergistic regulation of cell cycle in thyroid primary cultures. 1118 42

Large increases in cAMP concentration inside the cell are generally growth inhibitory for most cell lines of mesenchymal and epithelial origin. Moreover, recent data suggest a role of cAMP in survival of different cell types. Herein, the ability of forskolin (an adenylyl cyclase activator) and IBMX (3-isobutyl-1-methylxanthine) (a phosphodiesterase inhibitor) to modulate cell cycle progression and survival of human pancreatic cancer cells was evaluated. We showed that forskolin + IBMX inhibited serum-induced ERK activities, Rb hyperphosphorylation, Cdk2 activity, and p27(Kip1) downregulation and caused G1 arrest in MIA PaCa-2 cells. Furthermore, forskolin + IBMX protected pancreatic cells against apoptosis induced by prolonged inhibition of ERK activities by preventing Bcl-X(L) downregulation, activation of caspases 3, 6, 8, and 9, and PARP cleavage and by inducing Bad phosphorylation (ser112). Taken together, our data demonstrate for the first time that cAMP is an inhibitor of cell cycle progression and apoptosis in human pancreatic cancer cells.
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PMID:cAMP protection of pancreatic cancer cells against apoptosis induced by ERK inhibition. 1144 27

Proliferation of oligodendrocyte progenitor (OP) cells is a crucial process controlling myelination in the CNS. Previous studies demonstrated a correlation between OP proliferation rate and cyclin E/cyclin-dependent kinase-2 (cdk2) activity. To establish a causal link between cyclin E/cdk2 activity and OP proliferation, we selectively modulated cdk2 activity in vitro by transfection of cultured OP cells. Dominant-negative (Dn)-cdk2 overexpression inhibited mitogen-induced OP cell proliferation, whereas wild-type (wt)-cdk2 prevented cell cycle arrest caused by anti-mitotic signals. Dn-cdk2- or wt-cdk2-mediated regulation of G(1)/S transition, per se, did not influence initiation of OP differentiation. To study the function of cyclin E/cdk2 in OP cells during development in vivo, we analyzed cdk2 and cyclin E expression in cells acutely isolated from transgenic mice expressing the green fluorescent protein (GFP) under the control of the 2'-3'-cyclic nucleotide 3'-phosphodiesterase gene promoter. Both cyclin E/cdk2 protein levels and activity were decreased in GFP(+) oligodendrocyte lineage cells between postnatal days 4 and 30. Immunostaining of NG2(+)/GFP(+) OP cells in brain tissue sections showed a 90% decrease in overall cell proliferation and cdk2 expression between perinatal and adult cells. However, cdk2 expression within the proliferating (i.e., expressing the proliferating cell nuclear antigen) OP cell population was maintained throughout development. Our data indicate that: (1) cyclin E/cdk2 activity plays a pivotal function in OP cell cycle decisions occurring at G(1)/S checkpoint; (2) initiation of OP differentiation is independent of cyclinE/cdk2 checkpoint, and (3) intrinsic differences in cyclin E/cdk2 expression and activity may underlie the slowly proliferative state that characterizes so-called "quiescent" adult OP cells in vivo.
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PMID:Cyclin-dependent kinase-2 controls oligodendrocyte progenitor cell cycle progression and is downregulated in adult oligodendrocyte progenitors. 1235 29

Upregulation of the cAMP/protein kinase A (PKA) pathway has been shown to result in decreased proliferation, increased differentiation, and subsequent apoptosis of malignant glioma cells. Conventional cAMP analogs, however, are difficult to use in a clinical setting. Therefore, we investigated the effects of rolipram, a drug that has undergone clinical trials as an antidepressant and has also been proposed as a treatment for multiple sclerosis. Rolipram acts as a specific inhibitor of type IV phosphodiesterase (PDE4), leading to increased intracellular levels of cAMP. We report that the inhibition of PDE4 by rolipram results in the activation of the cAMP/PKA pathway, with potent stimulation of a reporter gene containing a cAMP-responsive element in its promoter region. Further, treatment of the human glioma cell line A-172 with rolipram results in increased expression of the cell cycle inhibitors p21(Cip1) and p27(KiP1), and decreased activity of cdk2, a cyclin-dependent kinase essential for cell cycle progression. As a result, the proliferation of A-172 cells is inhibited, with induction of a Gl block. Eventually, rolipram-treated A-172 cells undergo differentiation, which is followed by apoptotic cell death. As we observe this effect with other glioma cell cultures as well, our results suggest that rolipram could prove useful as a novel differentiating agent with both cytostatic and cytotoxic potential in the treatment of malignant gliomas.
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PMID:The type IV phosphodiesterase inhibitor rolipram induces expression of the cell cycle inhibitors p21(Cip1) and p27(Kip1), resulting in growth inhibition, increased differentiation, and subsequent apoptosis of malignant A-172 glioma cells. 1243 76

8-Chloro-cyclic AMP (8-Cl-cAMP) is known to be most effective in inducing growth inhibition and differentiation of a number of cancer cells. Also, its cellular metabolite, 8-Cl-adenosine was shown to induce growth inhibition in a variety of cell lines. However, the signaling mechanism that governs the effects of 8-Cl-cAMP and/or 8-Cl-adenosine is still uncertain and it is not even sure which of the two is the key molecule that induces growth inhibition. In this study using mouse fibroblast DT cells, it was found that adenosine kinase inhibitor and adenosine deaminase could reverse cellular growth inhibition induced by 8-Cl-cAMP and 8-Cl-adenosine. And 8-Cl-cAMP could not induce growth inhibition in the presence of phosphodiesterase (PDE) inhibitor, but 8-Cl-adenosine could. We also found that protein kinase C (PKC) inhibitor could restore this growth inhibition, and both the 8-Cl-cAMP and 8-Cl-adenosine could activate the enzymatic activity of PKC. Besides, after 8-Cl-cAMP and 8-Cl-adenosine treatment, cyclin B was down-regulated and a CDK inhibitor, p27 was up-regulated in a time-dependent manner. These results suggest that it is not 8-Cl-cAMP but 8-Cl-adenosine which induces growth inhibition, and 8-Cl-cAMP must be metabolized to exert this effect. Furthermore, there might exist signaling cascade such as PKC activation and cyclin B down-regulation after 8-Cl-cAMP and 8-Cl-adenosine treatment.
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PMID:8-Cl-cAMP and its metabolite, 8-Cl-adenosine induce growth inhibition in mouse fibroblast DT cells through the same pathways: protein kinase C activation and cyclin B down-regulation. 1533 62

Intrinsic abnormalities in transplanted eutopic endometrium are believed to contribute to the pathogenesis of pelvic endometriosis. Herein we investigated transcriptomic differences in human endometrial stromal fibroblasts (hESFs) from women with (hESF(endo)) vs. without (hESF(nonendo)) endometriosis, in response to activation of the protein kinase A (PKA) pathway with 8-bromoadenosine-cAMP (8-Br-cAMP). hESF(nonendo) (n = 4) and hESF(endo) (n = 4) were isolated from eutopic endometrium and treated +/- 0.5 mm 8-Br-cAMP for 96 h. Purified total RNA was subjected to microarray analysis using the whole-genome Gene 1.0 ST Affymetrix platform. A total of 691 genes were regulated in cAMP-treated hESF(nonendo) vs. 158 genes in hESF(endo), suggesting a blunted response to cAMP/PKA pathway activation in women with disease. Real-time PCR and ELISA validated the decreased expression of decidualization markers in hESF(endo) compared with hESF(nonendo). In the absence of disease, 8-Br-cAMP down-regulated progression through the cell cycle via a decrease in cyclin D1, cyclin-dependent kinase 6, and cell division cycle 2 and an increase in cyclin-dependent kinase inhibitor 1A. However, cell cycle components in hESF(endo) were not responsive to 8-Br-cAMP, resulting in persistence of a proliferative phenotype. hESF(endo) treated with 8-Br-cAMP exhibited altered expression of immune response, extracellular matrix, cytoskeleton, and apoptosis genes. Changes in phosphodiesterase expression and activity were not different among experimental groups. These data support that eutopic hESF(endo) with increased proliferative potential can seed the pelvic cavity via retrograde menstruation and promote establishment, survival, and proliferation of endometriosis lesions, independent of hydrolysis of cAMP and likely due to an inherent abnormality in the PKA pathway.
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PMID:The protein kinase A pathway-regulated transcriptome of endometrial stromal fibroblasts reveals compromised differentiation and persistent proliferative potential in endometriosis. 2006 8

Antidepressants increase adult hippocampal neurogenesis in animal models, but the underlying molecular mechanisms are unknown. In this study, we used human hippocampal progenitor cells to investigate the molecular pathways involved in the antidepressant-induced modulation of neurogenesis. Because our previous studies have shown that antidepressants regulate glucocorticoid receptor (GR) function, we specifically tested whether the GR may be involved in the effects of these drugs on neurogenesis. We found that treatment (for 3-10 days) with the antidepressant, sertraline, increased neuronal differentiation via a GR-dependent mechanism. Specifically, sertraline increased both immature, doublecortin (Dcx)-positive neuroblasts (+16%) and mature, microtubulin-associated protein-2 (MAP2)-positive neurons (+26%). This effect was abolished by the GR-antagonist, RU486. Interestingly, progenitor cell proliferation, as investigated by 5'-bromodeoxyuridine (BrdU) incorporation, was only increased when cells were co-treated with sertraline and the GR-agonist, dexamethasone, (+14%) an effect which was also abolished by RU486. Furthermore, the phosphodiesterase type 4 (PDE4)-inhibitor, rolipram, enhanced the effects of sertraline, whereas the protein kinase A (PKA)-inhibitor, H89, suppressed the effects of sertraline. Indeed, sertraline increased GR transactivation, modified GR phosphorylation and increased expression of the GR-regulated cyclin-dependent kinase-2 (CDK2) inhibitors, p27(Kip1) and p57(Kip2). In conclusion, our data suggest that the antidepressant, sertraline, increases human hippocampal neurogenesis via a GR-dependent mechanism that requires PKA signaling, GR phosphorylation and activation of a specific set of genes. Our data point toward an important role for the GR in the antidepressant-induced modulation of neurogenesis in humans.
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PMID:Antidepressants increase human hippocampal neurogenesis by activating the glucocorticoid receptor. 2148 29

Hepatocellular carcinoma (HCC) is the fifth common malignancy worldwide and the third leading cause of cancer-related death. Targeted therapies for HCC are being extensively developed with the limited success of sorafinib. In the present study, we investigated the potential antitumor activity of zardaverine, a dual-selective phosphodiesterase (PDE) 3/4 inhibitor in HCC cells both in vitro and in vivo. Although all zardaverine, PDE3 inhibitor trequinsin and PDE4 inhibitor rolipram increased intracellular cAMP levels through inhibiting PDE activity, only zardaverine significantly and selectively inhibited the proliferation of certain HCC cells, indicating that the antitumor activity of zardaverine is independent of PDE3/4 inhibition and intracellular cAMP levels. Further studies demonstrated that zardaverine induced G0/G1 phase cell cycle arrest of sensitive HCC cells through dysregulating cell cycle-associated proteins, including Cdk4, Cdk6, Cdk2, Cyclin A, Cyclin E, p21 and Rb. Notably, Rb expression was reversely related to the cell sensitivity to zardaverine. The present findings indicate that zardaverine may have potential as targeted therapies for some HCC, and the likely mechanism of action underlying its selective antitumor activity may be related to its regulation of Rb or Rb-associated signaling in cell cycles.
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PMID:Phosphodiesterase 3/4 inhibitor zardaverine exhibits potent and selective antitumor activity against hepatocellular carcinoma both in vitro and in vivo independently of phosphodiesterase inhibition. 2459 42


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