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)

Some hepatitis C virus (HCV) proteins, including core protein, deregulate the cell cycle of infected cells, thereby playing an important role in the viral pathogenesis of HCC. Thus far, there are only few studies that have deeply investigated in depth the effects of the HCV core protein expression on the progression through the G1/S and G2/M phases of the cell cycle. To shed light on the molecular mechanisms by which the HCV core protein modulates cell proliferation, we have examined its effects on cell cycle in hepatocarcinoma cells. We show here that HCV core protein perturbs progression through both the G1/S and the G2/M phases, by modulating the expression and the activity of several cell cycle regulatory proteins. In particular, our data provided evidence that core-dependent deregulation of the G1/S phase and its related cyclin-CDK complexes depends upon the ERK1/2 pathway. On the other hand, the viral protein also increases the activity of the cyclin B1-CDK1 complex via the p38 MAPK and JNK pathways. Moreover, we show that HCV core protein promotes nuclear import of cyclin B1, which is affected by the inhibition of both the p38 and the RNA-dependent protein kinase (PKR) activities. The important role of p38 MAPK in regulating G2/M phase transition has been previously documented. It is becoming clear that PKR has an important role in regulating both the G1/S and the G2/M phase, in which it induces M phase arrest. Based on our model, we now show, for the first time, that HCV core expression leads to deregulation of the mitotic checkpoint via a p38/PKR-dependent pathway.
 ...
PMID:Role of p38 MAPK and RNA-dependent protein kinase (PKR) in hepatitis C virus core-dependent nuclear delocalization of cyclin B1. 1644 63

This study examined the effect of dopamine on DNA synthesis and its related signal cascades in mouse embryonic stem (ES) cells. Dopamine inhibited DNA synthesis in both a dose- and time-dependent manner. Dopamine, SKF 38393 (D1 receptor agonist), and quinpirole (D2 receptor agonist) decreased the level of [(3)H]-thymidine incorporation. The level of cyclic adenosine 3, 5-monophosphate (cAMP) was increased by SKF 38393 but not by quinpirole. The protein kinase C (PKC) protein was translocated from the cytosolic fraction to the membrane compartment by dopamine. Dopamine also increased [Ca(2+)](i), which was blocked by EGTA (an extracellular Ca(2+) chelator), BAPTA-AM (an intracellular Ca(2+) chelator), nifedipine (a L-type Ca(2+) channel blocker), SQ 22536 [an adenylyl cyclase (AC) inhibitor] and neomycin [a phospholipase C (PLC) inhibitor]. Dopamine, SKF 38393, and quinpirole increased the level of p44/42 mitogen-activated protein kinases (MAPKs), p38 MAPK, and stress-activated protein kinase/Jun-N-terminal kinase (SAPK/JNK) phosphorylation. Dopamine also increased level of H(2)O(2) formation and activated the transcription factor family NF-kappaB. Moreover, SKF 38393, quinpirole, and dopamine inhibited cell cycle regulatory proteins, which is consistent with the change in the level of [(3)H]-thymidine incorporation observed. The dopamine-induced decrease in cyclin E, cyclin-dependent protein kinase-2 (CDK-2), and cyclin D1, CDK-4 were blocked by pertussis toxin (G protein inhibitor), SQ 22536, neomycin, bisindolylmaleimide I (PKC inhibitor), SB 203580 (p38 MAPK inhibitor), PD 98059 (p44/42 inhibitor), and SP 600125 (SAPK/JNK inhibitor). In conclusion, dopamine inhibits DNA synthesis in mouse ES cells via the cAMP, Ca(2+)/PKC, MAPKs, and NF-kappaB signaling pathways.
 ...
PMID:Dopamine regulates cell cycle regulatory proteins via cAMP, Ca(2+)/PKC, MAPKs, and NF-kappaB in mouse embryonic stem cells. 1668 61

In this paper we have explored the role of different kinase pathways of signal transduction in proliferation control of E1A + Ras transformants, using specific inhibitors of MAP-kinases ERK, JNK, p38 and PI3-kinase. According to our data, suppression of signalling cascades driven by RI3K only arrested proliferation of E1A + Ras cells, while suppression of either MAP-kinase did not lead to noticeable antiproliferative effect. We have shown that suppression of RI3K with LY294002 gave rise to accumulation of cyclin-dependent kinase inhibitor p27(KiP1) but not p21(Waf1). Accumulation of p27(KiP1) in LY294002-treated E1A + Ras cells was accompanied by a decrease in Cyclin E-Cdk2 and Cyclin A-Cdk2 activity, which caused diminution of Rb phosphorylation and strengthening of E2F-Rb binding. Binding of E2F with hypophosphorylated Rb resulted in inhibition of E2F activity and reduction of E2F-regulated gene transcription, these genes being necessary for S-phase entry and DNA synthesis. Thus, RI3K--Akt cascade plays the key role in maintenance of autonomous proliferation of cells transformed with E1A and cHa-ras oncogenes. Inhibition of PI3K leads to p27(Kip1) accumulation and cell cycle arrest, consequently.
 ...
PMID:[The role of different kinase pathways of signal transduction in proliferation of E1A + Ras transformants]. 1670 95

The reported studies on the metabolism in chicken hepatocytes in comparison with those of mammals are quite different. Therefore, this study examined the effect of EGF on DNA synthesis along with its related signal cascades in primary cultured chicken hepatocytes. EGF stimulated DNA synthesis in a dose (> or =10 ng/ml)-dependent manner, which correlated with the increase in CDK-2 and CDK-4 expression. The EGF-induced increase in [3H]-thymidine incorporation was blocked by AG 1478 (an EGF receptor tyrosine kinase antagonist), genistein, and herbimycin A (tyrosine kinase inhibitors), suggesting a role in the activation and tyrosine phosphorylation of the EGF receptor. In addition, the EGF-induced stimulation of [3H]-thymidine incorporation was prevented by staurosporine, H-7, or bisindolylmaleimide I (protein kinase C inhibitors), suggesting a role of PKC. In addition, PD 98059 (a MEK inhibitor), SB 203580 (a p38 MAPK inhibitor), and SP 600125 (a JNK inhibitor) blocked the EGF-induced stimulation of [3H]-thymidine incorporation and CDK-2/4 expression. Indeed, EGF increased the translocation of PKC from the cytosol to the membrane fraction, and increased the activation of p44/42 MAPK, p38 MAPK, and JNK. Moreover, EGF increased the CDK-2, CDK-4, cyclin D1, and cyclin E expression levels but decreased the p21 and p27 expression levels. These EGF-induced increases were blocked by an EGF receptor antagonist, tyrosine kinase inhibitors, PKC inhibitors, and MAPKs inhibitors. In conclusion, EGF stimulates DNA synthesis of primary cultured chicken hepatocytes via Ca2+/PKC and the MAPKs signaling pathways.
 ...
PMID:Effect of EGF on [3H]-thymidine incorporation and cell cycle regulatory proteins in primary cultured chicken hepatocytes: Involvement of Ca2+/PKC and MAPKs. 1682 72

Hippocampal kindling, a model of mesial temporal lobe epilepsy, is developed through repetitive stimulation of the hippocampus and leads to increased after-discharges as measured by EEG and an enduring seizure-prone state. Synthesis of new proteins is thought to form the basis for sustained seizure-induced physiological and/or pathological changes in synaptic reorganization and apoptotic/necrotic neuronal death. Here we examined the effect of kindling on stimulus-induced c-Jun N-terminal kinase (JNK) and p38 phosphorylation, events postulated to lie upstream of seizure-induced changes in gene transcription. We found that stimulus-induced phosphorylation of JNK, but not of p38, is significantly enhanced in kindled animals compared with their naive counterparts in the CA1 subregion of the hippocampus. Immunofluorescent staining confirmed this region-specific pattern of JNK activation and revealed that reactive astrocytes mediate this effect. Astrocyte proliferation and hypertrophy, as well as upregulation of vimentin protein levels, common markers of astrogliosis, were present after 4 d of kindling. Moreover, this reactive astrogliosis was associated with neuronal death as visualized with Fluoro-jade B and anti-active caspase-3 staining. Stimulus-induced phosphorylation of the JNK substrate paxillin was enhanced in kindled animals, but not that of c-Jun. Moreover, a pan-antibody against MAPK/CDK (mitogen-activated protein kinases/cyclin-dependent kinase) substrates indicated the presence of phosphorylated proteins in cytosolic, membrane, and nuclear fractions. The consequence of these phosphorylation events is not completely understood, but these findings suggest a selective astrocytic signaling response to aberrant synaptic activity, signaling that may modulate kindling progression and/or neuronal death.
 ...
PMID:c-Jun N-terminal kinase activation responses induced by hippocampal kindling are mediated by reactive astrocytes. 1689 24

We previously synthesized several K-vitamin derivatives, which are potent growth inhibitors of human tumor cells, including Hep3B human hepatoma cells. Among these, Cpd 5 was the most potent. However, being a quinone derivative, Cpd 5 has the potential for generating toxic reactive oxygen species (ROS). We therefore synthesized a fluorinated derivative of Cpd 5, F-Cpd 5. The calculated reduction potential of F-Cpd 5 was much higher than that for Cpd 5 and it was not predicted to generate ROS. This was supported by our observation that F-Cpd 5 generated significantly lower ROS than Cpd 5. F-Cpd 5 was three times more potent than Cpd 5 in inhibiting Hep3B cell growth. Interestingly, under identical culture conditions, F-Cpd 5 inhibited mitogen-induced DNA synthesis in normal rat hepatocytes 12-fold less potently than Hep3B cells. F-Cpd 5 was found to induce caspase-3 cleavage and nuclear DNA laddering, evidences for apoptosis. It preferentially inhibited the activities of the cell cycle controlling phosphatases Cdc25A and Cdc25B, by binding to their catalytic cysteines. Consequently, inhibitory tyrosine phosphorylation of the Cdc25 substrate kinases Cdk2 and Cdk4 were induced. F-Cpd 5 also induced phosphorylation of the MAPK proteins ERK1/2, JNK1/2 and p38 in Hep3B cells and the MAPK inhibitors (U0126, JNKI-II, and SB 203580) antagonized its growth inhibition. F-Cpd 5 inhibited the action of cytosolic ERK phosphatase activity, which likely caused the ERK phosphorylation. F-Cpd 5 thus differentially inhibited growth of normal and tumor cells by preferentially inhibiting the actions of Cdc25A and Cdc25B phosphatases and inducing MAPK phosphorylation.
 ...
PMID:Fluorinated Cpd 5, a pure arylating K-vitamin derivative, inhibits human hepatoma cell growth by inhibiting Cdc25 and activating MAPK. 1693 May 63

Honokiol, an active component in extracts of Magnolia officinalis, has been proposed to play a role in anti-inflammatory, antioxidant activity, anti-angiogenic and anti-tumor activity. Although honokiol has a variety of pharmacological effects on certain cell types, its effects on vascular smooth muscle cells (VSMC) are unclear. This issue was investigated in the present study, honokiol was found to inhibit cell viability and DNA synthesis in cultured VSMC. These inhibitory effects were associated with G1 cell cycle arrest. Treatment with honokiol blocks the cell cycle in the G1 phase, down-regulates the expression of cyclins and CDKs and up-regulates the expression of p21WAF1, a CDK inhibitor. While honokiol did not up-regulate p27, it caused an increase in the promoter activity of the p21WAF1 gene. Immunoblot and deletion analysis of the p21WAF1 promoter showed that honokiol induced the expression of p21WAF1 and that this expression was independent of the p53 pathway. Furthermore, the honokiol-mediated signaling pathway involved in VSMC growth inhibition was examined. Among the relevant pathways, honokiol induced a marked activation of p38 MAP kinase and JNK. The expression of dominant negative p38 MAP kinase and SB203580, a p38 MAP kinase specific inhibitor, blocked the expression of honokiol-dependent p38 MAP kinase and p21WAF1. Consistently, blockade of p38 MAPK kinase function reversed honokiol-induced VSMC proliferation and cell cycle proteins. These data demonstrate that the p38 MAP kinase pathway participates in p21WAF1 induction, subsequently leading to a decrease in the levels of cyclin D1/CDK4 and cyclin E/CDK2 complexes and honokiol-dependent VSMC growth inhibition. In conclusion, these findings concerning the molecular mechanisms of honokiol in VSMC provides a theoretical basis for clinical approaches to the use therapeutic agents in treating atherosclerosis.
 ...
PMID:Honokiol causes the p21WAF1-mediated G(1)-phase arrest of the cell cycle through inducing p38 mitogen activated protein kinase in vascular smooth muscle cells. 1696 92

We previously synthesized a K-vitamin derivative, Cpd 5, which was a potent growth inhibitor of human tumor cells, including Hep3B hepatoma cells. However, being a quinone compound, Cpd 5 has the potential for generating toxic reactive oxygen species (ROS). We therefore synthesized a nonquinone sulfone derivative, H32, which has a sufone group substituting the quinone. The IC50 of H32 for Hep3B cells was found to be 2.5 microM, which was 2.5 and 3.2 times more potent than Cpd 5 and vitamin K3 respectively. It induced apoptosis in Hep3B cells but did not generate ROS when compared to Cpd 5. Interestingly, under similar culture conditions, normal rat hepatocytes were 14-fold more and 7-fold more resistant to the growth inhibitory effects of H32 than Hep3B and PLC/PRF5 cells respectively. H32 preferentially inhibited the activities of the cell cycle controlling Cdc25A phosphatase likely by binding to its catalytic cysteine. As a consequence, it induced inhibitory tyrosine phosphorylation of the Cdc25 substrate kinases Cdk2 and Cdk4 in Hep3B cells and the cells undergo an arrest in the G1 phase of the cell cycle. H32 also induced persistent phosphorylation of the MAPK protein ERK1/2, but marginal JNK1/2 and p38 phosphorylation. The ERK inhibitor U0126, added at least 30 min prior to H32, antagonized the growth inhibition induced by H32. However, the JNK and p38 inhibitors, JNKI-II and SB203580, were not able to antagonize H32 induced growth inhibition. Thus, H32 differentially inhibited growth of normal and liver tumor cells by preferentially inhibiting the actions of Cdc25 phosphatases and inducing persistent ERK phosphorylation.
 ...
PMID:H32, a non-quinone sulfone analog of vitamin K3, inhibits human hepatoma cell growth by inhibiting Cdc25 and activating ERK. 1696 75

The cellular actions of genistein are believed to mediate the decreased risk of breast cancer associated with high soy consumption. We have investigated the intracellular metabolism of genistein in T47D tumorigenic and MCF-10A nontumorigenic cells and assessed the cellular actions of resultant metabolites. Genistein selectively induced growth arrest and G2-M phase cell cycle block in T47D but not MCF10A breast epithelial cells. These antiproliferative effects were paralleled by significant differences in the association of genistein to cells and in particular its intracellular metabolism. Genistein was selectively taken up into T47D cells and was subject to metabolism by CYP450 enzymes leading to the formation of both 5,7,3',4'-tetrahydroxyisoflavone (THIF) and two glutathionyl conjugates of THIF. THIF inhibited cdc2 activation via the phosphorylation of p38 MAP kinase, suggesting that this species may mediate genistein's cellular actions. THIF exposure activated p38 and caused subsequent inhibition of cyclin B1 (Ser 147) and cdc2 (Thr 161) phosphorylation, two events critical for the correct functioning of the cdc2-cyclin B1 complex. We suggest that the formation of THIF may mediate the cellular actions of genistein in tumorigenic breast epithelial cells via the activation of signaling through p38.
 ...
PMID:The intracellular genistein metabolite 5,7,3',4'-tetrahydroxyisoflavone mediates G2-M cell cycle arrest in cancer cells via modulation of the p38 signaling pathway. 1701 69

Development of new molecular target therapeutic agents is expected to improve clinical outcome, ideally with efficacy in both single and combined treatment modalities. Because of the potential for affecting multiple signaling pathways, inhibition of the molecular chaperone heat shock protein 90 (Hsp90) may provide a strategy for enhancing tumor cell radiation sensitivity. Therefore, we have investigated the effects of Hsp90 inhibitor 17-Allylamino-17-demethoxygeldanamycin (17-AAG) on radiation sensitivity of human tumor cells in vitro. We evaluated the effects of 17-AAG using oral squamous cell carcinoma (OSCC) cell lines (HSC2, HSC3 and HSC4), including two types of SAS cells with a wild-type (SAS/neo), or a mutated p53 status (SAS/Trp248). Apoptosis and clonogenic survival were examined after exposure of the cells to radiation. For mechanistic insight, we analyzed cell cycle, several signaling factors and molecular markers including Akt, Raf-1, p38 MAPK, Cdc25B, Cdc25C, Cdk2 and p21. Treatment of OSCC cell lines with 17-AAG resulted in cytotoxicity and, when combined with radiation, enhanced the radiation response. However, the responses depended on p53 status. 17-AAG enhanced the radiation sensitivity significantly and induced apoptosis in the SAS/neo cell which has a wild-type p53. But the radiation sensitizing effect of 17-AAG was limited in the SAS/Trp248 cell which has a mutated p53. We also measured the total levels of several prosurvival and cell cycle signaling proteins. Akt, Raf-1 and Cdc25C expression were down-regulated in 17-AAG-treated cells. These data indicate that 17-AAG inhibits the proliferation and enhances the radiation sensitivity of human OSCC cells in various levels. However, enhancement of radiation sensitivity by the Hsp90 inhibitor depended on p53 status. Therefore, Hsp90 therapy combined with radiation might synergize with conventional therapies in patients with wild-type p53.
 ...
PMID:P53-dependent radiosensitizing effects of Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin on human oral squamous cell carcinoma cell lines. 1701 41


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>