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

Protein kinases play important roles in regulating cellular signal transduction and other biochemical processes, and they are attractive targets for drug discovery programs in many disease areas. Most kinase inhibitors under development as drugs act by directly competing with ATP at the ATP-binding site of the kinase. There are more than 500 protein kinases, and the ATP-binding site is highly conserved among them. Therefore selectivity is an essential requirement for clinically effective drugs, and understanding the structural characteristics of ATP-binding sites is of crucial importance. The objective of the present study was to elucidate the structural characteristics of the adenosine-binding site of four major kinase groups, AGC (PKA, PKG, and PKC families), CaMK (calcium/calmodulin-dependent protein kinases), CMGC (CDK, MAPK, GSK3, and CLK families), and TK (tyrosine kinases). To do this, we classified the kinases into groups by using feed-forward multilayer perceptron (MLP) neural networks and structural, electronic, and hydrophobic descriptors of the amino acids at the adenosine-binding site. A total of 275 kinases were classified in two ways: (1) kinases belonging to a certain group were distinguished from those not belonging to that group, and (2) all of the kinases were classified into four groups. More than 85% of the kinases were correctly classified by both methods. Trained neural networks clarified which amino acids and which properties characterize the adenosine-binding site of each group, and the results were visualized by molecular graphics. Comparison of the modeled neural networks and the distributions of amino acids provided more detailed information on the structural characteristics of each group. Application of the present results to drug development is also discussed.
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PMID:Elucidation of characteristic structural features of ligand binding sites of protein kinases: a neural network approach. 1699 46

In PC Cl3 cells, a rat thyroid cell line, angiotensin (Ang II) activates the atypical protein kinase C-zeta (PKC-zeta) and the extracellular signal-regulated kinase (ERK) pathways. We here studied the Ang II effects on PC Cl3 cell proliferation. It was found that Ang II: (1) induced the phosphorylation of protein kinase B (PKB), (2) induced the growth-related early gene c-fos expression, (3) enhanced the cyclin E and p27(kip) expression, (4) had no effects on Cdk2, and (5) did not affect the transition from G0/G1 to S phase. Inhibition of phosphoinositide-3kinase by LY294002 further increased the effect of Ang II on p27(kip) induction, whilst PKCs inhibition by GF109203X decreased such effect. The role of PKC-zeta was recognized by the use of a synthetic myristoylated peptide with sequences based on the endogenous PKC-zeta pseudosubstrate and by PKC-zeta downregulation using the small interfering RNA (siRNA). Insulin had a replicating effect on PC Cl3 cells, induced the phosphorylation of PKB, decreased p27(kip) expression and had no effect on the PKC-zeta cytosol-to-membrane translocation. PC Cl3 cell proliferation was induced more potently by simultaneous stimulation with insulin and Ang II than by stimulation with insulin alone, and the effect on p27(kip) expression was similar to that obtained with insulin only. These observations demonstrate that in PC Cl3 cells Ang II causes a block in G1 phase, although both ERK and PKB pathways are activated, and this effect may be due to the upregulation of p27(kip) and PKC-zeta operativity.
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PMID:Angiotensin II does not stimulate proliferation of rat thyroid PC Cl3 cell line. 1717 Feb 29

Protein kinase C (PKC) alpha/betaI isoenzyme inhibitor Go6976 has been suggested to be a G2 checkpoint abrogator by direct Chk1 inhibition. In the present study, we demonstrate that Go6976 induces mitosis in doxorubicin treated G2-arrested 5637 urinary bladder transitional cell carcinoma cells and interestingly also in non-synchronized 5637 cells. Importantly, the results demonstrated that both doxorubicin treated and non-synchronized cancer cells are forced to mitosis by Go6976. However, part of the cells avoid the death in mitosis and continue in the cell cycle which may increase the probability of genomic instability. Cytotoxicity of Go6976 alone and in combination with chemotherapeutic agents was further studied. Go6976 treatment alone induced apoptotic cell death. Cytostatic doxorubicin pre-treatment induced G2 arrest and inhibited the cytotoxic effects of mitosis specific drug paclitaxel. Cytotoxicities of doxorubicin-paclitaxel and doxorubicin-Go6976 sequences could be markedly enhanced by combining Go6976 with paclitaxel after doxorubicin pre-treatment. In doxorubicin-Go6976+paclitaxel sequence, paclitaxel arrested the cells to mitosis and unfavourable progression of the cell cycle was inhibited. Analyzes of the molecular mechanisms underlying Go6976 induced mitosis showed that PKC inhibiting concentrations of Go6976 induced cdc2 activation concentration-dependently in non-synchronized and in DNA damaged cells. Simultaneously, Chk1/2 became deactivated and cdc25C activated in DNA damaged cells, indicating regulatory events upstream. In non-synchronized cells, activation of cdc25C, but not Chk1/2, was observed, suggesting inactivation of c-TAK1. The results of the current study suggest that Go6976 has a synergistic cytotoxic effect when combined with doxorubicin and paclitaxel.
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PMID:PKC inhibitor Go6976 induces mitosis and enhances doxorubicin-paclitaxel cytotoxicity in urinary bladder carcinoma cells. 1732 Feb 79

LFM-A13 (alpha-cyano-beta-hydroxy-beta-methyl-N-(2,5-dibromophenyl)propenamide) has recently been identified as an inhibitor of Polo-like kinases (Plk). LFM-A13 does not inhibit other serine/threonine kinases including CDK, CHK, RAF, DAPK, IKK, IRAK, JNK, MAPK, PKC and SAPK. LFM-A13-treated human cancer cells develop abnormal mitotic spindles and G(2)/M-arrest during cell cycle progression. LFM-A13 was not toxic to rodents or dogs at daily dose levels as high as 100 mg/kg. Notably, at a low dose level of 10 mg/kg, which does not result in delayed tumor progression in the MMTV/neu transgenic mouse model of HER2 positive breast cancer, LFM-A13 markedly enhanced the anti-cancer activity of the mitotic spindle poison paclitaxel. These results indicate that LFM-A13 may be useful in the treatment of cancer patients.
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PMID:Chemosensitizing anti-cancer activity of LFM-A13, a leflunomide metabolite analog targeting polo-like kinases. 1807 37

Meta-predictors make predictions by organizing and processing the predictions produced by several other predictors in a defined problem domain. A proficient meta-predictor not only offers better predicting performance than the individual predictors from which it is constructed, but it also relieves experimentally researchers from making difficult judgments when faced with conflicting results made by multiple prediction programs. As increasing numbers of predicting programs are being developed in a large number of fields of life sciences, there is an urgent need for effective meta-prediction strategies to be investigated. We compiled four unbiased phosphorylation site datasets, each for one of the four major serine/threonine (S/T) protein kinase families-CDK, CK2, PKA and PKC. Using these datasets, we examined several meta-predicting strategies with 15 phosphorylation site predictors from six predicting programs: GPS, KinasePhos, NetPhosK, PPSP, PredPhospho and Scansite. Meta-predictors constructed with a generalized weighted voting meta-predicting strategy with parameters determined by restricted grid search possess the best performance, exceeding that of all individual predictors in predicting phosphorylation sites of all four kinase families. Our results demonstrate a useful decision-making tool for analysing the predictions of the various S/T phosphorylation site predictors. An implementation of these meta-predictors is available on the web at: http://MetaPred.umn.edu/MetaPredPS/.
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PMID:Meta-prediction of phosphorylation sites with weighted voting and restricted grid search parameter selection. 1823 18

Cell signaling pathways induce Sp1 phosphorylation, which allows for the upregulation of Sp1-dependent genes that control cell growth, cell-cycle progression, survival and tumorigenesis. Sp1 activity is under constitutive repression through the sumoylation of Lysine-16, and Lysine-16 dependent N-terminal cleavage relieves this repression. The present investigation probes further into the mechanisms of Sp1 processing, desumoylation, and degradation to reveal that phosphorylation is the major driving force behind these coupled activities. The first 7 amino acid residues of Sp1 enhance the accessibility of Lysine-16 to the homologous modifiers SUMO-1 and ubiquitin; and Serine-7 specifically enhances ubiquitinylation. Our data show that Serine-59 regulates Sp1 proteolytic processing, and thereby provides a mechanism for the upregulation of Sp1-dependent transcription by CyclinA/cdk2 phosphorylation of Serine-59. Sp1 activators, forskolin and PMA, enhance Sp1 processing in MCFE cells through distinct signaling pathways. PKC, ERK, and ERBB2 kinase inhibitors suppress PMA induction of Sp1 and the specific isozyme PKCalpha enhances Sp1 cleavage. Sp1 contains several NFkappaB2-like proteolytic processing components including a functional phosphorylation-dependent beta-TrCP binding motif. From these data, we propose a model by which cell-cycle and mitotic kinases induce Sp1 proteolytic processing resulting in a desumoylated, derepressed and unstable Sp1 product.
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PMID:Phosphorylation mediates Sp1 coupled activities of proteolytic processing, desumoylation and degradation. 1823 66

Epidermal growth factor (EGF) has been shown to stimulate survival in diverse cells in vitro. In the present study, the effects of EGF and the EGF-related signaling pathway on proliferation of chicken primordial germ cells (PGCs) were investigated. Results showed that EGF (10-100 ng/ml) increased the number and area of PGC colonies in a time- and dose-dependent manner. EGF also activated PKC, a process that was inhibited by AG1478 (an EGFR tyrosine kinase inhibitor) and ethyleneglycol-bis-(beta-aminoethyl ether)-N,N'-tetraacetic acid (EGTA; an intracellular Ca(2+) chelator). In addition, the degradation of NFKBIA and NFKB1 (p65) translocation was observed after EGF treatment, which was significantly blocked by pretreatment with AG1478, EGTA, H(7), or SN50 (NFKB1-specific inhibitor). Furthermore, we found that EGF-induced cell proliferation was significantly attenuated by AG1478, EGTA, H(7), and SN50, respectively. On the other hand, inhibition of EGFR, Ca(2+)/PKC, or NFKB1 abolished the EGF-stimulated increase in the expression of cyclins CCND1 and CCNE1, cyclin-dependent kinase 6 (CDK6), CDK2, and BCL2, and restored the EGF-induced inhibition of BAX expression and caspase 3/9 activity, indicating that EGFR, PKC, and NFKB1 signaling cascades were involved in EGF-stimulated DNA synthesis and antiapoptosis action. In conclusion, EGF stimulated proliferation of chicken PGCs via activation of Ca(2+)/PKC involving NFKB1 signaling pathway. These observations suggest that EGF signaling is important in regulating germ cell proliferation in the chicken embryonic gonad.
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PMID:Epidermal growth factor-induced proliferation of chicken primordial germ cells: involvement of calcium/protein kinase C and NFKB1. 1900 68

The inhibition of PKC-zeta has been proposed to be a potential drug target for immune and inflammatory diseases. A series of 2-(6-phenyl-1H indazol-3-yl)-1H-benzo[d]imidazoles with initial high crossover to CDK-2 has been optimized to afford potent and selective inhibitors of protein kinase c-zeta (PKC-zeta). The determination of the crystal structures of key inhibitor:CDK-2 complexes informed the design and analysis of the series. The most selective and potent analog was identified by variation of the aryl substituent at the 6-position of the indazole template to give a 4-NH(2) derivative. The analog displays good selectivity over other PKC isoforms (alpha, betaII, gamma, delta, epsilon, mu, theta, eta and iota/lambda) and CDK-2, however it displays marginal selectivity against a panel of other kinases (37 profiled).
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PMID:2-(6-Phenyl-1H-indazol-3-yl)-1H-benzo[d]imidazoles: design and synthesis of a potent and isoform selective PKC-zeta inhibitor. 1909 91

A phosphoinositide signalling cycle is present in the nucleus, independent of that which occurs at the plasma membrane. The key enzyme involved in this cycle is phospholipase (PLC) beta1. This nuclear cycle has been shown to be involved in both cell proliferation and differentiation. Here, we report that nuclear PLCbeta1 activity is upregulated during differentiation of 3T3-L1 adipocytes. During differentiation there are two phases of PLCbeta1 activity; the first occurs within 5 min of treatment with differentiation media, does not require new PLCbeta1 to enter the nucleus and is regulated by pERK and PKC alpha while the second phase occurs from day 2 of differentiation, requires new PLCbeta1 protein to enter the nucleus and is independent of regulation by pERK and PKC alpha. Over-expression with the PLC mutants, Deltamk (which lacks the ERK phosphorylation site) and M2B (which lacks the nuclear localisation sequence), revealed that both phases of PLCbeta1 activity are required for terminal differentiation to occur. Inhibition of PLCbeta1 activity prevents the upregulation of cyclinD3 and cdk4 protein, suggesting that PLCbeta1 plays a role in the control of the cell cycle during differentiation. These results indicate nuclear PLCbeta1 as a key regulator of adipocyte differentiation.
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PMID:Nuclear PLCbeta1 is required for 3T3-L1 adipocyte differentiation and regulates expression of the cyclin D3-cdk4 complex. 1938 66

Alzheimer's disease (AD) is a late-life cognitive disorder associated, among other things, to the presence of extracellular aggregates of fibrillar amyloid beta protein (Abeta). However, there is growing evidence that early stages of AD may be due to neuronal network dysfunction produced by the actions of soluble forms of Abeta. Therefore, the development of new therapeutic strategies to treat AD, at least during its first stages, may be focused on preventing or reversing, the deleterious effects that soluble Abeta exerts on neuronal circuit function. In order to do so, it is necessary to elucidate the pathophysiological processes involved in Abeta-induced neuronal network dysfunction and the molecular processes underlying such dysfunction. Over the last decades, there has been extensive research about the molecular mechanisms involved in the effects of Abeta as well as possible neuroprotective strategies against such effects. Here we are going to review some of the intracellular pathways triggered by Abeta, which involve membrane receptors such as nicotinic-R, NMDA-R, integrins, TNF-R1, RAGE, FPRL and p75NTR and their intracellular mediators such as GSK3, PKC, PI3K, Akt, FAK, MAPK family, Src family and cdk5. Several of these pathways may constitute therapeutic targets for the treatment of the Abeta-induced neuronal network dysfunction which is, at least in part, the basis for cognitive dysfunction in AD.
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PMID:Pharmacology of the intracellular pathways activated by amyloid beta protein. 1951 98


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