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)

Progression through the cell cycle is regulated by CDKs (cyclin-dependent kinases), which associate with activating partners, named cyclins, to efficiently phosphorylate substrates. We previously reported the identification of RINGO, a Xenopus protein that can activate CDK1 and CDK2 despite lack of sequence similarity to cyclins, which plays a role in the regulation of the meiotic cell cycle in oocytes. In the present study we report the characterization of four mammalian RINGO proteins, which are 53-68% identical with Xenopus RINGO in a central core of about 75 residues. We show that all RINGO family members can bind to and activate CDK1 and CDK2, albeit with different efficiencies, but they do not bind to CDK4 or CDK6. The core RINGO sequences are critical for CDK activation. We also identified key residues in CDK2 that are required for RINGO binding. All RINGO proteins can also bind the CDK inhibitor p27Kip1, but with an inverse efficiency of their ability to bind to CDK1. Our results identify a new family of mammalian proteins that can activate CDKs and therefore potentially function as cell cycle regulators. The ability of RINGO proteins to activate CDK1 and CDK2 suggest also cyclin-independent roles for these kinases.
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PMID:Characterization of a new family of cyclin-dependent kinase activators. 1557 21

Mitotic and meiotic cell cycle regulation is essential for normal development and tumor prevention. The underlying molecular mechanisms are not completely characterized. The aim of our analysis was to derive a global expression map of cell cycle regulators in mitosis and meiosis. First, the expression of cyclins, CDKs and CDK inhibitors was determined during postnatal testis maturation in mice using microarrays and quantitative RT-PCR. The abundance of cyclins A1, B2, K, M4, CDK2, all CDKLs, CDKN2c, CDKN2d and INCA1 increased during testis maturation. In contrast, cyclins A2, B1, D2, G1, G2, CDK1, CDK4 and CDK2AP1 showed a maturation-associated decrease. Gene expression profiles of isolated germ cells and testicular somatic cells confirmed these results. Second, we determined cyclin expression patterns in human normal and malignant testis samples (n = 36) modeling the reciprocal difference between meiosis and mitosis. Testicular tumors strictly expressed cell cycle regulators identified in mitotically dividing germ cells. Expression of several transcripts was histology-specific in testicular tumors, providing novel molecular markers and potential therapeutic targets. Taken together, our data provide a comprehensive expression map of cell cycle regulators at the switch between mitosis and meiosis in testis development and in cancerogenesis.
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PMID:Expression patterns of mitotic and meiotic cell cycle regulators in testicular cancer and development. 1580 Sep 20

Src and Src-family protein-tyrosine kinases are regulatory proteins that play key roles in cell differentiation, motility, proliferation, and survival. The initially described phosphorylation sites of Src include an activating phosphotyrosine 416 that results from autophosphorylation, and an inhibiting phosphotyrosine 527 that results from phosphorylation by C-terminal Src kinase (Csk) and Csk homologous kinase. Dephosphorylation of phosphotyrosine 527 increases Src kinase activity. Candidate phosphotyrosine 527 phosphatases include cytoplasmic PTP1B, Shp1 and Shp2, and transmembrane enzymes include CD45, PTPalpha, PTPepsilon, and PTPlambda. Dephosphorylation of phosphotyrosine 416 decreases Src kinase activity. Thus far PTP-BL, the mouse homologue of human PTP-BAS, has been shown to dephosphorylate phosphotyrosine 416 in a regulatory fashion. The platelet-derived growth factor receptor protein-tyrosine kinase mediates the phosphorylation of Src Tyr138; this phosphorylation has no direct effect on Src kinase activity. The platelet-derived growth factor receptor and the ErbB2/HER2 growth factor receptor protein-tyrosine kinases mediate the phosphorylation of Src Tyr213 and activation of Src kinase activity. Src kinase is also a substrate for protein-serine/threonine kinases including protein kinase C (Ser12), protein kinase A (Ser17), and CDK1/cdc2 (Thr34, Thr46, and Ser72). Of the three protein-serine/threonine kinases, only phosphorylation by CDK1/cdc2 has been demonstrated to increase Src kinase activity. Although considerable information on the phosphoprotein phosphatases that catalyze the hydrolysis of Src phosphotyrosine 527 is at hand, the nature of the phosphatases that mediate the hydrolysis of phosphotyrosine 138 and 213, and phosphoserine and phosphothreonine residues has not been determined.
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PMID:Src kinase regulation by phosphorylation and dephosphorylation. 1584 50

Heteroaromatic quinols 4-(benzothiazol-2-yl)-4-hydroxycyclohexa-2,5-dienone (1) and 4-(1-benzenesulfonyl-1H-indol-2-yl)-4-hydroxycyclohexa-2,5-dienone (2) exhibit potent and selective antitumor activity against colon, renal, and breast carcinoma cell lines in vitro (GI50 < 500 nmol/L). In vivo growth inhibition of renal, colon, and breast xenografts has been observed. Profound G2-M cell cycle block accompanied down-regulation of cdk1 gene transcription was corroborated by decreased CDK1 protein expression following treatment of HCT 116 cells with growth inhibitory concentrations of 1 or 2. The chemical structure of the quinol pharmacophore 4-(hydroxycyclohexa-2,5-dienone) suggested that these novel agents would readily react with nucleophiles in a double Michael (beta-carbon) addition. Indeed, COMPARE analysis within the National Cancer Institute database revealed a number of chemically related quinone derivatives that could potentially react with sulfur nucleophiles in a similar manner and suggested that thioredoxin/thioredoxin reductase signal transduction could be a putative target. Molecular modeling predicted covalent irreversible binding between quinol analogues and cysteine residues 32 and 35 of thioredoxin, thereby inhibiting enzyme activity. Binding has been confirmed, via mass spectrometry, between reduced human thioredoxin and 1. Microarray analyses of untreated HCT 116 cells and those exposed to either 1 (1 micromol/L) or 2 (500 nmol/L and 1 micromol/L) determined that of > or =10,000 cancer-related genes, expression of thioredoxin reductase was up-regulated >3-fold. Furthermore, quinols 1 and 2 inhibited insulin reduction, catalyzed by thioredoxin/thioredoxin reductase signaling in a dose-dependent manner (IC50 < 6 micromol/L). Results are consistent with a mechanism of action of novel antitumor quinols involving inhibition of the small redox protein thioredoxin.
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PMID:Elucidation of thioredoxin as a molecular target for antitumor quinols. 1586 91

A series of molecular pathological investigations of the molecules that stimulate the cyclin dependent kinases (CDK1, 2, 4, and 6) have led to enormous accumulation of knowledge of the clinical significance of these molecules for cancer diagnosis. However, the molecules have yet to be applied to clinical cancer diagnosis, as there is no available technology for application of the knowledge in a clinical setting. We hypothesized that the direct measurement of CDK activities and expressions (CDK profiling) might produce clinically relevant values for the diagnosis. This study investigated the clinical relevance of CDK profiling in gastrointestinal carcinoma tissues by using originally developed expression and activity analysis methods. We have established novel methods and an apparatus for analyzing the expression and activities of the CDK molecules in lysate of tumor tissue in a clinical setting, and examined 30 surgically dissected gastrointestinal carcinomas and corresponding normal mucosal specimens. We demonstrate here that remarkably elevated CDK2 activity is evident in more than 70% of carcinoma tissues. Moreover, a G1-CDK activity profiling accurately mirrored the differences in proliferation between tumor and normal colonic tissues. Our results suggest that CDK profiling is a potent molecular-clinical approach to complement the conventional pathological diagnosis, and to further assist in the individualized medications.
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PMID:A new cancer diagnostic system based on a CDK profiling technology. 1599 Feb 81

Cyclin A-associated kinases, such as cyclin-dependent kinase 2 (CDK2), participate in regulating cellular progression from G(1) to S to G(2), and CDK2 has also been implicated in the transition to mitosis. The antitumor properties of CDK inhibitors, alone or in combination with taxanes, are currently being examined in clinical trials. Here, we examined whether the activity of kinases associated with cyclin A (such as CDK2) is important in determining cellular sensitivity to paclitaxel, a taxane and mitotic inhibitor used in chemotherapy for breast and ovarian cancer. We used adenoviral suppression or overexpression to manipulate the expression of CDK2 and cyclin A in one breast cancer and three ovarian cancer cell lines with different sensitivities to paclitaxel and assessed protein expression, kinase activity, cell cycle distribution, and sensitivity to paclitaxel. Transfection of a dominant-negative (DN)-CDK2 evoked resistance to paclitaxel by preventing cellular progression to mitosis through loss of CDK1 activity. Reexpression of wild-type CDK2 in DN-CDK2-transfected cancer cells restored CDK2 activity but not paclitaxel sensitivity. However, expression of cyclin A in DN-CDK2-transfected cells restored their sensitivity to paclitaxel. Although CDK2 activity was not directly involved in paclitaxel sensitivity, cyclin A-associated kinases did up-regulate CDK1 via phosphorylation. We conclude that cyclin A-associated kinase activity is required for these cells to enter mitosis and undergo paclitaxel-induced cell death. Combining taxane chemotherapy with any drug targeting cyclin A-associated kinases (e.g., pure CDK2 inhibitors) should be done with caution, if at all, because of the potential for enhancing taxane resistance.
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PMID:Cyclin A-associated kinase activity is needed for paclitaxel sensitivity. 1602 Jun 61

The identification of molecular determinants of tumor cell survival is an important objective in cancer research. Here, we describe a small-molecule kinase inhibitor (RGB-286147), which, besides inhibiting tumor cell cycle progression, exhibits potent cytotoxic activity toward noncycling tumor cells, but not nontransformed quiescent fibroblasts. Extensive yeast three-hybrid (Y3H)-based proteome/kinome scanning with chemical dimerizers revealed CDK1/2/3/5/7/9 and the less well-characterized CDK-related kinases (CRKs) p42/CCRK, PCTK1/3, and PFTK1 as its predominant targets. Thus, RGB-286147 is a proteome-wide CDK/CRK-specific kinase inhibitor whose further study could yield new insight into molecular determinants of tumor cell survival. Our results also suggest that the [1, 3, 6]-tri-substituted-pyrazolo[3,4-d]-pyrimidine-4-one kinase inhibitor scaffold is a promising template for the rational design of kinase inhibitors with potential applications to disease indications other than cancer, such as neurodegeneration, cardiac hypertrophic growth, and AIDS.
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PMID:A proteome-wide CDK/CRK-specific kinase inhibitor promotes tumor cell death in the absence of cell cycle progression. 1624 46

Pyrazolopyridazine 1a was identified in a high-throughput screening carried out by BASF Bioresearch Corp. (Worcester, MA) as a potent inhibitor of CDK1/cyclin B and shown to have selectivity for the CDK family. Analogues of the lead compound have been synthesized and their antitumor activities have been tested. A molecular model of the complex between the lead compound and the CDK2 ATP binding site has been built using a combination of conformational search and automated docking techniques. The stability of the resulting complex has been assessed by molecular dynamics simulations and the experimental results obtained for the synthesized analogues have been rationalized on the basis of the proposed binding mode for compound 1a. As a result of the SAR study, monofuryl 1o has been synthesized and is one of the most active compounds against CDK1 of this series.
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PMID:Pyrazolo[3,4-c]pyridazines as novel and selective inhibitors of cyclin-dependent kinases. 1625 Jun 43

Breast cancer is the most common malignancy and the second major cause of cancer-related deaths among women in the United States. Recent advances in the molecular genetics of breast cancer have identified various genes associated with tumorigenesis. There is evidence that non-steroidal anti-inflammatory drugs, e.g. sulindac, have some anti-proliferative effects on various tumors involving altered p53 function. Most of these studies have been performed with various human colon carcinoma cell lines and few of them focus on non-malignant proliferative human mammary epithelial cell lines. Therefore, the present study was undertaken to analyze the differentially expressed genes of the p53 signaling pathway by means of a gene array for the immortalized human breast epithelial cell line, MCF-10F, treated with sulindac. Out of the total 96 genes, only 17 were altered by the drug treatment. Among these 17 genes, 6 showed significant alteration (Q > 2.0), whereas 11 genes showed moderate alterations. Altered genes included BRCA1 associated protein-1 [ubiquitin carboxy-terminal hydrolase (bap1)]; cell division cycle 2, G1 to S and G2 to M [cdk1(cdc2)]; and DNA-damage-inducible transcript 1 (gadd45), which were down-regulated. However, N-myc gene 1 (rtp), promyelocytic leukemia (pml), and nuclear factor of kappa-light polypeptide gene enhancer in B-cell 3 and p65 [avian (rel A)] were up-regulated. Northern blot analysis confirmed some of these alterations. The alteration of p53 signaling pathway gene markers by sulindac treatment can give us valuable information about the response to drug treatments in a proliferative cell population.
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PMID:Differential gene expression of sulindac-treated human breast epithelial cells. 1627 29

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.
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PMID:Role of p38 MAPK and RNA-dependent protein kinase (PKR) in hepatitis C virus core-dependent nuclear delocalization of cyclin B1. 1644 63


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