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)

p57Kip2, a potent inhibitor of several cyclin/cyclin dependent kinase complexes (CDK ), is a paternally imprinted gene in both humans and mice, and here we show that pregnant mice which are heterozygous for p57Kip2 deficiency display symptoms similar to preeclampsia. p57-/+ (heterozygotes for p57Kip2 ) female mice that were mated with p57-/+ males showed hypertension, proteinuria, thrombocytopenia, decreased anti-thrombin III activity, and increased endothelin levels during late pregnancy. In their kidneys, endotheliosis of glomeruli were recognized along with fibrinoid or hyalinoid deposits. These characteristics were also observed in pregnant p57-/+ females that were mated with wild type males, but not in pregnant wild type females mated with p57-/+ males or wild type males. The pregnant p57-/+ mice had conceptuses both with and without p57Kip2 expression. The conceptuses without p57Kip2 expression showed trophoblastic hyperplasia, which mimics the hallmark proliferation of intermediate trophoblasts in clinical preeclampsia. It is suggested that the preeclampsia-like symptoms of the pregnant p57-/+ mice might have been induced by the conceptus(es) without p57Kip2 expression. In addition, pregnant p57-/+ mice might serve as a new animal model for preeclampsia characterized by trophoblastic hyperplasia.
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PMID:Deficiency in p57Kip2 expression induces preeclampsia-like symptoms in mice. 1246 47

The cyclin dependent kinase (cdk) inhibitor NU6027, 4-cyclohexylmethoxy-5-nitroso-pyrimidine-2,6-diamine (IC(50) vs cdk1/cyclinB1=2.9+/-0.1 microM and IC(50) vs cdk2/cyclinA3=2.2+/-0.6 microM), was used as the basis for the design of a series of 4-alkoxy-2,6-diamino-5-nitrosopyrimidine derivatives. The synthesis and evaluation of 21 compounds as potential inhibitors of cyclin-dependent kinases 1 and 2 is described and the structure-activity relationships relating to NU6027 have been probed. Simple alkoxy- or cycloalkoxy-groups at the O(4)-position were tolerated, with the 4-(2-methylbutoxy)-derivative (IC(50) vs cdk1/cyclinB1=12+/-2 microM and cdk2/cyclinA3=13+/-4 microM) retaining significant activity. Substitutions at the N(6) position were not tolerated. Replacement of the 5-nitroso substituent with ketone, oxime and semicarbazone groups essentially abolished activity. However, the derivative bearing an isosteric 5-formyl group, 2,6-diamino-4-cyclohexylmethoxy-pyrimidine-5-carbaldehyde, showed modest activity (IC(50) vs cdk1/cyclinB1=35+/-3 microM and cdk2/cyclinA3=43+/-3 microM). The X-ray crystal structure of the 5-formyl compound bound to cdk2 has been determined to 2.3A resolution. The intramolecular H-bond deduced from the structure with NU6027 bound to cdk2 is not evident in the structure with the corresponding formyl compound. Thus the parent compound, 4-cyclohexylmethoxy-5-nitrosopyrimidine-2,6-diamine (NU6027), remains the optimal basis for future structure-activity studies for cyclin-dependent kinase inhibitors in this series.
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PMID:4-Alkoxy-2,6-diaminopyrimidine derivatives: inhibitors of cyclin dependent kinases 1 and 2. 1248 27

HIV-1 enters the brain at the early stage of infection and resides primarily in a limited number of macrophages/microglia and astrocytes. Infection of these cells, however, may not explain the massive neuronal pathology which is seen in AIDS-associated dementia, suggesting a role for factors released from HIV-1 infected cells that trigger a cascade of events leading to neurodegeneration. Our results indicate that Tat, the potent regulatory protein of HIV-1 which is secreted by infected cells and can affect neighboring uninfected cells by transcellular means, can influence multiple biological events that lead to neuronal injury. These findings demonstrate that treatment of neuronal cells with Tat affects MAPK/ERK1/2 activity, the downstream central component of the nerve growth factor (NGF) signaling pathway. Furthermore, our data indicate that treatment of cells with Tat severely decreases expression of p35, a neuron-specific activator of cdk5, a cyclin dependent kinase that phosphorylates several neuronal proteins including neurofilament, and plays an important role in neuronal differentiation and survival. In parallel, Tat can bind to the cellular protein, Puralpha, which associates with cdk5. Further, results from Puralpha knockout animals revealed a decrease in p35 activity, pointing to the importance of Puralpha association with cdk5 in the activity of cdk5:p35 complex. These data demonstrate the cooperativity between HIV-1 Tat and the Puralpha in deregulation of the NGF signal transduction pathway in neuronal cells.
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PMID:Tat-induced deregulation of neuronal differentiation and survival by nerve growth factor pathway. 1249 Nov 58

The first series of synthetic 1-aza-9-oxafluorenes with cytostatic activities in the micromolar range was evaluated as cyclin-dependent kinase (CDK1) inhibitors. Activity was found to be selective in comparison to the inhibition of other kinases within the CDK family. Compounds were shown to inhibit the membrane-efflux pump P-glycoprotein responsible for multidrug resistance in cancer cells. First structure-activity relationships are discussed.
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PMID:Evaluation of the first cytostatically active 1-aza-9-oxafluorenes as novel selective CDK1 inhibitors with P-glycoprotein modulating properties. 1259 68

Increasing evidence has indicated that perturbation of cyclins is one of the major factors leading to cancer. The aim of this study was not only to investigate various cell cycle-related kinase activities in hepatocellular carcinoma (HCC), but also to analyze the difference of cell cycle-related kinase activity levels between hepatitis C virus (HCV)-induced HCC and HCV-induced cirrhosis. The protein levels of cyclins D1, E, A, and H, and of cyclin dependent kinase 1 (Cdk1), Cdk2, Cdk4, Cdk6, and Cdk7 in HCC and in surrounding nontumorous cirrhosis were determined by Western blot. The enzymatic activities of cyclins D1, E, A, Cdk1, Cdk4, Cdk6, Cdk7, and Wee1 were measured using in vitro kinase assays. Protein levels and kinase activities of cyclin D1, Cdk4, cyclin E, cyclin A, and Wee1 were significantly elevated in HCC compared with surrounding cirrhotic tissues. The enhanced cyclin D1-related kinase activity in HCC was accompanied by the up-regulation of Cdk4 activity, but not Cdk6 activity. The kinase activities of Cdk6, Cdk7, and Cdk1 did not differ between HCC and surrounding cirrhotic tissues. In addition, the protein levels and kinase activities of cyclin D1, Cdk4, and cyclin E were higher in poorly differentiated HCC and advanced HCC. In conclusion, the increases of cyclin D1, Cdk4, cyclin E, cyclin A, and Wee1 play an important role in the development of HCC from cirrhosis. Cyclin D1, Cdk4, and cyclin E activation may be closely related to the histopathologic grade and progression of HCC.
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PMID:Cyclins and cyclin-dependent kinases: comparative study of hepatocellular carcinoma versus cirrhosis. 1260 50

Overexpression of cyclin D1 is necessary but by itself insufficient for the development of mantle cell lymphoma (MCL). To identify pathways in the pathogenesis of MCL and the blastoid variant (MLC-BV), we compared the gene-expression profiles of microdissected normal mantle cells, MCL, and MCL-BV by oligonucleotide microarrays and quantitative reverse transcriptase PCR (QRT-PCR). We identified and confirmed the overexpression of several genes in MCL-BV that are involved in the cell cycle control at the G1/S and G2/M checkpoints or inhibit apoptotic cell death. The highly expressed cyclin dependent kinase 4 (CDK4) is a cell cycle kinase that associates with cyclin D1 for the progression through the G1/S checkpoint, whereas overexpression of cdc28 protein kinase 1 (CKS1) blocks the inhibition of the cyclin D1/CDK4 complex by the CDK inhibitor p27/Kip1. Other highly expressed genes in MCL-BV that promote the cells through the G1/S-checkpoint include the oncogenes B-Myb, PIM1, and PIM2, and passage through the G2/M-checkpoint is enhanced by high levels of cdc25B. Furthermore, two highly expressed genes that inhibit apoptosis are defender against cell death (DAD1) and RSK1. In summary, our microarray and QRT-PCR analyses identified several candidate genes whose expression increased when comparing normal follicular mantles with MCL and MCLBV, suggesting a potential pathogenic role in the evolution of MCL-BV.
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PMID:Cell cycle alterations in the blastoid variant of mantle cell lymphoma (MCL-BV) as detected by gene expression profiling of mantle cell lymphoma (MCL) and MCL-BV. 1260 34

The central involvement of estrogen in the development of the mammary gland and in the genesis of breast cancer has lent impetus to studies of the links between estrogen action and the cell cycle machinery. Recent studies of the estrogenic regulation of molecules with known roles in the control of G1/S phase progression have resulted in significant advances in understanding these links. Estrogens independently regulate the expression and function of c-Myc and cyclin D1 and the induction of either c-Myc or cyclin D1 is sufficient to recapitulate the effects of estrogen on cell cycle progression. These pathways converge at the activation of cyclin E-Cdk2 complexes. The active cyclin E-Cdk2 complexes are depleted of the cyclin dependent kinase (CDK) inhibitor p21(WAF1/CIP1) because of estrogen-mediated inhibition of nascent p21(WAF1/CIP1). Insulin and estrogen synergistically stimulate cell cycle progression, and the ability of estrogen to antagonize an insulin-induced increase in p21(WAF1/CIP1) gene expression appears to underlie this effect. Antiestrogen treatment of MCF-7 cells leads to an acute decrease of c-Myc expression, a subsequent decline in cyclin D1, and ultimately arrest of cells in a state with features characteristic of quiescence. An antisense-mediated decrease in c-Myc expression results in decreased cyclin D1 expression and inhibition of DNA synthesis, mimicking the effects of antiestrogen treatment and emphasizing the importance of c-Myc as an estrogen/antiestrogen target. These data identify c-Myc, cyclin D1, p21(WAF1/CIP1) and cyclin E-Cdk2 as central components of estrogen regulation of cell cycle progression and hence as potential downstream targets that contribute to the role of estrogen in oncogenesis.
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PMID:Estrogen and antiestrogen regulation of cell cycle progression in breast cancer cells. 1279 Jul 80

(Ataxia-telangiectasia mutated gene (ATM) functions in control of cell cycle checkpoints in responding to DNA damage and protects cells from undergoing apoptosis. Knock-out within tumor cells of endogenous ATM will achieve therapeutic benefits and enable a better understanding of the decisive mechanisms of cell death or survival in response to DNA damaging agents.) In present paper, we sought to characterize the cell cycle checkpoint profiles in U937-ASPI3K, a U937 cell mutant that was previously established with endogenous ATM knock-out phenotype. Synchronized U937-ASPI3K was exposed to 137Cs irradiation, G1, S, G2/M cell cycle checkpoint profiles were evaluated by determining cell cycle kinetics, p53/p21 protein, cyclin dependent kinase 2 (CDK2) and p34CDC2 kinase activity in response to irradiation. U937-ASPI3K exhibited multiple defects in cell cycle checkpoints as defined by failing to arrest cells upon irradiation. The accumulation of cellular p53/p21 protein and inhibition of CDK kinase was also abolished in U937-ASPI3K. It was concluded that the stable expression of anti-sense PI3K cDNA fragment completely abolished multiple cell cycle checkpoints in U937-ASPI3K, and hence U937-ASPI3K with an AT-like phenotype could serves as a valuable model system for investigating the signal transduction pathway in responding to DNA damaging-based cancer therapy.
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PMID:Multiple defects of cell cycle checkpoints in U937-ASPI3K, an U937 cell mutant stably expressing anti-sense ATM gene cDNA. 1284 Sep 9

Terminally differentiated neurons irreversibly withdraw from the cell cycle. The mechanisms governing the activity of cyclin D 1, a key regulator of the cell cycle, during neuronal cell cycle withdrawal are not fully understood. This study shows that cyclin D 1 became predominantly cytoplasmic in differentiated cortical neurons. Cytoplasmic cyclin D 1 assembled with cyclin dependent kinase 4 (CDK 4), and the CDK inhibitors p21Cip1 and p27Kip1. Although forced expression of p 21 caused cyclin D 1 nuclear accumulation, the inhibition of its nuclear export by inhibiting GSK-3 beta activity had no effect. Furthermore, ectopically expressed cyclin D 1 entered the nucleus of proliferating nervous, but not that of differentiated neurons, whereas ectopic cyclin D 1 in quiescent fibroblasts accumulated in the nucleus and induced cell cycle progression. These results indicate that cyclin D 1 nuclear localization is tightly inhibited in terminally differentiated neurons, and suggest that the regulation of its nuclear import plays a role in neuronal cell cycle withdrawal.
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PMID:[Prevention of cyclin D1 nuclear localization in terminally differentiated neurons]. 1287 51

Cyclins are essential regulators of the cell division cycle. Cyclin B associates with the cyclin-dependent kinase 1 (cdc2) to form a complex which is required for cells to undergo mitosis. In mammalian cells three B-type cyclins have been characterised, cyclin B1, B2 and B3. The cell cycle-dependent synthesis of cyclin B1 and B2 has been investigated in detail displaying maximum expression in G2 which is mainly regulated on the transcriptional level. We have previously shown that this regulation of the mouse cyclin B2 promoter is controlled by a cell cycle-dependent element (CDE) and the cell cycle genes homology region (CHR). Also in a number of other genes CDE/CHR elements repress transcription in G0 and G1 and lead to relief of repression later during the cell cycle. Here, we compare human and mouse cyclin B2 promoters. Both promoters share only nine regions with nucleotide identities. Three of these sites are CCAAT-boxes spaced 33 bp apart which can bind the NF-Y transcriptional activator. NF-Y binding to the human cyclin B2 promoter could be shown by chromatin immunoprecipitation (ChIP) assays. Activation by NF-Y is responsible for more than 93% of the total promoter activity as measured by cotransfecting a plasmid coding for a dominant-negative form of NF-YA. Cell cycle-dependent repression is regulated solely through a CHR. Surprisingly, in contrast to the mouse promoter the CHR in the human cyclin B2 promoter does not rely on a CDE site in tandem with it. Together with the recently described mouse cdc25C promoter, human cyclin B2 is the second identified gene which solely requires a CHR for its cell cycle regulation.
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PMID:Three CCAAT-boxes and a single cell cycle genes homology region (CHR) are the major regulating sites for transcription from the human cyclin B2 promoter. 1290 59


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