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)

The control of cell cycle progression is necessary for accuracy in the replication of DNA and the distribution of genetic information to daughter cells. Disturbances in progression of the cell cycle may result in the loss of genomic integrity, a 'hallmark' of cancer cells. Extensive consumption of alcoholic beverages is a risk factor associated with the development of various human epidermoid cancer including oral and pharyngeal squamous cell carcinomas. However, effects of ethanol on cell cycle progression and on the expression of genes associated with the cell cycle have not been studied. We report here that exposure of human epithelial cells to ethanol, at concentration (100-200 mM) that do not cause cell death, (a) does not affect or only reduces slightly the cellular level of p53 protein, (b) upregulates the transcription of the WAF1/CIP1 gene, (c) inhibits the Cdk2 activity, and (d) reduces the rate of cellular proliferation by inducing a delay in G1 phase transition. The results also indicate that, at these non-cytotoxic concentrations, ethanol exhibits its effects through a p53-independent mechanism.
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PMID:Ethanol upregulates the expression of p21 WAF1/CIP1 and prolongs G1 transition via a p53-independent pathway in human epithelial cells. 929 7

We have studied the effects of olomoucine, a selective inhibitor of cdk2, cdc2 and MAP kinase, on the rate of proliferation and the cell cycle progression in human cancer cells in culture. Olomoucine inhibited the growth of the KB 3-1, MDA-MB-231 and Evsa-T cell lines in a concentration-dependent manner, with EC50 values of 45, 75 and 85 microM, respectively. Incubation of exponentially growing KB 3-1 cells in the presence of olomoucine led to an increased proportion of cells in G1 phase after 24 h or more of incubation. Olomoucine failed to rapidly affect the phosphorylation of the Rb tumor-supressor gene product. However, [3H]thymidine incorporation into the cell DNA was rapidly inhibited. We show that this inhibition is due, at least in part, to the diminution of thymidine entry into the cells. Surprisingly, all these cell lines, when synchronized at the G1/S interface and relaxed in the presence of olomoucine, progressed unhindered through the S phase. Under these conditions, the G2 phase transit was markedly retarded but not prevented. Insufficient permeability of the cell membrane to olomoucine may explain the low activity of the drug.
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PMID:Effects of olomoucine, a selective inhibitor of cyclin-dependent kinases, on cell cycle progression in human cancer cell lines. 930 May 78

Microtubules are one of the major filament of the cytoskelton and play a role in various biological functions such as mitosis, cell motility and intracellular transport. Therefore, microtubules are considered one of the most important molecular targets for cancer chemotherapy. Tubulin is one of the major microtubular components, and its polymerization and depolymerization regulate microtubular dynamics. Other microtubular components such as microtubule-associated protein (MAPs), actin, and intermediate and microfilaments have also been demonstrated to be involved in microtubular dynamics. Recent studies provide evidence that the functions of MAPs and filaments in microtubule assembly are regulated by phosphorylation, which is catalyzed by mitogenactivated protein kinase (MAP kinase) and cdc2 kinase. Antimitotic agents that disrupt microtubules can be classified in two categories according to the mechanism of action, vinca alkaloids and taxanes. Vinca alkoloids, estramustine, rhizoxin, and E7010 inhibit microtubule polymerization. In contrast, taxanes such as paclitaxel and docetaxel promote polymerization of microtubules and enhance microtubule stability. We have demonstrated that paclitaxel inhibits the catalytic activity of MAP kinase and cdc2 kinase in lung cancer cell lines. This biological effect may be responsible for the increased affinity between MAP2 and tubulins, resulting in promotion of microtubule assembly. Factors that contribute to the resistance to antimitotic agents include intracellular accumulation of the drugs, genetic or functional alternations in tubulin, and alternations in MAP kinase cascade. Antimitotic agents showed a broad spectrum of preclinical antitumor activity. Clinical trials of taxanes revealed that they were effective for several cancers which were advanced or resistant against other anticancer drugs, especially for breast cancers, ovarian cancers and non-small cell lung cancers.
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PMID:[Antimitotic agents]. 930 50

Immunohistochemistry was used to analyze samples of 40 newly diagnosed childhood acute lymphoblastic leukemias (ALL) for their expression of cyclins (D1, E, A), cyclin-dependent kinases (cdk2, cdk4) and tumor-suppressor genes (pRb, p16INK4A), in order to discover whether or not the expression of these various proteins may be of prognostic relevance for the survival of children with ALL. Patients with ALL who were strongly positive for cyclin D1 had a lower probability of remaining in first continuous remission than ALL patients who were negative or weakly positive for this trait. There was also a significant correlation between expression of cyclin D1 and frequency of recurrence. For cyclin E and cyclin A, in contrast, there was no difference in the duration of relapse-free-intervals or the frequency of recurrence in patients. Children with cdk4-positive ALL had a lower probability of remaining in first continuous remission than children with cdk4-negative ALL. No prognostic relevance was found for cdk2. Patients with ALL who expressed pRb had a higher probability and patients who expressed p16 a lower probability of remaining in first continuous remission, but the results were not statistically significant. This investigation demonstrated that cyclin D1 and cdk4 were the most important prognostic factors for children with ALL, and that the combination of them showed the strongest prognostic relevance.
Int J Cancer 1997 Oct 21
PMID:Prognostic implications of cyclins (D1, E, A), cyclin-dependent kinases (CDK2, CDK4) and tumor-suppressor genes (pRB, p16INK4A) in childhood acute lymphoblastic leukemia. 935 72

Progression through the mammalian cell cycle is controlled by a series of cyclins, cyclin-dependent kinases (cdks) and cdk inhibitors. Cyclin D1, cdk4 and the tumour suppressors p16 and retinoblastoma protein (pRb) are thought to comprise a linked system governing cell passage through the G1 phase of the cell cycle. Extending an earlier study on cyclin D1 expression, a series of resectable non-small cell lung carcinomas (NSCLCs) was examined for defects in other elements of this control system. Forty-six of fifty-one NSCLC specimens exhibited at least one alteration of these cell-cycle regulators. Immunohistochemical analysis revealed that 33% and 47% of the tumours failed to express pRb and p16, respectively. Failure to detect pRb did not correlate with loss of heterozygosity at the RB1 locus. Eleven of 12 tumours showing positive (normal) pRb staining over-expressed nuclear localised cyclin D1, including 8 with amplification of the cyclin D1 gene (CCNDI). However, in a number of lesions (n = 5) where cyclin D1 was over-expressed but localised to the cytoplasm, pRb expression was undetectable. Sequencing of exons 1 and 2 of the p16 gene (CDKN2) revealed 3/51 tumours with somatic mutations (in addition to 1 case with a germ-line alteration). All of these lesions were positive for p16 protein. No clear homozygous deletions of CDKN2 were observed by multiplex PCR. As assessed by immunostaining using a p16 monoclonal antibody, there was an inverse correlation of pRb and p16 down-regulation. Whilst patients with tumours over-expressing cyclin D1 had a significantly lower incidence of local relapse, the group whose tumours failed to express pRb had a significantly greater risk of local relapse and tended to have shortened event-free survival. Our data show that alteration of at least one cell cycle-regulator gene occurs in the majority of resectable NSCLCs.
Int J Cancer 1997 Oct 21
PMID:G1 control gene status is frequently altered in resectable non-small cell lung cancer. 935 81

The retinoblastoma gene (RB-1) was originally identified as the gene involved in hereditary retinoblastoma. However, RB-1 mutations are found in a number of common mesenchymal and epithelial malignancies. The retinoblastoma protein (pRB) acts as a transcriptional regulator of genes involved in DNA synthesis and cell-cycle control. In this regard, the functional interaction between pRB and the E2F transcription factor family appears to be critical. The pRB-E2F interaction is, in turn, regulated by a pathway that includes cyclin D1, cdk4, and p16. Mutations that affect this pathway have been documented in nearly every type of adult cancer. Thus, perturbation of pRB function may be required for the development of cancer. Insights into the biochemical functions of pRB, and its upstream regulators, may form the basis for the development of novel antineoplastic agents.
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PMID:Role of the retinoblastoma protein in the pathogenesis of human cancer. 936 57

The passage of mammalian cells through the restriction point into the S phase of the cell cycle is regulated by the activities of Cdk4 and Cdk6 complexed with the D-type cyclins and by cyclin E/Cdk2. The activities of these holoenzymes are constrained by CDK inhibitory proteins. The importance of the restriction point is illustrated by its deregulation in many tumour cells and upon infection with DNA tumour viruses. Here we describe the properties of cyclins encoded by two herpesviruses, herpesvirus saimiri (HVS) which can transform blood lymphocytes and induce malignancies of lymphoid origin in New World primates, and human herpesvirus 8 (HHV8) implicated as a causative agent of Kaposi's sarcoma and body cavity lymphomas. Both viral cyclins form active kinase complexes with Cdk6 that are resistant to inhibition by the CDK inhibitors p16(Ink4a), p21Cip1 and p27Kip1. Furthermore, ectopic expression of a viral cyclin prevents G1 arrest imposed by each inhibitor and stimulates cell-cycle progression in quiescent fibroblasts. These results suggest a new mechanism for deregulation of the cell cycle and indicate that the viral cyclins may contribute to the oncogenic nature of these viruses.
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PMID:Herpes viral cyclin/Cdk6 complexes evade inhibition by CDK inhibitor proteins. 936 57

Arsenite, a unique human carcinogen, induces many types of cytogenetic alterations, such as sister chromatid exchanges, chromosome aberrations, and endoreduplication in a variety of in vivo and in vitro systems. Cytogenetic alterations are frequently associated with cancer development. The purpose of this study was to explore how arsenite induces cytogenetic alterations in human skin fibroblasts (HFW). The present results show that treatment of G2-enriched HFW cells with 5 microM arsenite results in significant delay of cell cycle progression, accumulation of mitotic cells, and prolongation of mitosis. Arsenite-induced G2 and mitotic delay are accompanied by accumulation of cyclin B1 and hyperphosphorylation of cdc2 and Mos proteins. In addition to mitotic delay and prolongation, arsenite treatment also induced out-of-phase centromere separation and alterations of chromosome segregation, such as the appearance of c-metaphase, ball-metaphase, and lagged chromosomes. Unlike spindle poisons, arsenite at the dose range used did not inhibit the spindle fiber formation but conceivably deranges the spindle apparatus. By analyzing the karyotype of established subclones surviving arsenite injury, 18% (8 of 44) showed one chromosome loss, whereas all 26 subclones derived from the untreated cultures were diploid. Furthermore, most arsenite-treated clones manifest prolonged life span (86 +/- 18 population doublings) as compared to those derived from the untreated cultures (44 +/- 11 population doublings). Unfortunately, none became immortal. Collectively, treatment of the G2-enriched HFW cells with arsenite can disturb the mitotic events and subsequently induce chromosome loss.
Cancer Res 1997 Nov 15
PMID:Sodium arsenite disturbs mitosis and induces chromosome loss in human fibroblasts. 937 2

To investigate the role of cyclin D1 in the regulation of lung cancer cell growth, we created five stably transfected cell lines carrying a cyclin D1 antisense construct. The transfected cells exhibited a marked decrease in the rate of cell growth, in contrast to the original lines (A549 and NCI-H441). The expression of several cell cycle-regulating proteins, including cyclin A, the cyclin-dependent kinases (cdk) 2 and cdk4, in addition to cyclin D1 itself, was markedly decreased. The expression of one cdk inhibitor, p21WAF1/CIP1, increased in the A549-derived cell lines. A specific target of cyclin D1 activity, the growth-suppressing product of the retinoblastoma gene, pRb, exhibited decreased expression and a decreased level of phosphorylation in the transfected cells. Decreased expression of pRb due to a significant increase in its turnover rate suggested that the stability of the protein may depend on phosphorylation by cyclin D1-dependent cdk activity. In addition to the impact on pRb stability, decreased expression of cyclin D1 induced susceptibility to cell death after withdrawal of exogenous growth factors in the antisense transfected cell lines, a response that was not observed in the original cancer cell lines. We conclude that abrogation of cyclin D1 overexpression in lung cancer cells disrupts several key pathways that are required for uncontrolled cell growth and induces those that lead to cell death after growth factor deprivation. Therefore, we speculate that use of antisense cyclin D1 expression in appropriate gene vectors could be a useful method for retarding lung cancer cell growth in accessible tumors such as those of the lung epithelium.
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PMID:Cyclin D1 antisense RNA destabilizes pRb and retards lung cancer cell growth. 937 20

Mantle cell lymphoma (MCL) has recently become generally accepted as a subentity of malignant lymphomas that is characterized by the chromosomal translocation t(11;14)(q13;q32), resulting in the overexpression of cyclin D1. Cyclin D1 forms a complex with cell cycle-dependent kinase (cdk) 4, which inactivates the retinoblastoma protein (pRB) via phosphorylation. However, in transgenic mice, the overexpression of cyclin D1 alone is not sufficient for the development of malignant lymphoma. To determine whether other members of the pRB pathway contribute to the malignant transformation of MCL, we analyzed 37 cases of MCL that were well characterized by morphology, immunophenotype, and/or interphase cytogenetics [detection of t(11;14)(q13;q32)]. Interphase fluorescence in situ hybridization was performed using a cosmid contig (250 kb) of the CDKN2/p16 region (encoding an inhibitor of the cyclin D1/cdk4 complex) and a phage contig (200 kb) of the Rb region. CDKN2/p16 deletion was detected in 15 cases (41%), including 6 homozygous deletions; Rb was deleted in 15 cases (41%), all of which were hemizygous deletions. Nine cases (24%) had deletions of both CDKN2/p16 and Rb. Further analysis of a subset of 17 MCLs revealed a highly significant correlation between CDKN2/p16 deletion and proliferation index, determined by the rate of Ki67 expression (P = 0.014; t test). No significant correlation was found between CDKN2/p16 deletion and the blastoid variant of MCL (P = 0.23; Fisher's test) or between proliferation index and blastoid morphology (P = 0.51; t test). Deletion of Rb did not have any impact on cell proliferation in addition to CDKN2/p16 deletion (P = 0.76; t test). Additional analysis of 13q14 deletions suggests that these deletions may target another gene telomeric to Rb. We conclude that deletion of CDKN2/p16 occurs in approximately one-half of MCLs and is a more relevant indicator of the proliferative features as compared to morphological criteria. In contrast, although deletions of chromosomal band 13q14 are frequent in MCL, inactivation of Rb seems not to be involved in the pathogenesis of MCL.
Cancer Res 1997 Oct 15
PMID:Alterations of the cyclin D1/p16-pRB pathway in mantle cell lymphoma. 937 76


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