Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Eukaryotic cell division is regulated by cyclins, cyclin-dependent kinases (CDK), and cyclin-dependent kinase inhibitors (CKI). Genes encoding these proteins are mutated or deleted in many types of cancer. For example, 20%-30% of B-lineage acute lymphoblastic leukemias (ALL) have deletions in the CKI known as INK4a. The contribution of INK4a deletions to the progression of B-lineage ALL is uncertain, partially due to a paucity of data on expression in normal B-cell precursors. We therefore conducted a comparative analysis of normal and leukemic human B-cell development for the expression of cyclins, CDK, and CKI. Specific stages of human B-cell development from normal bone marrow were purified by fluorescence-activated cell sorting. The sorted populations and B-lineage ALL cell lines (BLIN-1, 2, 3, 4) were examined for expression of cyclins, CDK, and CKI by reverse transcriptase polymerase chain reaction (RT-PCR) and Western blotting.RT-PCR analysis showed that cyclin D2, cyclin D3, CDK4, and CDK6 were ubiquitously expressed in normal B-cell development and in the BLIN ALL cell lines. The p19(INK4d) CKI was the most commonly expressed member of the INK4 family, whereas p16(INK4a) was more weakly and variably expressed. Expression of the p57(KIP2) CKI varied as a function of the stage of B-cell development. Analysis of normal B-cell precursors by Western blotting indicated that CDK4, CDK6, p19(INK4d), and p57(KIP2) were expressed, whereas p16(INK4a) was not detected. Cyclin D/CDK expression in normal and leukemic human B-cell precursors is similar to expression of these proteins in human and murine mature B cells. In contrast, the ubiquitous expression of p19(INK4d) has not been previously described in human or murine B-lineage cells. Our results suggest that loss of INK4a may only minimally contribute to tumor cell progression in B-lineage ALL, since expression of INK4d could provide a compensatory function as a cyclin-dependent kinase inhibitor.
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PMID:Novel expression of cyclin-dependent kinase inhibitors in human B-cell precursors. 1130 Nov 89

Progression through the mammalian cell cycle is facilitated by cyclin-cyclin-dependent kinase (cdk) complexes, which are activated at specific points during the cell cycle. Alteration in cyclin-cdk complexess may lead to altered cell cycle and tumorigenesis. In this study, we analyzed expression of cyclins A, D1, D3 and E in tumor tissue from 170 patients with primary invasive breast carcinomas. Immunohistochemical methods were used to detect protein expression of these cyclins. We detected positive immunoreactivity in 55 (32%), 22 (13%), 38 (22%) and 37 (21.8%) of the samples for cyclins A, D1, D3 and E, respectively. A highly statistically significant association was observed between expression of cyclin A and early relapse (p = 0.001 univariate analysis, p = 0.006 multivariate analysis) as well as cancer-specific death (p < 0.0001) during the follow-up time. No association was observed between cyclin D1 or cyclin E, respectively, and relapse of disease or survival, while cyclin D3 over-expression was associated with development of metastases during follow-up (p = 0.005 univariate analysis, p = 0.01 multivariate analysis). However, cyclin D3 did not show any statistically significant association when cancer-specific death was examined in a multivariate analysis (Cox regression for survival function).
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PMID:Over-expression of cyclin A is highly associated with early relapse and reduced survival in patients with primary breast carcinomas. 1141 Aug 78

Different studies have already shown that the isolated inactivation of p21, p16, or p27 cyclin-dependent kinase inhibitors (CKIs) is associated with increased growth fraction, tumor progression, or decreased overall survival in cases of non-Hodgkin's lymphoma. In this study we linked molecular study of the p53 and p16 genes with immunohistochemical analysis of p27 expression in a group of aggressive B-cell lymphomas [large B-cell lymphomas (LBCLs) and Burkitt's lymphomas]. This was done to analyze the relationship between p53 and p16 silencing, p27 anomalous overexpression, and clinical follow-up, testing the hypothesis that the accumulation of CKI alterations could confer to the tumors a higher aggressivity. In a group of 62 patients, p53 inactivation as a result of mutation was observed in 11 cases (18%) and p16 silencing was seen in 27 cases (43.5%) as a result of methylation (20 of 62), 9p21 deletion (7 of 44), or p16 mutation (2 of 62). The simultaneous inactivation of p53 and p16 was detected exclusively in five LBCL cases. Anomalous expression of p27, which has been proven to be associated with the absence of p27/CDK2 complexes and the formation of p27/cyclin D3 complexes where p27 is inactivated, was detected in 19 of 61 cases (31%). Cases characterized by p27 anomalous expression display concurrent inactivation of p21 (provided by p53 mutations) and/or p16 CKIs in 11 of 14 LBCL cases (P = 0.040). When the relationship between the association of inactivated CKIs and overall survival was considered, a significant relationship was found between a lower overall survival probability and an increased number of inactivated CKIs in LBCL cases, with the worst prognosis for the cases displaying concurrent p53, p16, and p27 alterations. This proves that simultaneous inactivation of different tumor suppressor pathways does indeed take place, and that tumor aggressiveness takes advantage of this CKI-concerted silencing. In this same series of data, Burkitt's lymphoma patients seem to behave in a different way than LBCLs, with p53 and p16 alteration being mutually exclusive and the association with p27 anomalous expression not being clinically significant. These facts seem to support that the additive effect of the inactivation of different CKIs could be dependent of the histological type.
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PMID:Overall survival in aggressive B-cell lymphomas is dependent on the accumulation of alterations in p53, p16, and p27. 1143 67

Peripheral homeostasis and tolerance requires the suppression or removal of excessive or harmful T lymphocytes. This can occur either by apoptosis through active antigen-induced death or cytokine withdrawal. Alternatively, T cell activation can be suppressed by agents that activate the cAMP-dependent protein kinase (PKA) signaling pathway, such as prostaglandin E2. Stimulation of PKA inhibits lymphocyte proliferation and immune effector functions. Here we have investigated the mechanism by which activation of PKA induces inhibition of proliferation in human leukemic T cell lines. Using a variety of agents that stimulate PKA, we can arrest Jurkat and H9 leukemic T cells in the G(1) phase of the cell cycle, whereas cell viability is hardly affected. This G(1) arrest is associated with an inhibition of cyclin D/Cdk and cyclin E/Cdk kinase activity. Interestingly, expression of cyclin D3 is rapidly reduced by PKA activation, whereas expression of the Cdk inhibitor p27(kip1) is induced. Ectopic expression of cyclin D3 can override the growth suppression induced by PKA activation to some extent, indicating that growth inhibition of leukemic T cells by PKA activation is partially dependent on down-regulation of cyclin D3 expression. Taken together our data suggest that immunosuppression by protein kinase A involves regulation of both cyclin D3 and p27(kip1) expression.
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PMID:Protein kinase A regulates expression of p27(kip1) and cyclin D3 to suppress proliferation of leukemic T cell lines. 1145 38

The nuclear hormone 1alpha,25-dihydroxyvitamin D(3) induces cell cycle arrest, differentiation, or apoptosis depending on target cell type and state. Although the antiproliferative effect of 1alpha,25-dihydroxyvitamin D(3) has been known for years, the molecular basis of the cell cycle blockade by 1alpha,25-dihydroxyvitamin D(3) remains largely unknown. Here we have investigated the mechanisms underlying the G(1) arrest induced upon 1alpha,25-dihydroxyvitamin D(3) treatment of the human breast cancer cell line MCF-7. Twenty-four-hour exposure of exponentially growing MCF-7 cells to 1alpha,25-dihydroxyvitamin D(3) impeded proliferation by preventing S phase entry, an effect that correlated with appearance of the growth-suppressing, hypophosphorylated form of the retinoblastoma protein (pRb), and modulation of cyclin-dependent kinase (cdk) activities of cdk-4, -6, and -2. Time course immunochemical and biochemical analyses of the cellular and molecular effects of 1alpha,25-dihydroxyvitamin D(3) treatment for up to 6 d revealed a dynamic chain of events, preventing activation of cyclin D1/cdk4, and loss of cyclin D3, which collectively lead to repression of the E2F transcription factors and thus negatively affected cyclin A protein expression. While the observed 10-fold inhibition of cyclin D1/cdk 4-associated kinase activity appeared independent of cdk inhibitors, the activity of cdk 2 decreased about 20-fold, reflecting joint effects of the lower abundance of its cyclin partners and a significant increase of the cdk inhibitor p21(CIP1/WAF1), which blocked the remaining cyclin A(E)/cdk 2 complexes. Together with a rapid down-modulation of the c-Myc oncoprotein in response to 1alpha,25-dihydroxyvitamin D(3), these results demonstrate that 1alpha,25-dihydroxyvitamin D(3) inhibits cell proliferation by targeting several key regulators governing the G(1)/S transition.
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PMID:Inhibitory effects of 1alpha,25-dihydroxyvitamin D(3) on the G(1)-S phase-controlling machinery. 1146 60

Tumor necrosis factor-alpha (TNF) is well known for its cytotoxic effect on malignant cells. Its role in cell cycle control is relatively less known. In this study, we found that TNF induced G(1) arrest of TF-1 and MV4-11 cells while simultaneously causing apoptosis. Treatment of the cells with TNF for 48 h caused cell cycle arrest, accompanied by dephosphorylation of pRb and reduction in D-type cyclin expression. The down-regulation of the D-type cyclins resulted in approximately 50-80% decrease of the cyclin-dependent kinase activities. Cells treated with calpain-dependent inhibitor ALLN and apoptosis inhibitor zVAD-FMK suppressed degradation of IkappaBalpha and activation of caspase 3, respectively. However, treatment of cells with these two inhibitors was not able to prevent TNF-induced down-regulation of the D-type cyclins. In contrast, proteasome inhibitor MG-132 and lactacystin blocked both TNF-induced degradation of IkappaBalpha and down-regulation of D-type cyclins. These data suggest that down-regulation of D-type cyclins by TNF may be proteasome-proteolysis dependent. Additional support for this conclusion was obtained from experiments showing an increase of proteasome activity in TNF-treated cells and in vitro degradation of cyclin D3 by 26 S proteasome.
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PMID:Ubiquitin/proteasome-dependent degradation of D-type cyclins is linked to tumor necrosis factor-induced cell cycle arrest. 1186 73

The p58(PITSLRE) is a p34(cdc2)-related protein kinase that plays an important role in normal cell cycle progression. Elevated expression of p58(PITSLRE) in eukaryotic cells prevents them from undergoing normal cytokinesis and appears to delay them in late telophase. To investigate the molecular mechanism of p58(PITSLRE) action, we used the yeast two-hybrid system, screened a human fetal liver cDNA library, and identified cyclin D3 as an interacting partner of p58(PITSLRE). In vitro binding assay, in vivo coimmunoprecipitation, and immunofluorescence cell staining further confirmed the association of p58(PITSLRE) with cyclin D3. This binding was observed only in the G(2)/M phase but not in the G(1)/S phase of the cell cycle; meanwhile, no interaction between p110(PITSLRE) and cyclin D3 was observed in all the cell cycle. The overexpression of cyclin D3 in 7721 cells leads to an exclusively accumulation of p58(PITSLRE) in the nuclear region, affecting its cellular distribution. Histone H1 kinase activity of p58(PITSLRE) was greatly enhanced upon interaction with cyclin D3. Furthermore, kinase activity of p58(PITSLRE) was found to increase greatly in the presence of cyclin D3 using a specific substrate, beta-1,4-galactosyltransferase 1. These data provide a new clue to our understanding of the cellular function of p58(PITSLRE) and cyclin D3.
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PMID:Interaction of p58(PITSLRE), a G2/M-specific protein kinase, with cyclin D3. 1208 95

Knowledge of the role of cell-cycle regulators in the pathogenesis of acquired immune deficiency syndrome-related non-Hodgkin's lymphomas (AIDS-NHLs) is scarce. Here we analyzed 86 systemic AIDS-NHLs and 20 AIDS-primary central nervous system lymphomas for expression of p27(Kip1), a negative regulator of cell-cycle progression belonging to the Kip family of cyclin-dependent kinase inhibitors. In parallel, we investigated the relationship between p27(Kip1), the lymphoma proliferation index, Epstein-Barr virus status, expression of cellular cyclin D3 and cyclin D1, and B-cell differentiation stage. We report that AIDS-immunoblastic lymphomas (AIDS-IBLs), either systemic or primarily localized to the central nervous system, consistently express p27(Kip1) protein (19 of 24 and 10 of 14, respectively) despite the high proliferative rate of the lymphoma clone, suggesting a failure of p27(Kip1) to inhibit the cell cycle in AIDS-IBL. Conversely, the remaining systemic AIDS-NHLs and AIDS-primary central nervous system lymphomas preferentially fail to express p27(Kip1). Expression of p27(Kip1) in Epstein-Barr virus-positive AIDS-NHLs generally associates with latent membrane protein 1 (LMP1) expression and is related to a late stage of B-cell differentiation, characterized by the BCL-6-/MUM1+/syn-1+/- phenotypic profile, whereas it seems to be unrelated to the expression of cellular cyclins. In B cells in vitro, induction of LMP-1 expression under the control of inducible promoters up-regulates expression of p27(Kip1), thus providing a putative mechanistic explanation for the association between LMP1 and p27(Kip1) observed in vivo. Overall, these data show that AIDS-IBL pathogenesis is characterized by loss of the inverse relationship between p27(Kip1) positivity and tumor growth fraction that is otherwise generally observed in normal lymphoid tissues and in most other types of NHLs.
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PMID:Expression of cyclin-dependent kinase inhibitor p27(Kip1) in AIDS-related diffuse large-cell lymphomas is associated with Epstein-Barr virus-encoded latent membrane protein 1. 1210 1

Cyclic AMP has been shown to inhibit cell proliferation in many cell types and to activate it in some. The latter has been recognized only lately, thanks in large part to studies on the regulation of thyroid cell proliferation in dog thyroid cells. The steps that led to this conclusion are outlined. Thyrotropin activates cyclic accumulation in thyroid cells of all the studied species and also phospholipase C in human cells. It activates directly cell proliferation in rat cell lines, dog, and human thyroid cells but not in bovine or pig cells. The action of cyclic AMP is responsible for the proliferative effect of TSH. It accounts for several human diseases: congenital hyperthyroidism, autonomous adenomas, and Graves' disease; and, by default, for hypothyroidism by TSH receptor defect. Cyclic AMP proliferative action requires the activation of protein kinase A, but this effect is not sufficient to explain it. Cyclic AMP action also requires the permissive effect of IGF-1 or insulin through their receptors, mostly as a consequence of PI3 kinase activation. The mechanism of these effects at the level of cyclin and cyclin-dependent protein kinases involves an induction of cyclin D3 by IGF-1 and the cyclic AMP-elicited generation and activation of the cyclin D3-CDK4 complex.
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PMID:The role of cyclic AMP and its effect on protein kinase A in the mitogenic action of thyrotropin on the thyroid cell. 1211 71

Surface-expressed BCR mediates the proliferation and expansion of antigen-specific B lymphocytes during a humoral immune response. Although several studies extensively characterize BCR proliferative signaling, the mechanisms linking these pathways to the cell cycle remain elusive. Using knockout mice, we show that c-Rel, a proto-oncogenic member of the NF-kappaB transcription factor family, is essential to BCR-mediated proliferation and cell cycle progression. Splenic B cells obtained from gene-targeted c-Rel knockout mice display a defective proliferation response to antigen receptor cross-linking, resulting in G(1) arrest. At the molecular level, we see that BCR stimulation of resting c-Rel(-/-) B cells fails to induce proper cyclin D3 and cyclin E expression, thereby negatively impacting G(1) phase cyclin-dependent kinase (CDK) activity. c-Rel-deficient B cells also exhibit incomplete phosphorylation of the Retinoblastoma protein (pRb) and poor expression of E2Fs, thus impeding the G(1) to S phase transition. Down-regulation of the pRb-related p130 protein during the G(0) to G(1) transition and removal of the CDK inhibitor p27(KIP1) in late G(1) parallel that of wild-type cells, suggesting that Rel-deficient B cells can exit the G(0) resting state and enter G(1) phase normally. Finally, we demonstrate that restoration of proliferation can be achieved partially upon reintroduction of cyclin E using a protein transduction method to reconstitute primary B cells. Collectively, these studies emphasize the importance of c-Rel in lymphocyte proliferation and oncogenesis, and highlight a requirement for c-Rel in establishing an effective humoral immune response.
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PMID:c-Rel regulation of the cell cycle in primary mouse B lymphocytes. 1214 27


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