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)

Anti-tumour and anti-carcinogenic activity of Picrorrhiza kurroa extract were studied in mice. Administration of 20-methylcholanthrene (20 MC) produced 100% induction of sarcoma in control mice, whereas the tumour incidence and tumour related deaths were significantly inhibited by the oral administration of P. kurroa extract 150 and 750 mg/kg body weight, respectively. The extract was also found to reduce the volume of transplanted solid tumours induced by Dalton's lymphoma ascites (DLA) tumour cell lines and increased the life span of ascites tumour bearing mice. P. kurroa extract inhibited yeast topoisomerase I and II enzyme activity when tested on Saccharomyces cerevisiae mutant cell cultures. The extract did not inhibit the enzyme involved in the activation of carcinogen and the cell cycle regulatory enzyme cdc2 kinase.
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PMID:Effect of Picrorrhiza kurroa extract on transplanted tumours and chemical carcinogenesis in mice. 1090 72

Five Epstein-Barr virus (EBV)-positive human lymphoma cell lines maintained in severe combined immune deficiency (SCID) mice were used to investigate the role of G1 cyclins in EBV-induced lymphomagenesis. All the primary tumors had been negative for EBV but became positive after establishment in SCID mice, with monoclonal immunoglobulin gene rearrangement and EBV monoclonality. To compare the expression status of G1 cyclins, these EBV-associated lymphoma lines (6 EBV[-] human SCID mouse lymphoma lines, 13 human B cell lymphomas and 8 samples of human tonsil tissue) were examined by reverse transcription-polymerase chain reaction-Southern blotting, Western blotting and immunohistochemistry. mRNA expression of cyclin D1 (CCND1), cyclin D2 (CCND2), cyclin E (CCNE), cyclin-dependent kinase 2 (CDK2) and 4 (CDK4) was found in all 3 types of lymphomas. Western blotting demonstrated identical results. Immunohistochemistry revealed CCND1 to be negative in all lymphomas. CCND2 was positive and restricted to the nuclei in all EBV(+) SCID mouse lymphoma lines, whereas it was limited to the cytoplasm in half of the EBV(-) counterparts. CCNE was positive in the nuclei in all EBV(+) but negative in all EBV(-) SCID mouse lymphoma lines. Immunoprecipitation of EBV(+) and (-) SCID mouse lymphomas for CCND1, CCND2 and CCNE vs. p21, PCNA and CDK2 or CDK4 demonstrated that, in EBV(+) SCID lines, CCND2/CDK4 complexes were present without binding to p21, suggesting independence from p21 regulation. In EBV(-) SCID mouse lymphomas, half of the cases showed complex formation of CCND2/CDK4 without binding of p21. In contrast, CCND1/CDK4 and CCNE/CDK2 were under regulation of p21 in both EBV(+) and (-) lymphomas. These results suggest that differential expression of CCNDs, CCNE and CDKs, as well as variation in their subcellular localization and association with CDK-inhibitor protein, could explain differences in cell proliferation between EBV(+) and EBV(-) lymphomas.
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PMID:Study on the role of G1 cyclins in Epstein-Barr virus-associated human lymphomas maintained in severe combined immune deficiency (SCID) mice. 1129 Oct 51

The cyclin-dependent kinase inhibitor p27KIP1 plays a key role in controlling cell proliferation. Here we show that p27KIP1 is commonly down-regulated in B-cells immortalized by Epstein-Barr virus (EBV) (lymphoblastoid cell lines, LCLs). The significance of this event for the immortal phenotype of LCLs is implied by a requirement for active cdk2-containing complexes for continued proliferation, and by the ability of the residual p27KIP1 to associate with cdk2. The mechanism of p27KIP1 attenuation is post-translational, but inhibitor studies reveal that the mechanism does not rely heavily on the proteasome. Instead we find that LCLs contain an activity that cleaves a caspase recognition site present in p27KIP1 (DPSD139). The activity is not associated with apoptosis and closely resembles a proliferation-associated caspase activity we previously described in the EBV-negative B-lymphoma-derived cell line BJAB. Importantly, proliferating LCLs contain a p27KIP1 product that is consistent with cleavage at this site. Inhibition of caspase(s) in vivo modulates p27KIP1 expression and strongly inhibits proliferation of IB4 cells. This inhibitor profile is identical to that displayed by the DPSD-directed caspase present in BJAB cells, suggesting that the caspase may fulfil a general role in controlling p27KIP1 expression in immortal lymphoid cell lines. Thus, apoptosis-independent cleavage appears to contribute to the maintenance of the low basal levels of p27KIP1 in B-cells immortalized by EBV.
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PMID:Regulation of p27KIP1 in Epstein-Barr virus-immortalized lymphoblastoid cell lines involves non-apoptotic caspase cleavage. 1171 84

To maintain the fidelity and integrity of blood formation, the cell cycle is under strict regulation during hematopoietic cell differentiation. This review summarizes recent studies, including our own, on the expression of cell cycle control genes in hematopoietic stem cells and its changes during differentiation. In our study, mRNA expression of cyclin-dependent kinases (cdks) and cyclins, except cdk4, was found to be generally suppressed in CD34+ cells isolated from the bone marrow of healthy volunteers. Among four major cdk inhibitors, p16 was expressed higher in CD34+ cells than in CD34 bone marrow mononuclear cells, whereas the amounts of p21 and p27 transcripts increased in the CD34 population. The behavior of cell cycle control genes during hematopoietic differentiation was classified into four patterns: (i) universal up-regulation (cdc2, cdk2, cyclin A, cyclin B, p21); (ii) up-regulation in specific lineages (cyclin D1, cyclin D3, and p5); (iii) no induction or stable expression (cdk4, cyclin D2, cyclin E, and p27); and (iv) universal down-regulation (p16). Lineage-specific changes include a sustained elevation of cdc2 and cyclin A during erythroid differentiation, cyclin D1 and p15 induction in myeloid lineage cells, and selective up-regulation of cyclin D3 during megakaryocyte development. These results suggest that the expression of cell cycle control genes is distinctively regulated in a lineage-dependent manner, reflecting the cell cycle characteristics of each lineage. Additional data from other laboratories are summarized and their significance is discussed in comparison with our findings.
Leuk Lymphoma 2002 Feb
PMID:Cell cycle control genes and hematopoietic cell differentiation. 1199 51

To investigate the role of cyclin B1 and cdc2 in the pathogenesis and progression of malignant lymphoma, 68 cases of nodal non-Hodgkin's lymphoma were examined about the expression of cyclin B1 and cdc2 along with p53 and Ki-67 by immunohistochemical method. The correlation of their expression with various clinicopathologic findings was also analyzed. Cyclin B1 and cdc2 were diffusely expressed in 39 cases (57.4%) and 54 cases (79.4%) out of 68 cases studied, respectively. The mean labeling indices of cyclin B1 and cdc2 in malignant lymphoma were 31.9% and 68.0%, respectively. In normal lymphoid tissues, cyclin B1 and cdc2 were expressed predominantly in the germinal center with mean labeling indices of 13.9% and 28.3%, respectively. The correlation between the expression of cyclin B1 and cdc2 was noted (p=0.013). The expression of Ki-67 was correlated with that of cyclin B1 (p=0.023) and marginally correlated with that of cdc2 (p=0.056). The expression of cdc2 and p53 in complete remission group to chemotherapy was lower than that of progressive disease group (p=0.047, p=0.049). In multivariate analysis, the clinical stage alone showed significance on overall survival (p=0.049). In conclusion, cyclin B1 and cdc2 appeared to be involved in the genesis or progression of malignant lymphoma and cdc2 can be a useful marker for response to chemotherapy.
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PMID:Expression of cyclin B1 and cdc2 in nodal non-Hodgkin's lymphoma and its prognostic implications. 1206 34

Monensin, a Na+ ionophore, regulates many cellular functions, including apoptosis. We investigated the in vitro antiproliferative effect of monensin on nine human lymphoma cell lines. Monensin significantly inhibited the proliferation of all the lymphoma cell lines examined with a 50% inhibition concentration of about 0.5 micromol/l, and induced a G1 and/or a G2-M phase arrest in these cell lines. To address the antiproliferative mechanism of monensin, we examined the effect of this drug on cell-cycle-related proteins in CA46 cells (both G1 and G2 arrest) and Molt-4 cells (G2 arrest). Treatment with monensin for 72 h decreased CDK4 and cyclin A levels in CA46 cells, and cdc2 levels in Molt-4 cells. In monensin-treated CA46 cells, increased p21-CDK2, p27-CDK2 and p27-CDK4 complex forms were observed. And, in monensin-treated Molt-4 cells, increased p21-cdc2 complex form was detected. Furthermore, the activities of CDK2- and CDK4-associated kinases were reduced in association with Rb hypophosphorylation in monensin-treated CA46 cells. The activity of cdc2-associated kinase was decreased in both cell lines, which was accompanied by induction of Wee1. Also, monensin induced apoptosis in these cell lines, as evidenced by annexin V binding assay and flow cytometric detection of sub-G1 DNA content. This apoptotic process was associated with loss of mitochondria transmembrane potential (Delta(psi)m). Taken together, these results demonstrated for the first time that monensin potently inhibits the proliferation of human lymphoma cell lines via cell cycle arrest and apoptosis.
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PMID:Monensin-mediated growth inhibition in human lymphoma cells through cell cycle arrest and apoptosis. 1240 77

3-Iodoacetamido benzoyl ethyl ester (3-IAABE) is a new compound synthesized in our laboratory. The primary action of 3-IAABE is to inhibit microtubule assembly by interacting with -SH groups on tubulin. In contrast to other known microtubule disrupters, 3-IAABE caused a double blockade in the cell cycle at G(1)-S transition and in M phase. The blockade was determined by cell cycle analysis and chromosome distribution. Kinase activities of cyclin E and cyclin-dependent kinase 2 responsible for the G(1)-S transition were increased, as were the activities of mitotic cyclin B and cdc2. 3-IAABE treatment also increased p53 expression and dephosphorylated (or activated) retinoblastoma protein. Investigation of the signal transduction pathway showed that 3-IAABE induced bcl-2 phosphorylation, followed by activation of caspase-9, -3, and -6, but not caspase-8. DNA fragmentation factor and poly(ADP-ribose) polymerase, the downstream substrates of caspase-3 and -6, were cleaved after 3 h of exposure to 3-IAABE, followed by DNA fragmentation. Pretreatment of the cells with inhibitors of caspase-9, -3, or -6, respectively, inhibited the cleavage of DNA fragmentation factor and poly(ADP-ribose) polymerase and thus inhibited the onset of apoptosis. 3-IAABE showed antitumor activities in the panel of 60 National Cancer Institute human tumor cell lines with total growth inhibition in the range of 0.22-4.3 micro M for solid tumor lines and 0.025-0.22 micro M for leukemia/lymphoma cell lines. The 3-IAABU total growth inhibition of phytohemagglutinin-stimulated healthy human lymphocytes was 450-fold greater than that of leukemic cells. 3-IAABE significantly inhibited the growth of human hepatocarcinoma (BEL-7402) in nude mice by 72% in tumor volume, more strongly than did vincristine (43 percent inhibition). Besides being a novel lead for the design of new anticancer tubulin ligands, the activity of 3-IAABE in the cell cycle may also help us to understand the molecular pharmacology of microtubule-active drugs.
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PMID:Double blockade of cell cycle at g(1)-s transition and m phase by 3-iodoacetamido benzoyl ethyl ester, a new type of tubulin ligand. 1241 32

Normal human B lymphocytes are sensitive to the growth-inhibitory action of transforming growth factor beta1 (TGFbeta1) whereas malignant B lymphoma cells are mostly resistant to TGFbeta1 effects. We examined the phosphorylation status of retinoblastoma protein and the activity of G(1) cyclin-dependent kinases (cdk) in TGFbeta1-sensitive malignant follicular lymphoma cells during the TGFbeta1 treatment. The kinase activity of cdk2, cdk4, and cdk6 was significantly reduced and hypophosphorylation of pRb on serine 795 (S795) and threonine 373 (T373) was observed. We examined the composition of cdk complexes and the level of cdk inhibitors to explain the inhibitory action of TGFbeta1 toward cdk activity. Both cdk4 and cdk6 were notably dissociated from cyclin D cofactors, while cyclin E-cdk2 complexes remained coupled in TGFbeta1-treated cells. TGFbeta1-induced growth arrest was associated with notably increased binding of p21(WAF1) to cdk4 and cdk6. No induction of cdk-inhibitor molecules of INK family was observed in TGFbeta1-treated DoHH2 cells. As shown, TGFbeta1-induced growth arrest of malignant B cells was associated with the activation of CIP/KIP family members of cdk inhibitors.
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PMID:Cyclin D-cdk6 complex is targeted by p21(WAF) in growth-arrested lymphoma cells. 1249 Jan 53

Previously, we showed that monensin, Na+ ionophore, potently inhibited the growth of acute myelogenous leukemia and lymphoma cells. Here, we demonstrate that monensin inhibited the proliferation of renal cell carcinoma cells with IC50 of about 2.5 micro M. Monensin induced a G1 or a G2-M phase arrest in these cells. When we examined the effects of this drug on ACHN cells, monensin decreased the levels of CDK2, CDK6, cdc2, cyclin A and cyclin B1 proteins. p21 and p27 proteins were increased by monensin. In addition, monensin markedly enhanced the binding of p21 with CDK2 and the binding of p27 with CDK6. Furthermore, the activities of CDK2- and CDK6-associated kinase were reduced in association with hypophosphorylation of Rb protein. Monensin also induced the apoptosis in several renal cell carcinoma cells. Apoptotic process of Caki-2 cells was associated with the changes of Bcl-2, Bcl-XL, caspase-9, caspase-3, caspase-7 proteins as well as mitochondria transmembrane potential (DeltaPsim) loss. Taken together, these results demonstrate for the first time that monensin inhibits the growth of renal cell carcinoma cells via cell cycle arrest or apoptosis.
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PMID:Monensin inhibits the growth of renal cell carcinoma cells via cell cycle arrest or apoptosis. 1263 79

Cyclin E and p27(Kip1) are key regulators for cyclin-dependent kinases (Cdks) acting at the G1-/S-phase transition of the cell cycle. Whereas cyclin E is required for the activation of Cdk2, p27(Kip1) is a specific Cdk inhibitor and can block cell division. High levels of cyclin E and low levels of p27(Kip1) expression have been associated with malignant lymphomas in humans; the level of p27(Kip1) is even considered of prognostic significance. However, mice that lack p27(Kip1) do not develop any malignant lymphomas despite a pronounced lymphoid hyperplasia in thymus and spleen. We have previously described transgenic mice that carry a construct in which the cyclin E cDNA is under the control of the CD2 promoter/enhancer region and thus express high levels of cyclin E in the T-cell compartment (CD2-cyclin E). These animals are not predisposed for T-cell lymphomas in the absence of other cooperating events. Here we show that T-cells from CD2-cyclin E mice that at the same time are deficient for p27(Kip1) show a significantly higher Cdk2 activity than cells from wild-type or single mutant animals. Accordingly, a higher percentage of T cells in S/G2/M phase is found in CD2-cyclin E/p27(Kip1-/-) mice. After a long latency period of over 200 days, these animals develop spontaneous monoclonal T cell lymphoma whereas none of the single CD2-cyclin E transgenic or the p27(Kip1)-deficient mice showed any sign of lymphoid malignancies. Our findings demonstrate that a deregulation of control mechanisms at the G1/S transition by the combination of high cyclin E levels in the absence of p27(Kip1) is sufficient to predispose mice to develop lymphoid malignancies and further support a role of p27(Kip1) as a tumor suppressor and of cyclin E as a dominant oncogene.
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PMID:Loss of p27(Kip1) cooperates with cyclin E in T-cell lymphomagenesis. 1264 75


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