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)

The antiproliferative effect of human bcl-2 gene transferred to E1A + c-Ha-ras-transformed rat embryo fibroblasts, which are characterized by the absence of cell cycle checkpoints after damage and by a high proapoptotic sensitivity was studied. Ionizing irradiation, adriamycin treatment, and serum starvation were shown to induce G1/S arrest in E1A + c-Ha-ras-transformants. Bcl-2 antiproliferative effect in E1A + c-Ha-ras-transformants was not associated with alterations in Cdk2, cyclin E and A contents. G1/S arrest following irradiation or serum starvation was accompanied by a decrease in kinase activity associated with cyclin E-cdk2, whereas G1/S arrest in tetraploid subpopulation after adriamycin treatment did not correlate with a decrease in cyclin E-associated kinase activity. Cyclin A-associated kinase activity did not decrease after any used treatment. Transfection of bcl-2 in E1A + c-Ha-ras-transformants resulted in elevated expression of cyclin-cdk complexes inhibitor p21/Waf-1, but not p27/Kip. Damaging agents caused p21/Waf-1 and p27/Kip accumulation, but bcl-2 overexpression did not restore functions of these inhibitors, since p21/Waf-1 and p27/Kip were unable to suppress cyclin-cdk complexes activity after damage. These results suggest that bcl-2 transfection in E1A + c-Ha-ras-transformants is likely to result in irradiation- or serum starvation-induced G1/S arrest accomplished by a selective decrease in cyclin E-associated kinase activity. Adriamycin-induced G1/S arrest seems to be realized via cyclin-cdk complexes activity-independent way involving antiproliferative targets downstream of cyclin E-cdk2 and cyclin A-cdk2 complexes.
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PMID:[Changes in the activity of cyclin-kinase complexes governing cell transition from G1 phase to DNA replication phase in E1A + c-Ha-ras transformants transfected with the bcl-2 gene]. 1272 79

Glucocorticoids (GC) induce cell cycle arrest and apoptosis in lymphoblastic leukemia cells. To investigate cell cycle effects of GC in the absence of obscuring apoptotic events, we used human CCRF-CEM leukemia cells protected from cell death by transgenic bcl-2. GC treatment arrested these cells in the G1 phase of the cell cycle due to repression of cyclin D3 and c-myc. Cyclin E and Cdk2 protein levels remained high, but the kinase complex was inactive due to increased levels of bound p27(Kip1). Conditional expression of cyclin D3 and/or c-myc was sufficient to prevent GC-induced G1 arrest and p27(Kip1) accumulation but, importantly, did not interfere with the induction of apoptosis. The combined data suggest that repression of both, c-myc and cyclin D3, is necessary to arrest human leukemia cells in the G1 phase of the cell division cycle, but that neither one is required for GC-induced apoptosis.
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PMID:Cyclin D3 and c-MYC control glucocorticoid-induced cell cycle arrest but not apoptosis in lymphoblastic leukemia cells. 1457 68

Epidemiological studies recently concluded that consumption of cruciferous vegetables such as broccoli, cabbage, and cauliflower, etc. is inversely related to prostate cancer risk, although the mechanism of prevention and the responsible phytochemicals are unknown. Since clinically significant prostate cancer eventually can grow independent of androgen, the association of the growth and tumorigenesis of such prostate cancer cells with sulforaphane (SFN) which is a predominant isothiocyanate in cruciferous vegetables, investigated. These vegetables contain high concentrations of glucosinolate glucoraphanin, which yield sulforaphane when hydrolyzed by the plant enzyme myrosinase. This study showed that exposure of human androgen-independent DU-145 prostate cancer cells to SFN resulted in the inhibition of growth and tumorigenesis, as revealed by a reduction in cell density, DNA synthesis, and clonogenesis. Analyses of the mechanism revealed that SFN mediated cell cycle arrest by modulating the expression and functions of cell cycle regulators. SFN induced signals that inhibited the activity of cyclin-dependent kinase cdk4 with an up-stream induction of cdk inhibitor p21WAF-1/Cip-1, and reduced cyclin D1. The inhibition of cdk kinase activity could be affected with <1 micro M SFN within 24 h. As a result, phosphorylation of Rb proteins, which activates the transition from G1- to S-phase, was significantly decreased and the cell cycle progression retarded. SFN also down-regulated the expression of bcl-2, a suppressor of apoptosis, and activated caspases to execute apoptosis in the prostate cancer cells. The regulators of cell cycle have thus been revealed as targets of sulforaphane for growth arrest and apoptosis induction. The potential of SFN, as an active dietary factor to inhibit initiation and post-initiation of prostate cancer carcinogenesis is discussed.
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PMID:Targeting cell cycle machinery as a molecular mechanism of sulforaphane in prostate cancer prevention. 1465 56

The molecular mechanism(s) behind the development of endocrine resistance in breast cancer remains controversial. Here, we compare the capability of oestrogen receptor (ER)-negative cells (MDA-231) versus ER-positive tamoxifen-sensitive cells (MCF-7) to handle DNA repair, transmit signals from damaged DNA, initiate cell death via apoptosis, and then to control transmitted signals from the cell cycle and to synthesize growth factors and receptors. Genes related to these events were studied by cDNA micro-array. Normal human breast cells (H2F) and human lymphoblastoid tumour cells (CEM) were used as controls. Of the 18 genes investigated, 10 genes showed differences in their expression between the cell types. The ER-negative cells showed higher expressions of BRCA1, BRCA2, cdc2, cyclin B1, cyclin D1, cyclin E, IGFBP-3, TGF-alpha, TGF beta 2 and a lower expression of TGF beta R1. No differences in the expressions of bax, bcl-2, p53, p21 and GADD45 were found between the two cell lines. We found that the ER-negative cells were characterized by: (1) a stimulated expression of growth factors and cell cycle regulation compounds, (2) improved DNA repair capacity, but (3) no change in DNA damage signals and apoptotic pathways. Improved DNA repair capacity of ER-negative cells would have a growth advantage over ER-positive tumours when receiving antitumour therapy.
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PMID:Genes related to growth regulation, DNA repair and apoptosis in an oestrogen receptor-negative (MDA-231) versus an oestrogen receptor-positive (MCF-7) breast tumour cell line. 1519 11

E1A + c-Ha-ras-transformants overexpressing bcl-2 oncogene are able to be arrested at the G1/S boundary of the cell cycle after DNA damage and upon serum starvation, this cell cycle blockage being accompanied by a decrease in the activity of cyclin E--Cdk2 complexes. Roscovitine-induced inhibition of cyclin-dependent kinases (Cdks) activity does not result in the G1/S arrest of E1A + c-Ha-ras + bcl-2-transformants. Roscovitine treatment causes an accumulation of G2/M cells, mainly at the expense of mitotic cells. However, the expression of Bcl-2 oncoproducts does not re-establish the regulation of mitotic events broken by introduction of E1A and c-Ha-ras oncogenes in normal cells, as revealed by the treatment of E1A + c-Ha-ras + bcl-2-transformants with nocodazole inducing mitotic arrest in normal cells. In spite of the elevated expression of antiapoptotic bcl-2 gene in transformants, nocodazole treatment results in mass apoptotic death preceded by polyploidy. Roscovitine also induces apoptosis with no polyploid cell accumulation being observed. Inhibition of Cdks activity with Roscovitine, as well as violation of microtubule depolymerization with nocodazole result in the apoptotic death in the tested cell lines sensitive (E1A + c-Ha-ras) and resistant (E1A + c-Ha-ras + bcl-2) to damaging agents. Thus, the application of Roscovitine, a specific inhibitor of Cdks, suggests that the decrease in Cdks activity in E1A + c-Ha-ras + bcl-2-transformants is not likely to be responsible for G1/S cell cycle arrest realization after damaging influences. Moreover, an antiproliferative effect of Bcl-2 in E1A + c-Ha-ras-transformants is restricted by restoration of cell cycle events at G1/S and G2/M boundaries, and does not concern the program of mitotic events regulation.
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PMID:[Antiproliferative effect of bcl-2 gene does not concern the control of mitotic events]. 1521 71

Malignant cell proliferation and accumulation depends on the balance between the rates of cell production and cell death. Recent evidence indicates that apoptosis is important in the development of cancer. Apoptosis is strictly controlled by various regulators, which can take part in the apoptotic process, proliferation and differentiation alike. Apoptosis was induced in myeloid cell line ML-2 by camptothecin, an inhibitor of topoisomerase I. After 18 hours of induction by camptothecin 50% of cells were apoptotic. The apoptotic effect of CAM was reversible in the cells studied. The induction of apoptosis influenced the expression of apoptosis and cell cycle regulators as detected by cDNA arrays, RT-PCR or Western blotting. According to cDNA arrays e.g. bax, bfl1, bak, pRb2, c-jun, jun-B were upregulated, and cdk4, cyclin B1, wee1, CRAF1, DP1 were downregulated. A number of other regulators like p21 and cdc25A, as well as some other genes linked with apoptosis, as p53 and the bcl-2 family, were up- or down-regulated as determined by real-time PCR. Changes in gene expression were found not only in the group of regulators of apoptosis and the cell cycle, but also among regulators of differentiation.
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PMID:Gene expression during camptothecin-induced apoptosis in human myeloid leukemia cell line ML-2. 1525 69

Here we show that introduction of human bcl-2 gene into E1A+c-Ha-ras-transformed rat embryo fibroblasts, which are highly susceptible to proapoptotic stimuli and fail to be arrested at the G(1)/S boundary following genotoxic stresses, results not only in inhibition of apoptosis, but also in restoration of the G(1)/S arrest. Overexpression of Bcl-2 did not affect proliferation rate and saturation density of E1A+c-Ha-ras transformants. Genotoxic stresses caused prolong G(1)/S arrest in Bcl-2-overexpressing transformants. Remarkably, levels and activities of Cdk2, cyclins E/A, cyclin E-Cdk2 and cyclin A-Cdk2 were unchanged during G(1)/S arrest. Introduction of Bcl-2 into E1A+c-Ha-ras-transformants resulted in accumulation of p21/Waf-1 without inhibiting cyclin-Cdk complexes. In both parental and Bcl-2-overexpressing cells, p21/Waf-1 was coimmunoprecipitated with ERK 1,2 and JNK 1,2, whereas p38 was found in complexes with p21/Waf-1 only in Bcl-2-overexpressing transformants. JNK 1,2 and p38 but not ERK 1,2 were detected in complexes with the exogenous Bcl-2. However, Bcl-2 did not affect phosphorylation of ERK 1,2, JNK 1,2 and p38. G(1)/S arrest induced by adriamycin and serum withdrawal (but not by IR) was accompanied by release of active forms of p38 from complexes with Bcl-2. We suggest that Bcl-2 restores stress-induced G(1)/S arrest without inhibiting cyclin-Cdk2 complexes and MAPK pathways.
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PMID:Restoration of G1/S arrest in E1A+c-Ha-ras-transformed cells by Bcl-2 overexpression. 1549 6

While the pesticide methoxychlor (MXC) has a variety of adverse effects on the female reproductive system, the effects of MXC on the ovarian surface epithelium (OSE) are unknown. Thus, this study tested the hypothesis that MXC alters the growth of the OSE. Mouse OSE cells were isolated by enzymatic digestion and cultured with vehicle, 3 microM of MXC, or 3 microM of 2,2-bis[p-hydroxyphenyl]-1,1,1,-trichloroethane (HPTE) for 14 days. After culture, proliferation and apoptosis were assessed by measurement of cell density, immunohistochemistry, and real-time polymerase chain reaction. Cell density was 66% greater for MXC-treated cells and 95% greater for HPTE-treated cells than controls (p < or = 0.05). The estrogen receptor blocker ICI 182,780 abolished MXC- and HPTE-induced increases in cell density. Proliferating cell nuclear antigen (PCNA) staining was positive in only 22 +/- 2.3% of controls, compared to 35 +/- 2.4% of MXC-treated cells and 40 +/- 2.4% of HPTE-treated cells (p < or = 0.05). The cell cycle regulators, cyclinD2 and cdk4, were significantly increased in MXC- and HPTE-treated cells compared to controls. The ApopTag assay demonstrated apoptotic cells in 4.8 +/- 0.45% of controls, 2.2 +/- 0.56% of MXC-treated cells, and 2.1 +/- 0.33% of HPTE-treated cells (p < or = 0.005). Expression of bcl-2 was significantly increased in MXC- and HPTE-treated cells, while bax was decreased in MXC- and HPTE-treated cells compared to controls. Collectively, these data indicate that MXC and HPTE stimulate OSE cell growth by increasing proliferation and inhibiting apoptosis. Further, since ICI 182,780 blocked MXC- and HPTE-induced OSE growth, these data suggest that the effects of MXC and HPTE on the OSE are mediated by estrogen receptors.
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PMID:Methoxychlor induces proliferation of the mouse ovarian surface epithelium. 1552 93

Previous studies demonstrated that live Bartonella quintana often induces angioproliferative lesions in humans. It modulates endothelial cell apoptotic and inflammatory patterns, thus inducing a very early overexpression of caspase 8 and Apaf-1 and increasing mRNA production of TNF-alpha, interleukin-8, and E-selectin. However, starting at 10 hours postinfection, the bacteria provoke antiapoptotic effects that induce an increase of bcl-2 gene transcription. To gain further insight into the cellular mechanisms that regulate apoptosis, survival and proliferation, we studied the modulation of mitogen-activated protein kinase (MAPK) and the activation state of cdc2 kinase, which regulates progression into mitosis. Confocal microscopy findings indicated a maximum rate of Bartonella entry into host cells between postinfection hours 6 and 10. Live bacteria caused substantially higher apoptosis of human umbilical vein endothelial cells-cryopreserved (HUVEC-C) than heat- and trypsin-inactivated microorganisms. During the first 6 hours postinfection, B. quintana triggered a peak of apoptosis, induced activation of p38 MAPK and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK), with bacterial clusters appearing at the cellular surface of the HUVEC-C. However, at 8 to 24 hours postinfection, B. quintana was internalized and inhibited proapoptotic signals such as p38 MAPK and SAPK/JNK while inducing antiapoptotic signals. Indeed, expression of the bcl-2 gene and the increase of the bcl-2 kinase active form was concomitant to activation of mitosis, as shown by cdc2 protein activation. These data thus suggest that mechanisms that induce mitotic activity and inhibit apoptotic signals may contribute to the ability of B. quintana to cause vascular proliferation.
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PMID:Bartonella quintana-induced apoptosis inhibition of human endothelial cells is associated with p38 and SAPK/JNK modulation and with stimulation of mitosis. 1554

Sarcoplasmic masses contain disorganized myofibrillar material and are a striking feature of myotonic dystrophy. However their significance is still unclear. Using immunocytochemistry we studied the expression of cytoskeletal proteins (desmin and vimentin), dystrophin, markers of myogenic differentiation (foetal myosin, neural cell adhesion molecule, bcl-2, insulin-like growth factor-I, fibroblast growth factor, retinoblastoma protein and myoD1), cell cycle regulators (Cdk2, p16, p27 and p57) and muscle proteases (ubiquitin, micro and m calpain and cathepsin D) in muscle biopsies from four patients with myotonic dystrophy. Sarcoplasmic masses were strongly positive for desmin, neural cell adhesion molecule, bcl-2, insulin-like growth factor I, retinoblastoma protein and p57, weakly positive for dystrophin and p16 and negative for vimentin, fibroblast growth factor, myoD1, Cdk2 and p27. Immunoreactivity for foetal myosin was detected only in a few fibres (< 1%). Our data suggest that the late myogenic differentiation programme is activated in sarcoplasmic masses although these areas do not reach complete maturation.
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PMID:Expression of late myogenic differentiation markers in sarcoplasmic masses of patients with myotonic dystrophy. 1563 30


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