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)

Polychlorinated biphenyls (PCBs) exhibit tumor-promoting effects in experimental animals. We investigated effects of six model PCB congeners and hydroxylated PCB metabolites on proliferation of contact-inhibited rat liver epithelial WB-F344 cells. The 'dioxin-like' PCB congeners, PCB 126, PCB 105, and 4'-OH-PCB 79, a metabolite of the planar PCB 77 congener, induced cell proliferation in a concentration-dependent manner. In contrast, the 'non-dioxin-like' compounds that are not aryl hydrocarbon receptor (AhR) agonists, PCB 47, PCB 153, and 4-OH-PCB 187, an abundant noncoplanar PCB metabolite, had no effect on cell proliferation at concentrations up to 10 muM. The concentrations of dioxin-like PCBs leading to cell proliferation corresponded with the levels inducing the expression of cytochrome P450 1A1 mRNA, suggesting that the release from contact inhibition was associated with AhR activation. The effects of PCB 126 and PCB 153 on expression of proteins controlling G0/G1-S-phase transition and S-phase progression were compared. Only PCB 126 was found to upregulate cyclin A and D2 protein levels, and to increase both total cyclin-dependent kinase 2 (cdk2) and cyclin A/cdk2 complex activities. Despite the observed upregulation of cyclin D2, no increase in cdk4 activity was observed. The expression of cdk inhibitor p27Kip1 was not affected by either PCB 126 or PCB 153. These results suggest that dioxin-like PCBs can induce cell proliferation of contact-inhibited rat liver epithelial cells by increasing cyclin A protein levels, a process that then leads to upregulation of cyclin A/cdk2 activity and initiation of DNA replication. This mechanism could be involved in tumor-promoting effects of dioxin-like PCBs.
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PMID:Aryl hydrocarbon receptor-activating polychlorinated biphenyls and their hydroxylated metabolites induce cell proliferation in contact-inhibited rat liver epithelial cells. 1548 85

The study was purposed to explore the molecular mechanisms of sodium butyrate (NaB) action on SKM-1 cell proliferation/differentiation and to study its synergistic effect with all-trans retinoic acid (ATRA). SKM-1 cells were grown in the absence or presence of NaB and/or ATRA; the percentage of viable cells was determined by trypan blue exclusion; differentiation was investigated by nitro-blue tetrazolium (NBT) reduction; adhesion molecules of cell surface were analysed by FACS; cell cycle distribution was studied after DNA staining by propidium iodide; D-type cyclins, CDK and P21 mRNA were detected by reverse transcription-polymerase chain reaction (RT-PCR). The results showed that NaB and/or ATRA blocked cells mainly in the G0/G1 phase of the cell cycle; ATRA inhibited the mRNA expression of CDK6, CDK4, cyclin D3 and cyclin D1; NaB inhibited the mRNA expression of CDK2, cyclin D2 and cyclin D1; ATRA and NaB inhibited the mRNA expression of CDK6, CDK4, CDK2, cyclin D1, cyclin D2 and cyclin D3; ATRA and/or NaB both stimulated p21 expression at the mRNA levels. It is concluded that the NaB effect on cell proliferation/differentiation may be linked to its ability to induce expression of p21 mRNA and inhibit the cyclin D-CDK complexes. These observations support the claim that NaB has the synergistic effect with ATRA.
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PMID:[Effect of sodium butyrate in combination with ATRA on the proliferation/differentiation of MDS cell line SKM-1]. 1549 18

The most well understood function of the D-type cyclins is to activate the G(1) kinases, cdk4 and cdk6, and target the retinoblastoma gene product (pRb) for phosphorylation and inactivation. pRb can suppress S phase entry, cause a transient G(1) arrest following DNA damage, and is critical in establishing terminal cell cycle withdrawal in cells exposed to differentiation or senescence-inducing signals. Each of these functions of pRb can be demonstrated in cultured cells derived from human tumors that have suffered RB1 gene inactivation. In such in vitro assays, coexpression of D type cyclins has been shown to inhibit the function of pRb, likely reflecting an oncogenic role of cyclin D1 in vivo. Two regions of cyclin D, the LxCxE pRb-binding motif, and the cyclin box, are thought to be critical for the proper function of cyclin D. Here we show that the LxCxE motif is dispensable in cyclin D1 for all functions tested, but is required by cyclin D2. This observation suggests that there is a functional difference between cyclins D1 and D2 in pRb regulation, and argues against complete functional redundancy of these D cyclins. In addition, the ability of cyclins D1 and D2 to activate cdk partners is required for induction of pRb phosphorylation and S phase entry. However, mutant forms of cyclins D1 and D2 that are incapable of activating kinase partners were still able to prevent pRb-induced senescence. Thus, D cyclins have both kinase-dependent and kinase-independent mechanisms of interfering with proliferation arrest and senescence.
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PMID:Multiple functions of D-type cyclins can antagonize pRb-mediated suppression of proliferation. 1568 4

Dopamine (DA) is a classical neurotransmitter modulating various brain functions by acting on its specific receptors. In addition, DA is a reactive molecule that has been implicated in neurodegeneration, especially in Parkinson's disease. Here we show that DA inhibited cell growth of dopamine transporter transfected cells by intracellularly blocking cell cycle progression. To pinpoint the site of this effect, we measured DNA distribution and 5-bromo-2'-deoxyuridine (BrdU) incorporation, as well as the levels of the key cell cycle proteins. DA increased number of cells with a G1 DNA content, decreased BrdU incorporation and simultaneously increased cyclin A but had no effect on cyclin D2, D3, E, nor on cdk4 and p21. These results narrowed down the DA effect to the beginning of S phase, suggesting inhibition of the ribonucleotide reductase, an enzyme essential for DNA synthesis. Indeed, measurement of enzyme activity in situ revealed that DA, within 1h of addition to cells labelled with [3H]cytidine, strongly reduced the cell content of [3H]2'-deoxycytidine 5'-triphophate. The time course of this DA effect preceded the cell cycle progression. This novel molecular mechanism of intracellular DA action independent of plasmamembrane receptors may be involved in processes controlling the development and survival of brain dopaminergic neurons.
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PMID:Dopamine inhibits cell growth and cell cycle by blocking ribonucleotide reductase. 1575 80

Initiation and progression through G1 requires the activity of signaling complexes containing cyclins (D- or E-type) and cyclin-dependent kinases (CDK4/6 and CDK2, respectively). We set out to identify the G1-phase cyclins and CDKs that are operative during late gestation liver development in the rat. This is a period during which hepatocytes show a high rate of proliferation that is, at least in part, independent of the mitogenic signaling pathways that are functional in mature hepatocytes. RNase protection assay and Western immunoblotting indicated that cyclin D1 is expressed at similar levels in fetal and adult liver. When cyclin D1 was induced after partial hepatectomy, its predominant CDK-binding partner was CDK4. In contrast, cyclins D2 and D3 predominated in fetal liver and were complexed with both CDK4 and CDK6. Little CDK6 protein was expressed in quiescent or regenerating adult liver. Cyclins E1 and E2 were both transcriptionally up-regulated in fetal liver. Activity of complexes containing cyclins E1 and E2 was higher in fetal liver, as was content of the cell cycle regulator, Rb. In fetal liver, Rb was highly phosphorylated at both cyclin D- and cyclin E-dependent sites. In conclusion, liver development is associated with a switch from cyclin D2/D3-containing complexes to cyclin D1:CDK4 complexes. We speculate that the switch in D-type cyclins may be associated with the dependence on mitogenic signaling that develops as hepatocytes mature.
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PMID:D-type cyclins and G1 progression during liver development in the rat. 1580 57

The ras oncogene transforms immortalized, contact-inhibited non-malignant murine fibroblasts into cells that are focus forming, exhibit increased saturation density, and are malignant in suitable hosts. Here, we examined changes in cell cycle control complexes as normal and Ras-transformed cells ceased to grow exponentially, to reveal the molecular basis for Ras-dependent focus formation. As normal cells entered density-dependent arrest, cyclin D1 decreased while cyclin D2 was induced and replaced D1 in Cdk4 complexes. Concomitantly, p27(Kip1) levels rose and the inhibitor accumulated in both Cdk4 and Cdk2 complexes, as these kinases were inactivated. Ras-transformed cells failed to arrest at normal saturation density and showed no significant alterations in cell control complexes at this point. Yet, at an elevated density the Ras-transformed cells ceased to proliferate and entered a quiescent-like state with low Cdk4 and Cdk2 activity. Surprisingly, this delayed arrest was molecularly distinct from contact inhibition of normal cells, as it occurred in the absence of p27(Kip1) induction and cyclin D1 levels remained high. This demonstrates that although oncogenic Ras efficiently disabled the normal response to contact inhibition, a separate back-up mechanism enforced cell cycle arrest at higher cell density.
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PMID:High-density growth arrest in Ras-transformed cells: low Cdk kinase activities in spite of absence of p27(Kip) Cdk-complexes. 1599 48

Multiple myeloma, the second most common hematopoietic cancer, ultimately becomes refractory to treatment when self-renewing multiple myeloma cells begin unrestrained proliferation by unknown mechanisms. Here, we show that one, but not more than one, of the three early G(1) D cyclins is elevated in each case of multiple myeloma. Cyclin D1 or D3 expression does not vary in the clinical course, but that alone is insufficient to promote cell cycle progression unless cyclin-dependent kinase 4 (cdk4) is also elevated, in the absence of cdk6, to phosphorylate the retinoblastoma protein (Rb). By contrast, cyclin D2 and cdk6 are coordinately increased, thereby overriding the inhibition by cdk inhibitors p18(INK4c) and p27(Kip1) and phosphorylating Rb in conjunction with the existing cdk4. Thus, cyclin D1 pairs exclusively with cdk4 and cdk6 pairs only with cyclin D2, although cyclin D2 can also pair with cdk4 in multiple myeloma cells. The basis for this novel and specific cdk/D cyclin pairing lies in differential transcriptional activation. In addition, cyclin D1- or cyclin D3-expressing multiple myeloma cells are uniformly distributed in the bone marrow, whereas cdk6-specific phosphorylation of Rb occurs in discrete foci of bone marrow multiple myeloma cells before proliferation early in the clinical course and is then heightened with proliferation and disease progression. Mutually exclusive cdk4/cyclin D1 and cdk6/cyclin D2 pairing, therefore, is likely to be a critical determinant for cell cycle reentry and progression and may play a pivotal role in the expansion of self-renewing multiple myeloma cells.
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PMID:Mutually exclusive cyclin-dependent kinase 4/cyclin D1 and cyclin-dependent kinase 6/cyclin D2 pairing inactivates retinoblastoma protein and promotes cell cycle dysregulation in multiple myeloma. 1635 41

Arabidopsis contains seven Kip-related protein (KRP) genes encoding CDK (cyclin-dependent kinase) inhibitors (CKIs), which shares a restricted similarity with mammalian p27Kip1. Here, we analyze the characteristics of the KRPs. Although KRP1-KRP7 interact with active cyclin D2 (CYCD2)/CDKA and CYCD2/CDKB complexes to a similar extent, they inhibit kinase activity to a different extent. Our results suggest that inhibitory activity is related to the binding ability between KRP proteins and cyclin/CDK complexes, but secondary and tertiary structure may be also involved. These data provide the first evidence that KRPs inhibit kinase activity associated with plant-specific CDKB.
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PMID:Arabidopsis KRPs have distinct inhibitory activity toward cyclin D2-associated kinases, including plant-specific B-type cyclin-dependent kinase. 1637 85

Treatment of adult Philadelphia chromosome-positive lymphocytic leukemia is rarely successful. We report here the effects of TZD18, a novel dual ligand specific for peroxisome proliferator-activated receptor alpha and gamma (PPARalpha/gamma) on Ph(+) lymphocytic leukemia cell lines BV173, SD1, and SupB-15. Exposure of these cells to TZD18 resulted in growth inhibition in a dose- and time-dependent manner that was associated with G(1) cell cycle arrest. This effect was much stronger than that mediated by the PPARgamma ligand pioglitazone (PGZ), which also belongs to the thiazolidinediones (TZD) class of ligands. However, it may not be mediated through PPARgamma or PPARalpha activation because antagonists of PPARgamma and PPARalpha cannot reverse it. Study of the key regulators of cell cycle progression by Western blot analysis showed that the expression of the cyclin-dependent kinase inhibitor (CDKI) p27(kip1), but not that of p21(cip1), was enhanced, whereas that of c-Myc, cyclin E, cyclin D2, and cyclin-dependent kinases 2 and 4 (CDK-2 and CDK-4) was decreased when these cells were treated with TZD18 (10 or 20 microM). Therefore, the up-regulation of p27(kip1) and the down-regulation of CDK-2 and CDK-4 may, at least in part, account for the G(1) cell cycle arrest. Furthermore, a remarkable induction of apoptosis was observed in the cells treated with this dual ligand. No obvious alteration of bcl-2 protein level occurred, but bax was up-regulated in these TZD18-treated cells. Activation of caspase 8 and caspase 9 by TZD18 was also observed. Importantly, NF-kappaB DNA-binding activity was markedly decreased by the TZD18 treatment. In addition, TZD18 enhanced the growth inhibitory effect of imatinib, a specific tyrosine kinase inhibitor therapeutically used in the treatment of Ph(+) leukemia. Overall, our findings strongly suggest that TZD18 may offer a new therapeutic approach to aid in the treatment of Ph(+) lymphocytic leukemia.
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PMID:Growth inhibition and apoptosis in human Philadelphia chromosome-positive lymphoblastic leukemia cell lines by treatment with the dual PPARalpha/gamma ligand TZD18. 1640 7

Improved understanding of the signals that regulate growth and maintenance of adult beta-cells remains one of the main challenges in diabetes research. However, new advances in identifying the specific components involved in G1 cell cycle progression of beta-cells suggest that the molecular determinants of this pathway could ultimately be revealed. We find that cyclin D2, and to a minor degree cyclin D1, are required for adult beta-cell growth. Our observations complement previous data regarding cdk4, and suggest that mitogenic signals could act via this pathway to influence acquisition of adult beta-cell mass. Although cyclin D2/cdk4 activity is critically important for beta-cell growth, it was unclear how much ongoing replication is required to maintain beta-cell mass. Our recent long-term beta-cell labeling studies reveal that adult beta-cells could conceivably live for the life of the organism. This new paradigm of long-lived beta-cells challenges previous notions of rapid turnover of adult beta-cell mass. Thus, much remains to be learned in order to expand adult beta-cell mass in diabetes patients.
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PMID:Beta-cell growth: an unusual paradigm of organogenesis that is cyclin D2/Cdk4 dependent. 1641 Jul 29


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