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)

Despite intensive investigation, no clearly defined mechanism explaining human immunodeficiency virus (HIV)-induced cell killing has emerged. HIV-1 infection is initiated through a high-affinity interaction between the HIV-1 external envelope glycoprotein (gp120) and the CD4 receptor on T cells. Cell killing is a later event intimately linked by in vitro genetic analyses with the fusogenic properties of the HIV envelope glycoprotein gp120 and transmembrane glycoprotein gp41. In this report, we describe aberrancies in cell cycle regulatory proteins initiated by cell-cell contact between T cells expressing HIV-1 envelope glycoproteins and other T cells expressing CD4 receptors. Cells rapidly accumulate cyclin B protein and tyrosine-hyperphosphorylated p34cdc2 (cdk1) kinase, indicative of cell cycle arrest at G2 phase. Moreover, these cells continue to synthesize cyclin B protein, enlarge and display an abnormal ballooned morphology, and disappear from the cultures in a pattern previously described for cytotoxicity induced by DNA synthesis (S phase) inhibitors. Similar changes are observed in peripheral blood mononuclear cells infected in vitro with pathogenic primary isolates of HIV-1.
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PMID:Human immunodeficiency virus 1 envelope-initiated G2-phase programmed cell death. 852 69

We previously described that V3 loop derived from the HTLV-III BH10 clone V3-BH10 markedly suppressed IL-2-driven T cell proliferation and produced G1 arrest of the cells. Here, we tested the effect of V3-BH10 on the molecules that are involved in transition from the G1 to S phase of the cell cycle. The effect of V3-BH10 on the IL-2-induced expression of G1 cyclins, Cdk inhibitors, and phosphorylation of retinoblastoma protein (pRb) was tested by immunoblotting, using the IL-2-dependent CD4-positive cell line Kit 225. Furthermore, IL-2-dependent kinase activity of the cyclin E-Cdk2 complex was investigated with histone H1 as a substrate. V3-BH10 reduced the IL-2-dependent expression of cyclin E, but not that of cyclin D and Cdk inhibitors such as p21 and p27. As the result of reduction of cyclin E, histone H1 kinase activity of the cyclin E-Cdk2 complex was markedly reduced even in the presence of rIL-2, followed by incomplete phosphorylation of pRb. The reduction in hyperphosphorylation of pRb by V3-BH10 led to G1 arrest of the cell cycle. Thus, V3-BH10 induced G1 arrest in IL-2-dependent cell cycle progression by reducing cyclin E expression, which may be one of the mechanisms underlying the dysfunction of T cells in HIV-1-infected people.
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PMID:V3 loop of human immunodeficiency virus type 1 reduces cyclin E expression and induces G1 arrest in interleukin 2-dependent T cells. 945 49

Human herpesvirus 7 (HHV-7) infection of both primary CD4(+) T lymphocytes and SupT1 lymphoblastoid T-cell line induced a progressive accumulation of cells exibiting a gap 2/mitosis (G2/M) and polyploid content coupled to an increased cell size. The expression of both cyclin-dependent kinase cdc2 and cyclin B was increased in HHV-7-infected cells with respect to the uninfected ones. Moreover, the simultaneous flow cytometric analysis of cyclin B and DNA content showed that cyclin B expression was not only increased but also unscheduled with respect to its usual cell cycle pattern. However, the levels of kinase activity associated to cdc2 were decreased in HHV-7-infected cells with respect to uninfected cultures. To elucidate the origin of the enlarged HHV-7-infected cells, extensive electron and confocal microscopy analyses were performed. Membrane fusion events associated to cytoplasmic bridges, which characterize the formation of syncytia, were never observed. On the other hand, analysis of serial sections of the same cells strongly suggested that enlarged HHV-7-infected cells contained a single polylobated nucleus. This was confirmed by flow cytometry analysis performed on nuclei isolated from HHV-7-infected cells, which showed multiple peaks with a DNA content >4n. Taken together, these data indicate that giant cells, which represent the hallmark of in vitro HHV-7 infection, arise from single CD4(+) T cells undergoing a process of polyploidization.
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PMID:Human herpesvirus 7 infection induces profound cell cycle perturbations coupled to disregulation of cdc2 and cyclin B and polyploidization of CD4(+) T cells. 971 97

To define the link between the early activation defects and the impaired proliferation response of cells from old mice, we characterized the influence of age on expression and activity of proteins that participate in cell-cycle regulation. We found that aging led to significant declines in the ability of mouse CD4(+) T cells to respond to CD3 and CD28 stimuli by induction of the cyclin-dependent kinases CDK2, CDK4, and CDK6, whether the defect was assessed by protein level or functional activity. Induction of CDK2 activity was also impaired in cells from old mice that were activated with PMA plus ionomycin, stimuli that bypass the TCR/CD3 complex, or by CD3/CD28 in the presence of IL-2, indicating that the age-related changes lie, at least in part, downstream of the enzymes activated by these stimuli. We also noted an impairment in the ability of CD4(+) cells from old mice to down-regulate the CDK inhibitor p27 after activation, but we found no change in induction of p21, an inhibitor of CDK that may also play other roles in cell-cycle control. Altered CDK activation is likely to mediate the age-related decline in T cell proliferation to polyclonal stimulation.
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PMID:Aging impairs induction of cyclin-dependent kinases and down-regulation of p27 in mouse CD4(+) cells. 1061 47

Productive high-titer infection by human immunodeficiency virus type 1 (HIV-1) requires the activation of target cells. Infection of quiescent peripheral CD4 lymphocytes by HIV-1 results in incomplete, labile reverse transcripts and lack of viral progeny formation. An interplay between Tat and p53 has previously been reported, where Tat inhibited the transcription of the p53 gene, which may aid in the development of AIDS-related malignancies, and p53 expression inhibited HIV-1 long terminal repeat transcription. Here, by using a well-defined and -characterized stress signal, gamma irradiation, we find that upon gamma irradiation, HIV-1-infected cells lose their G(1)/S checkpoints, enter the S phase inappropriately, and eventually apoptose. The loss of the G(1)/S checkpoint is associated with a loss of p21/Waf1 protein and increased activity of a major G(1)/S kinase, namely, cyclin E/cdk2. The p21/Waf1 protein, a known cyclin-dependent kinase inhibitor, interacts with the cdk2/cyclin E complex and inhibits progression of cells into S phase. We find that loss of the G(1)/S checkpoint in HIV-1-infected cells may in part be due to Tat's ability to bind p53 (a known activator of the p21/Waf1 promoter) and sequester its transactivation activity, as seen in both in vivo and in vitro transcription assays. The loss of p21/Waf1 in HIV-1-infected cells was specific to p21/Waf1 and did not occur with other KIP family members, such as p27 (KIP1) and p57 (KIP2). Finally, the advantage of a loss of the G(1)/S checkpoint for HIV-1 per se may be that it pushes the host cell into the S phase, which may then allow subsequent virus-associated processes, such as RNA splicing, transport, translation, and packaging of virion-specific genes, to occur.
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PMID:Loss of G(1)/S checkpoint in human immunodeficiency virus type 1-infected cells is associated with a lack of cyclin-dependent kinase inhibitor p21/Waf1. 1079 78

The induction of anergy in T cells, although widely accepted as critical for the maintenance of tolerance, is still poorly understood at the molecular level. Recent evidence demonstrates that in addition to blockade of costimulation using monoclonal antibodies (mAbs) directed against cell surface determinants, treatment of mixed lymphocyte reaction (MLR) cultures with interleukin 10 (IL-10) and transforming growth factor-beta (TGF-beta) results in induction of tolerance, rendering alloreactive murine CD4(+) T cells incapable of inducing graft-versus-host disease (GVHD) after in vivo transfer to histoincompatible recipients. The present study, using these cells prior to adoptive transfer, determined that IL-10 + TGF-beta-tolerant CD4(+) T cells exhibit an altered pattern of T-cell receptor (TCR) + CD28-mediated signaling and are incapable of progressing out of the G(1) phase of the cell cycle during stimulation with HLA class II disparate antigen-presenting cells. TGFbeta + IL-10-tolerant cells were incapable of phosphorylating TCR-zeta, or activating ZAP-70, Ras, and MAPK, similarly to T-cell tolerized by blockade of B7/CD28 and CD40/CD40L pathways. Moreover, these cells were incapable of clonal expansion due to defective synthesis of cyclin D3 and cyclin A, and defective activation of cyclin-dependent kinase (cdk)4, cdk6, and cdk2. These cells also exhibited defective down-regulation of p27(kip1) cdk inhibitor and lack of cyclin D2-cdk4 activation, Rb hyperphosphorylation, and progression to the S phase of the cell cycle. These data link anergy-specific proximal biochemical alterations and the downstream nuclear pathways that control T-cell expansion and provide a biochemical profile of IL-10 + TGF-beta-tolerant alloreactive T cells that do not induce GVHD when transferred into MHC class II disparate recipients in vivo.
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PMID:Altered T-cell receptor + CD28-mediated signaling and blocked cell cycle progression in interleukin 10 and transforming growth factor-beta-treated alloreactive T cells that do not induce graft-versus-host disease. 1115 38

Like living Trypanosoma cruzi, its AGC10 membrane glycoprotein inhibits interleukin-2 (IL-2) secretion and membrane expression of CD25, CD122, and CD132 (the components of the high-affinity IL-2 receptor) by activated human lymphocytes. Since these molecules are required for effective lymphocyte division, we explored the molecular mechanism underlying these alterations. In the presence of AGC10 the cytoplasmic levels of IL-2 protein of CD4(+) and CD8(+) blood lymphocytes stimulated with phorbol myristate acetate (PMA) plus ionomycin were markedly reduced. AGC10 also decreased the intracellular levels of CD25, CD122, and CD132 in CD4(+) and CD8(+) cells stimulated with the T-cell mitogen phytohemagglutinin (PHA). These results indicated that the AGC10-induced alterations preceded IL-2 secretion and transport of IL-2 receptor components to the cell membrane. Supporting this view were the substantially diminished levels of IL-2, CD25, CD122, and CD132 mRNA found in AGC10-containing cultures of PHA-activated lymphocytes. These decreases were not due to increased mRNA instability. Thus, the rates of decay for each of these mRNA species were comparable in the presence or absence of AGC10, suggesting a mechanism involving transcription inhibition. AGC10 targeted an early lymphocyte activation event since inhibition of lymphoproliferation subsided when AGC10 was added to cultures at or after 20 h post-activation. AGC10 also caused large reductions in the mRNA levels of cyclin D2 and cdk4, both critical for progression through G1. These results show for the first time that AGC10-induced inhibition of lymphoproliferation entails curtailed biosynthesis of IL-2 and, IL-2 receptor molecules, and suggest that the effect involves inhibition of gene transcription.
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PMID:The Trypanosoma cruzi membrane glycoprotein AGC10 inhibits human lymphocyte activation by a mechanism preceding translation of both, interleukin-2 and its high-affinity receptor subunits. 1246 77

Initiation of T-lymphocyte-mediated immune responses involves two cellular processes: entry into the cell cycle (G(0)-->G(1)) for clonal proliferation and coordinated changes in surface and secreted molecules that mediate effector functions. However, a point during G(0)-->G(1) beyond which T cells are committed to enter the cell cycle has not been defined. We define here a G(0)-->G(1) commitment point that occurs 3 to 5 h after CD3 and CD28 stimulation of human CD4 or CD8 T cells. Transition through this point requires cdk6/4-cyclin D, since inhibition with TAT-p16(INK4A) during the first 3 to 5 h prevents cell cycle entry and maintains both naive and memory T cells in G(0). Transition through the G(0)-->G(1) commitment point is also necessary for T cells to increase in size, i.e., to enter the cellular growth cycle. However, transition through this point is not required for the induction of effector functions. These can be initiated while cells are maintained in G(0) with TAT-p16(INK4A). We have termed this quiescent, activated state G(0(A)). Our data provide proof of the principle that entry of T cells into the cell cycle and cellular growth cycles are coupled at the G(0)-->G(1) commitment point but that these processes can be uncoupled from the early expression of molecules of effector functions.
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PMID:Commitment point during G0-->G1 that controls entry into the cell cycle. 1264 Jan 20

To investigate the regulatory effects of decoy receptor 3 (DcR3) on the differentiation and function of dendritic cells (DCs), bone marrow-derived DCs (BM-DCs) from nonobese diabetic (NOD) mice were cultured with recombinant DcR3.Fc protein. Their differentiating phenotypes and T cell-stimulating functions were then evaluated. Expression of CD11c, CD40, CD54, and major histocompatibility complex I-A(g7) was reduced in cells cultured with additional DcR3.Fc, compared with DCs incubated with granulocyte macrophage-colony stimulating factor and interleukin (IL)-4, indicating that DcR3 interferes with the differentiation and maturation of BM-DCs. One of the most striking effects of DcR3.Fc on the differentiation of DCs was the up-regulation of CD86 and down-regulation of CD80, suggesting a modulatory potential to skew the T cell response toward the T helper cell type 2 (Th2) phenotype. Consistent with this, the proliferation of CD4(+) T cells cocultured with DcR3.Fc-treated DCs was significantly reduced compared with that of T cells stimulated by normal DCs. Moreover, the secretion of interferon-gamma from T cells cocultured with DcR3.Fc-treated DCs was profoundly suppressed, indicating that DcR3 exerts a Th1-suppressing effect on differentiating DCs. Furthermore, adoptive transfer experiments revealed that NOD/severe combined immunodeficiency mice received DcR3.Fc-treated DCs, and subsequently, autoreactive T cells showed delayed onset of diabetes and a decrease in diabetic severity compared with mice that received normal DCs and T cells, suggesting a future therapeutic potential in autoimmune diabetes. Data from two-dimensional gel electrophoresis and matrix-assisted laser desorption/ionization-time-of-flight analysis show an up-regulation of some proteins-such as mitogen-activated protein kinase p38 beta, cyclin-dependent kinase 6, and signal-induced proliferation-associated gene 1-and a down-regulation of the IL-17 precursor; tumor necrosis factor-related apoptosis-inducing ligand family member-associated nuclear factor-kappaB activator-binding kinase 1; and Golgi S-nitroso-N-acetylpenicillamine in cells treated with DcR3, further demonstrating its effect on DC differentiation and function.
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PMID:Immunomodulatory effect of decoy receptor 3 on the differentiation and function of bone marrow-derived dendritic cells in nonobese diabetic mice: from regulatory mechanism to clinical implication. 1463 66

Novel targets for the management of HIV infection have become increasingly relevant in view of extensive drug resistance, side effects and high pill burden of some of the conventional anti-retroviral agents. Structure based drug design using X-ray crystallography, nuclear magnetic resonance, and mass spectrometry have lead to the identification of novel class of drugs targeting new stages of HIV life cycle. These agents include chemokine receptor antagonists and the integrase inhibitors which were recently approved for HIV treatment, as well as numerous other agents directed to previously untested targets such as the maturation inhibitors, zinc finger inhibitors, pharmacological CDK inhibitors, Tat-TAR interaction inhibitors, anti-CD4 monoclonal antibody, antisense oligonucleotides, oxidisers of the HIV lipid envelope and agents acting on the proviral DNA. Use of new agents with novel mechanism of action requires the development of new laboratory assays to detect viral tropism and new resistance mutations. Despite the new developments providing hope to patients and clinicians in the fights against HIV, eradication of the disease still remains elusive. This review discusses issues surrounding the development of these new agents.
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PMID:Novel targets for anti-retroviral therapy. 2168 93


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