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)

We examined the expression of the cyclin-dependent kinase 4, p34PSK-J3/cdk4 protein, in small dense, activated, and proliferating primary B lymphocytes. A small steady state level of cdk4 synthesis was detected in resting B cells. Stimulation of resting B cells with mitogenic amounts of F(ab')2 fragments of goat anti-mouse IgM (anti-Ig) resulted in increased synthesis of cdk4 protein during the mid to late G1 phase of the cell cycle; LPS or the combination of phorbol ester and calcium ionophore also elevated cdk4 levels. Resting B cells that we rendered competent by treatment with IL 4 or low doses of anti-Ig or, alternatively, were activated by phorbol ester or ionomycin alone also exhibited heightened cdk4 protein levels. Subsequent analysis of potential cdk4 regulatory subunit D-type cyclins revealed that cyclin D2, not cyclin D1 or D3, is expressed in primary mature B lymphocytes. The induction of cyclin D2 synthesis in response to mitogenic anti-Ig paralleled cdk4 expression; however, IL-4 or low dose anti-Ig alone did not increase the rate of de novo cyclin D2 synthesis above that of resting B cells. The significance of the lack of cyclin D2 regulation by competence-inducing growth factors was demonstrated, in that only mitogenic factors that stimulated DNA synthesis 1) led to the formation of stable cyclin D2/cdk4 holoenzyme complexes during G1 phase progression, and 2) afforded the isolation of anti-cyclin D2 or anti-cdk4 immunoprecipitates that phosphorylated retinoblastoma. These findings suggest a role for these proteins during the mid to late G1 phase progression and possibly the G1/S phase transition in primary mature B lymphocytes.
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PMID:Regulation of the catalytic subunit (p34PSK-J3/cdk4) for the major D-type cyclin in mature B lymphocytes. 854 4

In contrast to mature B cells, immature stage B cells do not proliferate following Ag receptor cross-linking with anti-Ig Abs. To determine where in the cell cycle immature B cells arrest, we have examined the expression of specific G, cell cycle regulators. Following surface IgM (sIgM) cross-linking on mature B cells, we observed increased expression of the early G1 kinase, cyclin-dependent kinase 4 (cdk4), and one of its regulatory subunits, cyclin D2. Mature B cells also showed increased expression of components required for G1/S transition, including cyclin E and cdk2. Whereas immature stage B cells increased expression of cyclin D2 and cdk4 after anti-IgM stimulation, unlike mature stage B cells they failed to express cyclin E and cdk2. Expression of cyclin D2 and cdk4 indicates that these cells can exit G0 and enter the initial G1 phase following sIgM ligation. Interestingly, IL-4, which by itself does not stimulate proliferation of immature B cells, induced expression of cyclin E and cdk2. These latter results suggest that IL-4 complements sIgM, signaling for proliferation by increasing the basal levels of late G1 cell cycle regulators. Consistent with this idea, IL-4 synergizes with anti-Ig Abs to promote cell cycle progression and proliferation of immature B cells. Finally, c-myc, a transcriptional regulator of some members of the cell cycle machinery, is not induced following sIgM cross-linking of immature cells. This lack of inducible expression contrasts with that seen in mature stage B cells, and in immature stage cells stimulated to proliferate with LPS. These results suggest that c-myc may be a component of the signaling pathway that induces cyclin E and cdk2 expression.
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PMID:Immature stage B cells enter but do not progress beyond the early G1 phase of the cell cycle in response to antigen receptor signaling. 864 97

Progression through the cell cycle is a tightly controlled process that integrates signals generated at the plasma membrane with the proteins that form the cell cycle machinery. The current study chronicles the induction of cyclins, cyclin-dependent kinases (cdk), and cdk inhibitors in low density primary mouse B lymphocytes after anti-immunoglobulin plus interleukin 4 (IgM + IL-4) stimulation. In this system, > 85% of cells remain in the G0/G1 phase of cell cycle for an initial 24-h period, followed by entry of up to 50% of the cells into S phase, commencing around 30 h and peaking at 48 h. Extensive time course analyses of these anti-IgM + IL-4-stimulated B cells revealed that the G1-associated D-type cyclins D2 and D3 were induced by 3 h after stimulation, and that cyclins E, A, and B were subsequently induced sequentially, beginning at mid-G1, G1/S transition, and S phase, respectively. The G1-associated cyclin D1 was not expressed at any stage of the anti-Ig + IL-4-induced B cell cycle. cdk2, cdk4, and cdk6 were induced during G1, whereas cell division cycle-2 (cdc2) was induced concomitantly with S phase. Irrespective of their expression, the kinases cdk2 and cdc2 were only active from S phase onwards, suggesting that productive cyclin/kinase complex formation did not occur until that time. Cell cycle inhibitors p21 and p19 were induced by anti-Ig + IL-4, peaking in expression at mid-G1 and S phase, respectively. Stimulation of low density B cells with anti-Ig + IL-4 caused rapid down regulation of the p27 inhibitor, however this protein was reexpressed at 54-96 h after stimulation. In contrast, B cells stimulated with anti-CD40, a stimulus which induces long-term B cell proliferation, permanently down regulated p27. These findings are consistent with the concept that p27 reexpression contributes to the G1 arrest that follows antigen receptor crosslinking. Low density B cells cultured in the viability-enhancing cytokine IL-4 alone also showed induction of D2 and D3 cyclin expression. However, the D2 expression was transient, and the D3 expression was substantially lower than that observed in B cells induced to proliferate by anti-Ig + IL-4. This partial induction of D2 and D3 expression may explain IL-4's ability to promote B cell entry into G1 but not S phase of cell cycle, and furthermore, its ability to truncate G1 progression when B cells are subsequently stimulated with anti-Ig.
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PMID:Induction of cell cycle regulatory proteins in anti-immunoglobulin-stimulated mature B lymphocytes. 876 Jul 94

IL-4 activates resting B cells and, in conjunction with cosignals such as anti-IgM (anti-mu) Ab or CD40 ligand, modulates progression of B cells through the cell cycle, leading to proliferation. In this study, we show that the mitogenic combination of IL-4 and anti-mu Ab triggered induction of cyclin D3 and up-regulated cyclin-dependent kinase (cdk) 6 expression, whereas such regulation was not observed in B cells activated by IL-4 or anti-mu Ab alone. Furthermore, cyclin D3 immunoprecipitated fron as associated with cdk6, and the cyclin D3/cdk6 complex was able to phosphorylate recombinant retinoblastoma protein in vitro. In addition, B cells activated with either IL-4 or 1L-13 alone expressed a higher amount of p27kip1 (p27) cdk inhibitor than nonstimulated cells. In contrast, p27 expression was decreased when cells were activated with mitogenic combinations of IL-4 and anti-mu Ab or anti-CD40 mAb. We also observed that the IL-4-mediated inhibition of the proliferation of anti-mu/IL-2- or anti-mu/phorbol 12,13-dibutyrate-activated human leukemic B cells was associated with the maintenance of large amounts of p27 in these cells. These data suggest that IL-4 controls B cell proliferation by action during at least two steps of the regulation of the cell cycle, cyclin D3/cdk6 complex regulation and p27 inhibitor expression.
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PMID:Modulation of the p27kip1 cyclin-dependent kinase inhibitor expression during IL-4-mediated human B cell activation. 912 Feb 57

IL-4 is a pleiotrophic cytokine that has been shown to affect cells of the central nervous system. We have demonstrated that IL-4 inhibits DNA synthesis and proliferation in human astroglia expressing IL-4 receptors. In this study, we sought to identify mechanisms that could account for the antimitogenic effects of IL-4. Epidermal growth factor (EGF)-stimulated human astroglia were arrested in G1 phase by IL-4, even though IL-4 stimulated levels of the G1 cyclins, D1 and E. Histone H1 kinase activity of cdk2 immunoprecipitates, however, was sharply reduced by IL-4; impairment of kinase activity was also evident in cyclin E immunoprecipitates, which contained evidence of hypophosphorylated (inactive) cdk2 product. Reduced cyclin E-associated cdk2 activity was not due to impaired cyclin-dependent kinase-activating kinase (CAK) activity, which was unaffected by IL-4. Inactive cyclin E/cdk2 complexes from IL-4 + EGF-treated cells contained, however, strikingly elevated p27Kip1 cdk inhibitor. Elevated p27 was also detectable in whole cell lysates after 24 and 48 h of IL-4 treatment; by 72 h, p27 was no longer elevated. Pretreatment with antisense but not mismatch p27 oligonucleotides attenuated the inhibitory effects of IL-4 on DNA synthesis and histone kinase activity of cyclin E/cdk2 complexes. Antisense p27 also abrogated IL-4-mediated elevation of p27 in whole cell lysates and cyclin E/cdk2 complexes. These findings demonstrate that IL-4 regulates the cell cycle machinery of astroglial cells via a p27Kip1 braking mechanism.
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PMID:The CDK inhibitor, p27Kip1, is required for IL-4 regulation of astrocyte proliferation. 921 99

The functional differences between IgDhighCD38- naive and IgD-CD38- memory (M) or IgDlowCD38+ germinal center (GC) B cells may stem from their variable response to signals that regulate activation, proliferation, and differentiation. In this report, we provide evidence for differential induction of cell cycle regulators in tonsillar human B cell subpopulations that were activated with anti-IgM and anti-CD40 in the presence or absence of IL-2, IL-4, or IL-10. Naive (IgDhigh) B cells exhibited a significant proliferative response to IL-4, but not to IL-2 or IL-10, whereas these cytokines triggered variable levels of growth in the combined GC/M subpopulation (referred to as IgDlow), as measured by [3H]thymidine incorporation. Induction of growth by cytokines in B cell subpopulations strictly correlated with the increased levels of cyclin D3 and cyclin-dependent protein kinase (cdk) 6. Moreover, only cyclin D3/cdk6 complexes were functional as observed in both naive and GC/M B cells stimulated in the presence of IL-4. In addition, active growth was associated with cytokine-mediated elimination of the cell cycle inhibitor p27. The significance of p27 in human B cell cycle was further demonstrated by rapamycin-mediated growth inhibition of IL-4-dependent proliferation, which resulted in strikingly increased p27 levels. Taken together, our findings suggest that cyclin D3, cdk6, and p27 play key roles in IL-2-, IL-4-, and IL-10-mediated human B cell proliferation. Furthermore, these results may provide a molecular basis for different cycling characteristics of naive and GC/M B cell subpopulations.
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PMID:A pivotal role of cyclin D3 and cyclin-dependent kinase inhibitor p27 in the regulation of IL-2-, IL-4-, or IL-10-mediated human B cell proliferation. 968 70

Elevation of the cyclin-dependent kinase (cdk) inhibitor, p27(kip1) is necessary for Interleukin (IL)-4-mediated growth arrest of human low grade astrocytoma (RTLGA) cells and occurs at 24 h of treatment. Pathways involved in IL4 alteration of p27(kip1) are unknown, however. Here we investigated whether other cdk inhibitors contributed to the actions of IL-4 on RTLGA cells. By 12 h of IL-4 treatment, both cdk4 and cdk2 kinase activities against the retinoblastoma protein (pRb) were reduced and nuclear entry of pRb was prohibited. Twelve-hour cdk complexes contained elevated p21(waf1/cip1) but not p27(kip1), p15(ink4B) or p16(ink4A). IL-4 increased p21(waf1/cip1) but not p27(kip1) mRNA levels, and stimulated luciferase activity of a p21(waf1/cip1) promoter-luciferase reporter. In p53-mutant WITG3 cells, IL-4 did not alter p21(waf1/cip1) mRNA and promoter-luciferase activity or p27(kipl) protein, suggesting a need for functional p53. STAT6 phosphorylation by IL-4, however, occurred in both p53-mutant WITG3 and p53-functional RTLGA cells. Pre-treatment of RTLGA with anti-sense but not missense p21(waf1/cip1) oligonucleotide prior to IL-4: (a) restored cdk activities; (b) reduced cdk4-associated p21(waf1/cip1) levels; (c) prevented p27(kipl) elevation; and (d) reversed growth arrest. These results are the first to suggest that p21(waf1/cip1) is essential for IL-4-mediated elevation of p27(kip) and growth arrest of astrocytoma cells.
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PMID:Anti-sense oligonucleotide of p21(waf1/cip1) prevents interleukin 4-mediated elevation of p27(kip1) in low grade astrocytoma cells. 1069 11

Modulation of signal transduction pathways represents a promising approach for altering the biological behavior of hematopoetic malignancies. The cells of chronic lymphocytic leukemia were treated in vitro with CD40-ligand or IL-4 to explore their effects on survival and sensitivity to apoptosis induced by Fluda. The expression of G1 cell cycle regulatory proteins was also measured. Stimulation via CD40-CD40L resulted in increased viability, as did stimulation with IL-4. A combination of the two stimulators (CD40L plus IL-4) induced increased expression of cyclins D3 and E, pRb phosphorylation and downregulated p27. Cdk2 and Cdk4 activities were not detected. It seems that this combination induced also some progression in the cell cycle. Furthermore, Fluda-induced apoptosis was not prevented by CD40L, IL-4, or a combination of both agents, although a delay in the onset of apoptosis was observed. Taken together, these results support the view that CD40L and IL-4 sustain B-cell chronic lymphocytic leukemia (B-CLL) survival by different pathways and their synergistic action might induce cell cycle progression in B-CLL. The exposure of B-CLL to CD40L, IL-4 or both did not impair the sensitivity of B-CLL to Fluda. CD40L and IL-4 postponed apoptosis induced by Fluda, depending on a fashion of administration.
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PMID:Influence of CD40 ligation on survival and apoptosis of B-CLL cells in vitro. 1286 16

In the hope of identifying agents of therapeutic value in tissue inflammation, we tested ethanolic extracts of six Chinese herbs for their effects on human peripheral blood mononuclear cells (PBMC) proliferation in vitro. The results indicated that the extracts from Nelumbo nucifera Gaertn, used in treatment of tissue inflammation in traditional Chinese medicine, inhibited PBMC proliferation activated with phytohemagglutinin (PHA). By a bioassay-guided fractionation procedure, NN-B-4 identified from N. nucifera ethanolic extracts significantly suppressed activated PBMC proliferation. The inhibitory action of NN-B-4 did not involve direct cytotoxicity. In an attempt to further localize the point in the PBMC proliferation where arrest occurred, a set of key regulatory events leading to the cell proliferation, including cell cycle progression, production and gene expression of interleukin-2 (IL-2), IL-4, IL-10, and interferon-gamma (IFN-gamma) was examined. Cell cycle analysis indicated that NN-B-4 arrested the cell cycle progression of activated PBMC from the G1 transition to the S phase. The cyclin-dependent kinase (cdk) 4 mRNA expression in PBMC stimulated with PHA was reduced by NN-B-4. NN-B-4 suppressed, in activated PBMC, the production and mRNA expression of IL-2, IL-4, IL-10, and IFN-gamma in a dose-dependent fashion. The suppressant effects of NN-B-4 on proliferation of PBMC activated by PHA therefore appear to be mediated, at least in part, through inhibition of early transcripts of PBMC, especially those of important IL-2, IFN-gamma, and cdk4 and arrest of cell cycle progression in the cells.
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PMID:The extracts from Nelumbo Nucifera suppress cell cycle progression, cytokine genes expression, and cell proliferation in human peripheral blood mononuclear cells. 1517 79

Human Th17 cells have a limited proliferative capacity compared to other T-cell subsets. We have shown that human Th17 cells display impaired IL-2 production due to IL-4-induced gene 1 (IL4I1) upregulation. Here, we show that in human Th17 cells, IL4I1 also maintains high levels of Tob1, a member of the Tob/BTG (B-cell traslocation gene) antiproliferative protein family, which prevents cell-cycle progression mediated by TCR stimulation. Indeed, Th17 cells exhibited higher levels of Tob1 than Th1 cells in both resting and TCR-activated conditions. Accordingly, the expression of positive regulators of the cell cycle (cyclin A, B, C, and E and Cdk2), as well as of Skp2, which promotes Tob1 degradation, was lower in Th17 cells than in Th1 cells. Tob1 expression in human Th17 cells correlated with both RAR (retinoic acid receptor)-related orphan receptor C (RORC) and IL4I1 levels. However, RORC was not directly involved in the regulation of Tob1 expression, whereas IL4I1 silencing in Th17 cells induced a substantial decrease of Tob1 expression. These data suggest that IL4I1 upregulation in human Th17 cells limits their TCR-mediated expansion not only by blocking the molecular pathway involved in the activation of the IL-2 promoter, but also by maintaining high levels of Tob1, which impairs entry into the cell cycle.
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PMID:IL-4-induced gene 1 maintains high Tob1 expression that contributes to TCR unresponsiveness in human T helper 17 cells. 2449 9


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