Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The proliferative effects of colony-stimulating factor 1 (CSF-1) on macrophages are exerted only throughout the G1 phase of the cell cycle. Genetic targets of the delayed early response to CSF-1 include novel G1 cyclin (CYL or cyclin D) genes. In macrophages, cyclin D1 is induced early in G1 and is expressed throughout the cell cycle as long as CSF-1 is present. The cyclin D1 protein turns over rapidly in CSF-1-stimulated cells and its level declines precipitously upon CSF-1 withdrawal. Cyclin D2 is induced later in G1 and its expression is periodic, whereas cyclin D3 is not expressed in macrophages but is regulated by growth factors in other cell types. The cyclin D1 protein associates during G1 with a polypeptide antigenically related to p34cdc2 and binds in vitro to a histone H1 kinase present in lysates of CSF-1-starved macrophages. The instability of the cyclin D1 protein and its ability to rescue a cyclin-dependent kinase activity from growth factor-deprived macrophages together suggest that the cyclin D protein is the dynamic partner in the complex. The timing of expression of cyclin D genes suggests that they act to link growth factor signals with cell cycle transitions during G1.
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PMID:Regulation of CYL/cyclin D genes by colony-stimulating factor 1. 148 47

Steel factor (SF) synergizes with a variety of hemopoietins to support the growth and differentiation of human progenitor cells. The human factor-dependent cell line MO7 has been used as a model to study the interaction of SF with other growth factors such as GM-CSF, because both factors support the proliferation of this cell line and are synergistic in combination. Previous studies have shown that this effect is not readily explained by the synergistic activation of early, cytosolic signal transduction intermediates such as tyrosine kinases, Raf-1, MAP2 kinase, or phospholipase C gamma. In an attempt to further explore the biological and biochemical mechanisms of the synergy between SF and GM-CSF, we examined the effects of these growth factors on the regulation of nuclear proto-oncogenes, cell cycle control genes, and G1-->S transition of MO7 cells. Individually, GM-CSF was a much more potent growth factor for MO7 cells than SF, particularly under serum-free conditions. Only GM-CSF, but not SF, was able to stimulate G1-->S transition of MO7 cells after factor deprivation for 24 h. Northern blot analyses showed also differential effects of GM-CSF and SF on the expression of some nuclear proto-oncogenes and G1 cyclins. GM-CSF (10 ng/ml), but not SF (20 ng/ml) increased the expression of c-myc and cyclin D2 mRNA, whereas both factors caused transient increases of c-fos and cyclin D3 mRNAs. When added simultaneously, GM-CSF and SF induced an at least additive increase of c-fos mRNA expression; this effect required the presence of fetal calf serum. No additive effects of GM-CSF and SF on c-myc, cyclin D2 or D3 mRNA expression were observed. C-jun and c-myb mRNAs were constitutively expressed in the MO7 cell line, but not further increased after stimulation with GM-CSF or SF for 15 min to 48 h. The inability of SF to induce growth promoting genes such as c-myc and cyclin D2 may explain why this cytokine does not support sustained proliferation of MO7 cells. These observations suggest that SF and GM-CSF exert different effects on the expression of genes involved in regulatory pathways of cell proliferation, but the molecular mechanism of synergy remains to be elucidated.
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PMID:Signal transduction of steel factor and granulocyte-macrophage colony-stimulating factor: differential regulation of transcription factor and G1 cyclin gene expression, and of proliferation in the human factor-dependent cell line MO7. 751 43

While testing purines related to the non-specific protein kinase inhibitors N6-dimethylaminopurine and N6-(delta 2-isopentenyl)adenine as potential inhibitors of the p34cdc2/cyclin B kinase, we discovered a compound with high specificity, 2-(2-hydroxyethylamino)-6- benzylamino-9-methylpurine (olomoucine). Kinetic analysis of kinase inhibition reveals that olomoucine behaves as a competitive inhibitor for ATP and as a non-competitive inhibitor for histone H1 (linear inhibition for both substrates). The kinase specificity of this inhibition was investigated for 35 highly purified kinases (including p34cdk4/cyclin D1, p40cdk6/cyclin D3, cAMP-dependent and cGMP-dependent kinases, eight protein kinase C isoforms, calmodulin-dependent kinase II, myosin light-chain kinase, mitogen-activated S6 kinase, casein kinase 2, double-stranded RNA-activated protein kinase, AMP-stimulated kinase, eight tyrosine kinases). Most kinases are not significantly inhibited. Only the cell-cycle regulating p34cdc2/cyclin B, p33cdk2/cyclin A and p33cdk2/cyclin E kinases, the brain p33cdk5/p35 kinase and the ERK1/MAP-kinase (and its starfish homologue p44mpk) are substantially inhibited by olomoucine (IC50 values are 7, 7, 7, 3 and 25 microM, respectively). The cdk4/cyclin D1 and cdk6/cyclin D3 kinases are not significantly sensitive to olomoucine (IC50 values greater than 1 mM and 150 microM, respectively). N6-(delta 2-Isopentenyl)adenine is confirmed as a general kinase inhibitor with IC50 values of 50-100 microM for many kinases. The purine specificity of cyclin-dependent kinase inhibition was investigated: among 81 purine derivatives tested, only C2, N6 and N9-substituted purines exert a strong inhibitory effect on the p34cdc2/cyclin B kinase. An essentially similar sensitivity to this olomoucine family of compounds was observed for the brain-specific cdk5/p35 kinase. Structure/activity relationship studies allow speculation on the interactions of olomoucine and its analogues with the kinase catalytic subunit. Olomoucine inhibits in vitro M-phase-promoting factor activity in metaphase-arrested Xenopus egg extracts, inhibits in vitro DNA synthesis in Xenopus interphase egg extracts and inhibits the licensing factor, an essential replication factor ensuring that DNA is replicated only once in each cell cycle. Olomoucine inhibits the starfish oocyte G2/M transition in vivo. Through its unique selectivity olomoucine provides an anti-mitotic reagent that may preferentially inhibit certain steps of the cell cycle.
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PMID:Inhibition of cyclin-dependent kinases by purine analogues. 792 96

To understand how the growth of T-cells transformed by Human T-cell leukemia virus type I (HTLV-I) is deregulated, we analysed the expression of cell-cycle regulatory genes in HTLV-I infected and non-infected T-cell lines. We investigated the gene for 6 cyclins, 4 cyclin-dependent kinases, and 5 cyclin-dependent kinase inhibitors, and found the following: (1) HTLV-I infected T-cell lines preferentially expressed cyclin D2, whereas cyclin D3 was the major D-type cyclin in HTLV-I negative T-cell lines; (2) HTLV-I infected T-cell lines expressed strikingly low levels of p18Ink4 compared with those that were HTLV-I negative; (3) HTLV-I infected T-cell lines expressed high levels of p21Waf1/Cip1/Sdi1, whereas p21Waf1/Cip1/Sdi1 was undetectable in HTLV-I negative T-cell lines. These features were also found in T-cells immortalized by Tax1, which we established. Therefore, it is strongly suggested that Tax1 alters the expression of these cell-cycle regulatory genes.
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PMID:Expression of cell-cycle regulatory genes in HTLV-I infected T-cell lines: possible involvement of Tax1 in the altered expression of cyclin D2, p18Ink4 and p21Waf1/Cip1/Sdi1. 862 84

We have studied the regulation of cyclins and cyclin-dependent kinase activities during differentiation of primary mouse keratinocytes. Differentiation was induced by placing primary murine keratinocytes into suspension culture, under conditions which prevent cells from attaching to any surface. This treatment induces synthesis of keratin 1, one of the earliest known markers of keratinocyte differentiation, and also results in a profound change in the regulation of G1 and S-phase cyclins and their associated proteins as well as their activities. The placement of cells in suspension culture reduced cyclin A, D1, and E kinase activity within 6 h, accompanied by the cessation of DNA synthesis. K1 mRNA levels were observed to increase after this period, supporting the hypothesis that cell cycle withdrawal precedes the differentiation program. Our data further revealed that the p27kip1 protein level and associated cyclin-dependent kinase inhibitory activity increased when keratinocytes were induced to differentiate. Pretreatment of adherent keratinocytes with p27kip1 antisense oligonucleotides dramatically reduced the accumulation of p27kip1 protein upon subsequent suspension culturing and prevented the onset of differentiation independently of the loss of cyclin-dependent kinase activities. Although antisense oligonucleotide treatment inhibited differentiation, it did not prevent growth arrest. Therefore, the differentiation of primary mouse keratinocytes required a function of Kip other than the inhibition of cyclin-associated activities, and we suggest that this requirement may reflect a novel Rb kinase activity present in Kip immune complexes, which is dependent on the presence of cyclin D3. Thus, the placement of keratinocytes in suspension induces a program that includes loss of cyclin activity, which is linked to terminal growth arrest, and an induction of p27kip1, which is linked to the differentiation program.
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PMID:The role of p27kip1 in the in vitro differentiation of murine keratinocytes. 904 Sep 42

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

Quiescent Swiss 3T3 cells can be induced to re-enter the cell cycle by stimulation of a variety of growth factor-dependent signal transduction cascades. We have utilised this cell system to investigate the point of convergence of mitogenic signalling by analysing the changes that distinct mitogens induce in the components of the cell cycle regulatory machinery (the G1 cyclins, cdks and their inhibitors). In the presence of insulin, activation of cAMP-dependent protein kinase caused a dramatic post-transcriptional down-regulation of p27(Kip1), an increase in cyclin D3 but had little effect on cyclin D1 levels, whilst activation of protein kinase C had a more modest effect on cyclin D3 and p27(Kip1) but caused a striking elevation in the expression of cyclin D1. The neuropeptide bombesin, when combined with insulin, caused increased expression of cyclin D1 and down-regulation of p27(Kip1) mRNA and protein. Thus each combination of mitogenic agents had different effects on the components responsible for regulating the orderly progression of the cell cycle. This outcome is incompatible with a single route to mitogenesis and demonstrates that different mitogens remain distinct in the signalling responses they initiate, only converging at the levels of the expression of the D-type cyclins and the inhibitor p27(Kip1).
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PMID:Differential control of cyclins D1 and D3 and the cdk inhibitor p27Kip1 by diverse signalling pathways in Swiss 3T3 cells. 915 Mar 81

Glucocorticoids inhibit proliferation of many cell types, but the events leading from the activated glucocorticoid receptor (GR) to growth arrest are not understood. Ectopic expression and activation of GR in human osteosarcoma cell lines U2OS and SAOS2, which lack endogenous receptors, result in a G1 cell cycle arrest. GR activation in U2OS cells represses expression of the cyclin-dependent kinases (CDKs) CDK4 and CDK6 as well as their regulatory partner, cyclin D3, leading to hypophosphorylation of the retinoblastoma protein (Rb). We also demonstrate a ligand-dependent reduction in the expression of E2F-1 and c-Myc, transcription factors involved in the G1-to-S-phase transition. Mitogen-activated protein kinase, CDK2, cyclin E, and the CDK inhibitors (CDIs) p27 and p21 are unaffected by receptor activation in U2OS cells. The receptor's N-terminal transcriptional activation domain is not required for growth arrest in U2OS cells. In Rb-deficient SAOS2 cells, however, the expression of p27 and p21 is induced upon receptor activation. Remarkably, in SAOS2 cells that express a GR deletion derivative lacking the N-terminal transcriptional activation domain, induction of CDI expression is abolished and the cells fail to undergo ligand-dependent cell cycle arrest. Similarly, murine S49 lymphoma cells, which, like SAOS2 cells, lack Rb, require the N-terminal activation domain for growth arrest and induce CDI expression upon GR activation. These cell-type-specific differences in receptor domains and cellular targets linking GR activation to cell cycle machinery suggest two distinct regulatory mechanisms of GR-mediated cell cycle arrest: one involving transcriptional repression of G1 cyclins and CDKs and the other involving enhanced transcription of CDIs by the activated receptor.
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PMID:Glucocorticoid receptor-mediated cell cycle arrest is achieved through distinct cell-specific transcriptional regulatory mechanisms. 915 17

The herpes simplex virus 1 (HSV-1) infected-cell protein 0 (ICP0) has the characteristics of a promiscuous transactivator of genes introduced into cells by infection or transfection. To identify cellular proteins interacting with ICP0, we used a domain of exon II of ICP0 that is known to be crucial for regulatory function of the protein as bait in the yeast two-hybrid screen. Our results were as follows. (i) A cDNA in a positive yeast colony was found to encode cyclin D3, a cell cycle regulator of G1 phase. (ii) A purified chimeric protein consisting of glutathione S-transferase (GST) fused to cyclin D3 specifically formed complexes with ICP0 contained in HSV-1-infected cell lysate. (iii) To enhance the expression of cyclin D3, the gene was inserted into the viral genome and overexpressed in infected cells. The overexpressed cyclin D3 colocalized with ICP0 in nuclear structures characteristic of ND10 and which earlier have been reported to contain ICP0. (iv) The accumulation of cyclin D3 protein in Vero cells infected with an alpha0 deletion mutant was reduced relative to that of cells infected with wild-type virus or a recombinant virus in which the deleted alpha0 sequences were restored. (v) Lysates of Spodoptera frugiperda Sf9 cells doubly infected with baculoviruses genetically engineered to express cyclin D3 and cyclin-dependent kinase 4 (CDK4) phosphorylated GST fused to retinoblastoma protein (GST-pRb) but did not phosphorylate the GST-alpha0(20-241) or GST-alpha0(543-768) fusion protein or immunoprecipitated ICP0 proteins. Moreover, the chimeric GST-ICP0(exon II) protein shown to bind cyclin D3 had no effect on the activity of the kinase on GST-pRb when added to mixtures of lysates of Sf9 cells which coexpressed cyclin D3 and CDK4. These results indicate that ICP0 interacts with, colocalizes with, and stabilizes the cyclin D3 cell cycle regulator and does not affect its interaction with the cyclin-dependent kinase.
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PMID:Herpes simplex virus 1 alpha regulatory protein ICP0 interacts with and stabilizes the cell cycle regulator cyclin D3. 931 10

The cyclin-dependent kinases (CDKs) promote cell cycle transitions in mammalian cells by phosphorylation of key substrates. To characterize substrates of the G1 and S phase cyclin-CDK complexes, including cyclin D1-CDK4, cyclin D3-CDK4, cyclin D3-CDK6, cyclin E-CDK2, and cyclin A-CDK2, which are largely undefined, we phosphorylated T-47D breast cancer cell nuclear lysates partially purified by ion-exchange chromatography with purified baculovirus expressed cyclin-CDK complexes. A comparison of the substrates that were phosphorylated by the different cyclin D-CDKs revealed some common as well as specific substrates. Hence, cyclin D1-CDK4 specifically phosphorylated a 38-kDa protein while cyclin D3-CDK4 specifically phosphorylated proteins of 105, 102, and 42 kDa. A 24-kDa protein was phosphorylated by both complexes. Cyclin D3-CDK6 exhibited similar substrate preferences to cyclin D3-CDK4, phosphorylating the 105- and 102-kDa proteins but not the 24-kDa protein. Hence, both the cyclin D1 and D3 as well as CDK4 and CDK6 subunits can confer substrate specificity on the overall cyclin D-CDK complex. Cyclin E-CDK2 and cyclin A-CDK2 phosphorylated a greater number of substrates than the cyclin D-CDKs, ranging in size from 10 kDa to over 200 kDa. Twenty-two substrates were common to both complexes, while six were specific for cyclin A-CDK2 and only one protein of 34 kDa was specific for cyclin E-CDK2. These studies indicate that cyclins E and A modulate the specificity of CDK2 and have demonstrated substrates that may be important for the specific roles of these cyclin-CDKs during G1 and S phase progression. Protein sequencing of one of the cyclin-CDK substrates characterized in this study identified this protein as nucleolin, a previously characterized CDC2 (CDK1) substrate, thus indicating the utility of this approach in identifying cyclin-CDK targets. These results show that both the cyclin and CDK subunits can regulate the substrate specificity of the overall cyclin-CDK complex and have demonstrated numerous substrates of D-, E-, and A-type cyclin-CDK complexes potentially involved in regulating transit through the G1 and S phases of the cell cycle.
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PMID:Differential phosphorylation of T-47D human breast cancer cell substrates by D1-, D3-, E-, and A-type cyclin-CDK complexes. 940 25


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