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)

Phorbol-12,13-dibutyrate and 1,2-dioctanoylglycerol, activators of protein kinase C (PKC) that stimulate DNA synthesis in serum-deprived Swiss 3T3 fibroblasts, induce histone H1 kinase activity associated with anti-cdc2 immunoprecipitates after a lag period of 15h, a time point close to G1/S boundary of the cell cycle in these cells. Downregulation of PKC does not affect the basal cdc2 kinase activity, but potently inhibits both phorbol dibutyrate- and dioctanoylglycerol-induced cdc2 kinase activation. Phorbol dibutyrate induces a dramatic increase in the p34cdc2 protein level as well as the appearance of p35-p36 forms of cdc2 on Western blot. In PKC-downregulated cells, the p34 form of cdc2 remains elevated but p35-p36 forms do not appear upon phorbol dibutyrate stimulation. These results demonstrate that PKC activation leads to cdc2 kinase activation in mitogenically responsive Swiss 3T3 cells, and strongly suggest that both expression of p34cdc2 protein and its posttranslational modification(s) are involved in this process. Western blot analysis of PKC isozymes suggests that either PKC alpha, PKC delta or PKC epsilon may be involved in p34cdc2 kinase activation and mitogenesis.
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PMID:Activators of protein kinase C induce p34cdc2 histone H1 kinase stimulation in Swiss 3T3 fibroblasts. 144 45

Human myeloid leukemia cells (i.e., HL-60, U937, THP-1) which are induced to differentiate along the monocytic pathway by 12-O-tetradecanoylphorbol-13-acetate (TPA), revert back to the undifferentiated phenotype after 3 to 4 weeks. During this differentiation and retrodifferentiation process the cells obviously establish a distinct sequence of biological processes which is integrally regulated to simultaneously control differentiation and cell growth. Thus, induction of monocytic markers by TPA is associated with a down-regulation of cell cycle genes and cessation of proliferation. In particular, crosstalk between the TPA-induced translocation of protein kinase C (PKC) and the activation of transcription factors, especially AP-1, enhances the expression of genes associated with the monocytic phenotype. This is accompanied by induction of intermediate filament proteins, surface glycoproteins, changes in membrane properties and intracellular metabolism. In parallel, the cells cease to divide, and genes associated with cell cycle progression including cdc2, cyclins, cdc25, and histones are down-regulated. Although signals responsible for arrested cell growth remain unclear, there are several control mechanisms regarding cell cycle genes and differentiation parameters (for a review, see Nigg, E. A., Seminars in Cell Biol., 2, 262-270, 1991). For example, activated p34cdc2 kinase is involved in lamina disassembly by direct phosphorylation of lamin proteins which may contribute to nuclear envelope breakdown during mitosis (Enoch, T., M. Peter, P. Nurse, J. Cell Biol. 112, 797-807 (1991)). Moreover, endomembrane traffic is arrested by a cdc2-like kinase probably via phosphorylation of members of the rab protein family which contributes to vesiculation and membrane transport by hydrolyzing GTP (Tuomikoski, T., et al., Nature 342, 942-945 (1989)). Although there are several reports on a possible feedback control between differentiation and cell cycle, including phosphorylation of cyclins and activation of a ubiquitin-dependent proteolytic degradation, signaling pathways and possible mechanisms for retrodifferentiation and reentry into the cell cycle remain unclear. While some terminally differentiated cells are committed to die, the major part of the differentiated monocytic population undergoes retrodifferentiation. All cellular signals characterized so far are reverted during retrodifferentiation: Redistribution of PKC and down-regulation of c-fos and c-jun contribute to an interruption of the differentiation-associated transsignaling cascade. Thus, down-regulation of markers associated with monocytic differentiation in combination with metabolic changes restore the original cell phenotype. At the same time cell cycle genes are up-regulated, and the cells regain proliferative capacity. Finally, retrodifferentiated and untreated control cells demonstrate indistinguishable properties.
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PMID:Retrodifferentiation--an alternative biological pathway in human leukemia cells. 164 56

HLA class I antigens seem to be involved in the proliferative response of PHA-activated human T-lymphocytes. We have previously reported that the treatment of PHA-activated peripheral blood mononuclear cells (PBMC) with an anti-HLA class I monoclonal antibody, 01.65, (i) inhibits the tritiated thymidine incorporation, (ii) inactivates cytosolic protein kinase C (PKC) and (iii) causes an increase in the duration of the cell cycle. Northern Blot kinetic analysis of c-fos, c-myc, cdc2, IL-2R, c-myb, ODC, TK and H3, from 10 minutes to 120 hours, was performed in MAb 01.65 treated cultures. We found that the expression of four genes (c-myc, IL-2R, cdc2 and TK) was depressed 24 hours after PHA stimulation.
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PMID:Molecular analysis of cell cycle-related gene expression in anti-HLA class I monoclonal antibody (01.65) treated PHA-activated human T-lymphocytes. 177 40

We sought the mammalian neurofilament tail domain-specific kinase. Several well known kinases including cAMP-dependent protein kinase, protein kinase C, Ca(2+)-calmodulin-dependent protein kinase II, casein kinase I, and casein kinase II phosphorylated the high (NF-H) and middle molecular mass subunit (NF-M) of bovine neurofilaments, but they did not reduced the electrophoretic mobility of the dephosphorylated form of NF-M and NF-H by phosphorylation nor was the amount of phosphorylation increased by dephosphorylation of NF proteins, indicating that the phosphorylation sites by these kinases are not major in vivo phosphorylation sites at the tail domain. In contrast, cdc2 kinase phosphorylated specifically the dephosphorylated form of NF-H. 4 mol of phosphates were incorporated per mol of NF-H and this phosphorylation returned the electrophoretic mobility of the dephosphorylated form of NF-H to the position of the isolated, fully phosphorylated form of NF-H. Furthermore, the phosphorylation by cdc2 kinase dissociated the binding of dephosphorylated NF-H to microtubules. Phosphorylation sites were located at the carboxyl-terminal tail domain. The KSPXK motif, but not KSPXX, in the repetitive sequence was suggested to be the phosphorylation site by using synthetic peptides.
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PMID:Phosphorylation of neurofilament H subunit at the tail domain by CDC2 kinase dissociates the association to microtubules. 193 2

Isolated interphase lamin C, obtained from Ehrlich ascites tumor cells, was digested by Lys-C endoproteinase, the resulting peptides separated by reversed-phase HPLC and subjected to microsequencing in order to identify phosphorylation sites in interphase and following phosphorylation in vitro by cdc2-kinase, protein kinase C (PKC) and protein kinase A (PKA), respectively. Nuclear lamin C showed partial phosphorylation of Ser392 and Ser409, and possibly Ser407 in interphase. Phosphorylation was increased in response to cdc2-kinase at Ser390 and Ser392 and to PKC at Ser572. The N-terminal peptide (aa 1-32) containing consensus sequences for the 3 kinases was phosphorylated by cdc2-kinase, PKC and PKA. The sequence data suggests that multiple molecular switches via lamina modification control the dynamic behaviour of the nucleoskeleton during the cell cycle.
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PMID:Identification of phosphorylation sites on murine nuclear lamin C by RP-HPLC and microsequencing. 195 8

In 3T3-F442A cells, TGF-beta caused cellular proliferation in a time and dose-dependent manner. TGF-beta induced cyclin D1 and cdk2 proteins in 3T3-F442A cells. The mitogenic effect of TGF-beta was specific in nature. The antimitogenic agent, hGH, inhibited the mitogenic effect of TGF-beta and was associated with inhibition of cyclin D1 expression. The protein kinase c inhibitor, staurosporine, inhibited the mitogenic effect of TGF-beta. Taken together, these results suggest that TGF-beta affects expression levels of cell cycle-regulated proteins and its mitogenic effect is mediated through protein kinase C in 3T3-F442A cells.
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PMID:Mitogenic response to TGF-beta in 3T3-F442A cells. 748 18

Protein phosphorylation has evolved as the most versatile posttranslational modification widely used by cells. Signal transduction pathways mediated by activation of MAP kinases and protein kinase C trigger the exit of cells from the quiscence (Go-->G1 transition). Indeed, binding of growth factors at the cell surface triggers their receptors, usually possessing a tyrosine kinase on the cytoplasmic side, to phosphorylate other molecules passing on the information sequentially to GRB2 protein, to p21ras, to c-Raf-1, to MAP kinase kinase, to MAP kinase, to p90rsk, to transcription factors. Activated PKC, MAP kinase, and pp90src can translocate to the nucleus where they phosphorylate a number of protein transcription regulators in a cell cycle-dependent manner or in response to cell stimulation for exit from quiescence. The cell cycle is mainly regulated by p34cdc2 or otherwise called cdc2 in association with cyclins B at G2/M and by Cdk2 in association with cyclins A, D1, and E at G1/S checkpoints; phosphorylation of histone H1 and lamins by cdc2 triggers chromosome assembly and nuclear envelope breakdown, respectively, as a prelude to mitosis. Cdc2 activities functioning as a G2/M regulator are controlled by its phosphorylation and dephosphorylation at Ser/Thr residues. MAP kinases might be the missing link in the chain connecting the Go to G1 transition with the cell cycle regulation, whereas phosphorylation of replication protein factors, retinoblastoma, and p53 might link the G1 to S transition with the control of DNA synthesis. A number of transcription factors are known to stimulate DNA replication, including p53, c-Myc, AP-1, Oct-1, T-antigen; the DNA binding activities of all these proteins and their interaction with other transcription factors are controlled by phosphorylation. The nuclear import of several proteins including NF kappa B, Dorsal, glucocorticoid receptor, ISGF3, rNFIL-6, T antigen, and the kinases PKC, MAP, and p90rsk, are dependent on their phosphorylation at specific sites. Histone phosphorylation stimulated at discrete stages of the cell cycle or in response to cAMP or other stimuli might induce profound changes in chromatin organization.
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PMID:Phosphorylation of transcription factors and control of the cell cycle. 754 80

Human diploid fibroblasts have a finite proliferative lifespan in culture, at the end of which they are arrested with G1 phase DNA contents. Upon serum stimulation, senescent cells are deficient in carrying out a subset of early signal transduction events such as activation of protein kinase C and induction of c-fos. Later in G1, they uniformly fail to express late G1 genes whose products are required for DNA synthesis, implying that they are unable to pass the R point. Failure to pass the R point may occur because senescent cells are unable to phosphorylate the retinoblastoma protein, owing to the accumulation of inactive complexes of cyclin E/Cdk2 and possibly cyclin D/Cdk4. Senescent cells contain high amounts of p21, a potent cyclin-dependent kinase inhibitor whose levels are also elevated in cells arrested in G1 following DNA damage, suggesting that both arrests might share a common mechanism. Cell aging is accompanied by a progressive shortening of chromosomal telomeres, which could be perceived by the cells as a form of DNA damage that gives rise to the signals that inactive the cell cycle machinery.
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PMID:Origins of G1 arrest in senescent human fibroblasts. 757 95

We identified two major substrates for the proline-directed protein kinases--cdc2 kinase and tau protein kinase II (TPKII)--in the cytosol fraction from rat brains. The molecular masses of the proteins were 80 and 46 kDa. Because the 80-kDa protein was phosphorylated by protein kinase C and was heat stable, we examined the possibility that the protein might be myristoylated alanine-rich C kinase substrate (MARCKS). On the basis of a comparison between the properties of the 80-kDa protein and purified MARCKS, we concluded that the 80-kDa protein is indeed MARCKS. The amounts of phosphate incorporated into MARCKS by protein kinase C, cdc2 kinase, and TPKII were 1.7, 1.4, and 0.6 mol/mol of the protein, respectively. Two-dimensional tryptic peptide mapping indicated that phosphorylation sites by protein kinase C and proline-directed protein kinases completely differed. Only the seryl residue was phosphorylated by protein kinase C, whereas both seryl and threonyl residues were phosphorylated by cdc2 kinase and TPKII. Phosphorylation of MARCKS by protein kinase C inhibited the binding to calmodulin, whereas phosphorylation by cdc2 kinase and TPKII significantly increased the binding to calmodulin. The holoenzyme of protein phosphatase 2A dephosphorylated MARCKS that had been phosphorylated by protein kinase C, cdc2 kinase, or TPKII, whereas calcineurin was unable to dephosphorylate it. These results suggest that cdc2 kinase and TPKII regulate the functions of MARCKS in different ways from protein kinase C.
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PMID:Phosphorylation of myristoylated alanine-rich C kinase substrate (MARCKS) by proline-directed protein kinases and its dephosphorylation. 761 38

Tumor necrosis factor-alpha (TNF-alpha) demonstrated antimitogenic activity in MCF-7 cells (estrogen receptor-positive human breast cancer cells) in a dose- and time-dependent manner (EC-50 of 2.5 ng/ml). This antimitogenic effect of TNF-alpha was accompanied by a decreased number of cells in S phase in a dose- and time-dependent manner. Based on growth arrest experiments using aphidicolin, it is apparent that TNF-alpha acted in early G1 phase. It did not show antimitogenic effects once cells reentered the S phase based on [3H]thymidine incorporation into DNA and cell cycle analysis. Specificity of TNF-alpha was established by using monoclonal anti-human TNF-alpha antibody. On the basis of Western immunoblot analysis of Rb, p53 and cell cycle inhibitory protein (Cip1) (p21) proteins, TNF-alpha decreased Rb protein expression in a dose- and time-dependent manner whereas it increased the expression level of tumor suppressor p53 protein. TNF-alpha also increased the expression level of Cip1 (p21) protein in a dose-dependent manner. This induction of Cip1 (p21) protein was preceded by the induction of p53 protein in MCF-7 cells. Cip1 (p21) protein associated with cyclin D was also increased. Tumor suppressor Rb protein expression was increased during G1 to S phase progression. Cyclin D protein expression levels were not changed in response to TNF-alpha treatment, although serine/threonine kinase inhibitors such as H7 and the protein kinase C inhibitor staurosporine decreased cyclin D expression levels in MCF-7 cells. Based on experiments with staurosporine, it appears that TNF-alpha does not utilize a protein kinase C pathway in MCF-7 cells. Other cell cycle-related proteins such as Cdk2, Cdc2, and Cdk4 did not show any change in response to TNF-alpha. TNF-alpha did not affect complexes between cyclin D and Cdk2, Cdk4, and Rb proteins in MCF-7 cells. Taken together these results suggest that Rb, p53, and Cip1 (p21) proteins mediate TNF-alpha antimitogenic activity, and TNF-alpha induces growth arrest in the G1 phase in MCF-7 cells.
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PMID:Effects of tumor necrosis factor-alpha on antimitogenicity and cell cycle-related proteins in MCF-7 cells. 762 60


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