Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Id is a helix-loop-helix protein which forms heterodimer with ubiquitous and/or tissue-specific basic helix-loop-helix proteins and inhibits their DNA binding. It has been noted that putative phosphorylation sites for various protein kinases exist in rat Id1, Id2 and Id3. We show here that Id1 and Id2 can be phosphorylated in vitro by cAMP-dependent protein kinase, Id2 and Id3 by cdc2 kinase, and all three Ids by protein kinase C. The phosphorylated Id1 was actually immunoprecipitated in nerve-growth-factor-stimulated PC12 cells. Gel mobility shift assays, however, demonstrated that neither phosphorylation of Id proteins by cAMP-dependent protein kinase nor phosphorylation of E47 by protein kinase C affected the inhibition of E47 homodimer formation and its DNA binding. Taken together with other observations, phosphorylation of Id proteins may play a role in regulation of cell differentiation but not directly in the dimerization and DNA binding.
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PMID:Phosphorylation of helix-loop-helix proteins ID1, ID2 and ID3. 786 97

The effects of prostaglandin E2 (PGE2) on cytokine production and proliferation of the CD4+ human helper T cell clone SP-B21 were investigated. In cells stimulated with anti-CD3 mAb, PGE2 inhibited cell proliferation and the production of all the cytokines examined. Addition of rIL-2 fully restored the proliferative response and partially restored the production of IL-4 and IL-5, but not that of other cytokines. In contrast, in cells stimulated with phorbol myristate acetate (PMA)/A23187, PGE2 enhanced the production of IL-4 and IL-5, and only partially inhibited the production of other cytokines. Therefore, the effects of PGE2 vary depending on the mode of T cell activation, and the IL-4 and IL-5 are regulated differently from other cytokines. In a mobility shift assay, only the NF-kappa B (p50/p50) homodimer was observed in a complex formed with the kappa B sequence in unstimulated SP-B21 cells. When cells were stimulated with anti-CD3 mAb or PMA/A23187, a complex formation of NF-kappa B (p50/p65) heterodimer with the kappa B sequence was induced. Interestingly, PGE2 or di-butyryl (Bt2)cAMP abolished the binding of NF-kappa B (p50/p65) heterodimer to the kappa B sequence in cells stimulated with anti-CD3 mAb but not with PMA/A23187. Our results suggest that the target of PGE2 action is a component in the signal transduction pathway leading to the activation of protein kinase C. However, the inhibition of the T cell activation signals by PGE2 is selective. PGE2 enhanced the complex formation with NF-AT, AP-1 and CLE0 sequences when the cells were activated by either anti-CD3 mAb or PMA/A23187 stimulation. It seems therefore that PGE2, by elevating cAMP levels, interferes with the activation pathway for NF-kappa B but not for NF-AT, AP-1 or CLE0 binding protein.
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PMID:Effects of prostaglandin E2 on Th0-type human T cell clones: modulation of functions of nuclear proteins involved in cytokine production. 801 94

We have characterized regulation of type-1 plasminogen activator inhibitor (PAI-1) gene expression by phorbol 12-myristate 13-acetate (PMA) and the cAMP-inducing agent forskolin in the human breast carcinoma cell line MCF-7. PMA caused a strong induction of PAI-1, while forskolin suppressed the PMA response. Transfection experiments with fusion genes showed that sequences mediating PMA induction as well as forskolin suppression were present between base pairs -100 and -30 of the 5'-flanking region of the PAI-1 gene. The region was found to contain two Sp1 binding sites. A proximal sequence in the region, TGAGTTCA (P box), with sequence similarity to phorbol ester response elements (TRE) as well as to cAMP response elements (CRE), bound a low-abundance, as yet unidentified nuclear protein in MCF-7 cells. This sequence had a higher affinity to purified c-jun homodimer than to c-jun/c-fos heterodimer in MCF-7 nuclear extracts; it had no affinity to the proteins binding to CRE consensus sequences in these extracts. A distal TRE-like sequence, TGAGTGG (D box), had a weak affinity to c-jun/c-fos heterodimer and c-jun homodimer; binding of proteins to this sequence was facilitated by binding of proteins to the P box. Both the P box and the D box were necessary for PMA responsiveness, suggesting a cooperativity between the two binding sites. A mutation of the P box removing the CRE similarity abolished the forskolin suppression of the PMA response. We propose that the protein kinase C and the protein kinase A signal-transduction pathways, with opposite effects on PAI-1 gene expression converge by modulating differently P-box-binding proteins.
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PMID:A common response element mediates differential effects of phorbol esters and forskolin on type-1 plasminogen activator inhibitor gene expression in human breast carcinoma cells. 811 99

Protein F1/GAP43 is neuron-specific, associated with neurite outgrowth during development and a substrate for PKC. This protein is present in high levels in serotonergic neurons which in culture sprout in response to the glial-derived S100b, the beta-beta homodimer. As an initial step in determining whether S100b acts on F1/GAP43 we studied the regulation by S100b of PKC phosphorylation of F1/GAP43. Either the S100b or a mixture of S100a and S100b, both from a brain glial cell source, inhibited in vitro phosphorylation of purified F1/GAP43 by purified PKC in a dose-dependent manner. Using recombinant PKC subtypes, purified S100b preferentially inhibited the F1/GAP43 phosphorylation by the beta subtype. The IC50 of S100b for beta I and beta II PKC was 8 microM while for alpha and gamma PKC it was 64 microM. S100b inhibition was thus subtype-selective. Histone III-S phosphorylation by the four PKC subtypes was not inhibited by S100b. S100b inhibition was thus substrate-selective. Moreover, the effect of S100b on phosphorylation could not be explained by a direct inhibition of kinase activity. Together with earlier studies implicating a role for S100 in synaptic plasticity and neurite outgrowth, the present results suggest that S100b may regulate such functions through its inhibition of neuron-specific PKC substrate (F1/GAP43) phosphorylation. The regulation of this neuron-specific substrate phosphorylation by glial S100 suggests the potential for a novel neuro-glial interaction. Finally, the location of S100 gene on chromosome 21, trisomic in Down's syndrome, and over-expressed in this disorder, as well as in Alzheimer's disease, suggests a link to cognitive impairments in human.
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PMID:Glial-derived S100b protein selectively inhibits recombinant beta protein kinase C (PKC) phosphorylation of neuron-specific protein F1/GAP43. 816 23

PDGF heterodimer of A and B chains, a complete mitogen for 3T3 mouse fibroblasts, exemplifies those growth factors interacting with membrane associated tyrosine kinase receptors. Its binding to the PDGF-receptors results in receptor dimerization and subsequent activation of tyrosine kinase activity in the cytoplasmic protein domain, autophosphorylation of the receptor being the first event in the transduction cascade. Before the ligand-receptor complex is internalized and degraded, receptor stimulation is transmitted to the general transduction network, in which several tyrosine kinase substrates are activated by phosphorylation and changes the cytoplasmic biochemistry. These changes include cytoplasmic alkalinization, increases in the intracellular concentration of cyclic-AMP and Ca2+ and activation of protein kinase C through the degradation of phosphoinositides. The known substrates recruited by the PDGF-receptor association are phosphatidylinositol-3'-kinase, ras-GTPase-activating protein, phospholipase C-gamma, serine-threonine kinase Raf-1 and src and src-related tyrosine kinases. Upon binding of PDGF to its receptor, transactivation of transcriptional and nuclear factors such as c-fos and c-myc genes and dephosphorylation of c-jun occurs, V-sis, the oncogen of the simian sarcoma virus (SSV), is highly homologous to the c-sis/PDGF-B gene that encodes the homodimer of the B-chain of the PDGF receptor. Cells transformed by SSV have been studied as a model system for the autocrine stimulation of the PDGF receptor.
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PMID:Platelet derived growth factor/tyrosine kinase receptor mediated proliferation. 822 Jan 10

Platelet-derived growth factor (PDGF) plays an important role in the process of atherosclerosis which is characterized by the presence of macrophage-derived foam cells. In the present study, the induction of the mRNA of PDGF-beta receptor was demonstrated during cell differentiation of human monocyte-macrophages, whereas no mRNA was detected in the cells during the early days of culture. Flow cytometry analysis using antibodies specific for PDGF-beta receptor and CD14 showed the presence of both PDGF-beta receptor and CD14 on human monocyte-derived macrophages, whereas no PDGF-beta receptor was detected on human monocytes 4 h after cell adhesion to a culture dish. In the binding assay of PDGF-BB on human monocyte-derived macrophages, a saturable and high affinity binding site with Kd of 27.5 pM and Bmax of 23.3 fmol/mg of cell protein was demonstrated. When human monocytes were cultured in the presence of the protein kinase C inhibitor staurosporine, PDGF-beta receptor induction was inhibited, and tetradecanoylphorbol acetate enhanced PDGF-beta receptor expression in human monocyte-derived macrophages, indicating that PDGF-beta receptor expression is associated with maturation and differentiation of monocyte-macrophages through the activation of protein kinase C. In response to PDGF-BB homodimer, PDGF-beta receptor was phosphorylated, and thymidine uptake and inositol trisphosphate production were stimulated in monocyte-derived macrophages. Furthermore, PDGF-BB suppressed the production of macrophages colony-stimulating factor in macrophages. The expression of PDGF-beta receptor on human monocyte-derived macrophages suggests that PDGF influences the process of atherosclerosis by regulating the function of macrophages as well as smooth muscle cells in the vascular wall.
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PMID:Expression of platelet-derived growth factor beta receptor on human monocyte-derived macrophages and effects of platelet-derived growth factor BB dimer on the cellular function. 822 85

Mechanisms of Mn-superoxide dismutase (Mn-SOD) expression in human umbilical endothelial cells were investigated by Northern blot analysis, enzyme-linked immunosorbent assay, and immunoelectron microscopy. The Mn-SOD in human endothelial cells was markedly induced by the cytokines tumor necrosis factor (TNF), interleukin-1, and lipopolysaccharide as well as by phorbol esters [12-O-tetradecanoylphorbol 13-acetate (TPA)]. The induction was partially blocked by dexamethasone and 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine, a potent inhibitor of protein kinase C (PKC). In endothelial cells in which PKC had been desensitized to TPA by pretreatment for 24 h, addition of TNF caused overexpression of Mn-SOD. These facts suggested that at least two separate signal-transducing pathways are involved in expression of the Mn-SOD gene. Immunoelectron-microscopic studies showed that Mn-SOD was localized to the mitochondrial matrix of the capillary vascular endothelial cells of cardiac tissues and cultured endothelial cells. Mn-SOD, which is normally abundant in endothelial cells relative to other cell types, may play an important protective role against stresses such as ischemia and inflammation.
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PMID:Manganese-superoxide dismutase in endothelial cells: localization and mechanism of induction. 823 2

NF-kappa B and related factors are important transducers of external signals to the cell nucleus. They are abundant in the brain, where they may be significant for the regulation of gene transcription in plasticity-related processes for instance, via activation of protein kinase C. The subunit composition and levels of these factors in the mouse and rat brain and other tissues, using an assay based on gel retardation of the oligonucleotides corresponding to the kappa B DNA-element, are reported here. Three major kappa B-binding factors were observed. Factors I and II were activated by the dissociating agent deoxycholate. DNA protein cross-linking and antibody neutralization experiments suggest that factor I is a heterodimer of c-Rel and p65; factor II is a heterodimer of p50 and p65 (authentic NF-kappa B), and of p50 and c-Rel; factor III is the p50 homodimer (KBF1). All three factors were generally expressed in the 17-day-old rat embryo and 5-day-old pup, whereas in the adult rat, expression was more limited and showed certain tissue specificity. Factor II was the most generally expressed and the only factor observed in adult brain. Factor I was only detected in the adult testis whereas factor III was observed in the adult spleen and, in small amounts, in the liver and lung. Two minor kappa B-specific factors (A and B), distinctive to the brain and spleen, respectively, showed very slow gel mobility. Their estimated molecular weights were about 125 kDa and 95 kDa, respectively. Expression of factor A was stable in the rat brain during development. Factor A may be identical to a previously described brain-specific factor, BETA (Korner et al., Neuron, 3 (1989) 563-572). Thus, the expression pattern of kappa B-binding activities is apparently developmentally regulated and tissue-specific particularly in the adult. In the adult mouse and rat brain, only factors II (probably NF-kappa B and p50/c-Rel heterodimer) and A (probably BETA) could be observed.
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PMID:NF-kappa B-like factors in the murine brain. Developmentally-regulated and tissue-specific expression. 825 75

The physiological form of vitamin D, 1 alpha,25-dihydroxyvitamin D3 (1,25D3) is not only a powerful regulator of calcium homeostasis but also a hormone with important roles in cell growth and differentiation. The differentiating effects of 1,25D3 have been studied extensively in a large number of in vitro systems but primarily using cultured leukemia cells, keratinocytes, and bone cells. In spite of this attention, the understanding of the mechanisms that lead to the diverse forms of cell differentiation by 1,25D3 is fragmentary. It seems likely, however, that the effects of 1,25D3 on calcium homeostasis and on cell differentiation are both signaled by direct effects on the cell membrane and by the transduction of the signal to the genome. The direct effect may be mediated by a hypothetical membrane recognition element, the G proteins, phosphoinositide metabolism, and protein kinase C (PKC). Signals to the nucleus may include PKC, the Ca2+ gradient, and protein phosphorylation cascades, but the protein receptor (VDR) plays a principal role in this form of signal transduction. The VDR interacts with the promoter elements of a number of nuclear genes, either as a homodimer or a heterodimer with a retinoid or orphan receptors. The key nuclear responses include the increased expression of phenotype-specifying proteins and the appearance of G1/S and G2+M cell cycle blocks, which result in cessation of cell proliferation. The attempts to improve control of neoplastic cell proliferation will depend on a selective exploitation of these properties of 1,25D3 to design novel analogs of 1,25D3 with low hypercalcemic but high differentiation-inducing properties. It is anticipated that a better understanding of the multiple pathways that transduce the signals from 1,25D3 to the nucleus and to the cell membrane, a consideration of the structure-function relationships of the derivatives of 1,25D3, and the use of synergistic combinations of 1,25D3 with other biological response modifiers or cytotoxic drugs will lead to improved therapy of several hyperproliferative and malignant diseases.
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PMID:Signaling pathways for vitamin D-induced differentiation: implications for therapy of proliferative and neoplastic diseases. 828 48

CTLA-4 is an adhesion receptor expressed on activated T cells. The amino acid sequence of CTLA-4 is related to CD28, and although the function of CTLA-4 remains unknown, it shares several features with CD28, including a common counter-receptor, B7, that is present on Ag-presenting cells. In a recent study we found that CD28 and CTLA-4 were coexpressed at the mRNA level on activated T cells but that only CD28 was expressed on resting T cells. Here we show that within the T cell population, CTLA-4 expression is restricted to the subset of T cells that also express cell surface CD28. CTLA-4 mRNA expression can be induced on quiescent T cells via phorbol ester-mediated activation of protein kinase C but not with calcium ionophore treatment alone. Phorbol ester-induced expression of CTLA-4 mRNA could be enhanced with calcium ionophore treatment, and treatment of cells in this manner resulted in a reciprocal decrease in expression of CD28 mRNA. Ligation of CD28 with monoclonal antibody also resulted in the specific and rapid induction of CTLA-4 mRNA. To study the expression of CTLA-4 at the protein level, a rabbit antiserum against a recombinant protein derived from CTLA-4 cDNA was generated. When activated T cells were labeled with [35S]methionine, the rabbit antiserum precipitated a 41- to 43-kDa protein from whole cell lysates. Similar results were found when detergent-soluble lysates from 125I surface-labeled resting and activated T cells were analyzed by SDS-PAGE. Surprisingly, under the conditions tested, CTLA-4 migrated primarily as a monomer at the cell surface, and could not be shown to exist as a disulfide-bonded homodimer or as a heterodimer consisting of CTLA-4 and CD28. These results suggest that B7 can bind to T cells via distinct receptor complexes consisting of either CD28 or CTLA-4, and that these complexes may potentially mediate distinct biologic functions. Further, the present results suggest that noncovalent interactions might mediate association of CTLA-4 and/or CD28 at the cell surface.
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PMID:Characterization of CTLA-4 structure and expression on human T cells. 839 58


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