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)

In cultured vascular smooth muscle cells, angiotensin II and endothelin stimulate a variety of intracellular signals, including generation of inositol trisphosphate and diacylglycerol, mobilization of intracellular calcium, and activation of protein kinase C. These latter two events have been shown to mediate the phosphorylation of numerous proteins, but these substrates and the specific pathways mediating their phosphorylation have not been identified in vascular smooth muscle. Angiotensin II (100 nM, 10 min) induced a characteristic pattern of protein phosphorylation, which included the phosphorylation of many proteins, ranging in molecular mass from 20 to 76 kD. Three of these proteins have been identified as vimentin (M(r) 57,000), a specific protein kinase C substrate (M(r) 76,000) and the myosin light chain (M(r) 20,000). The 76-kD protein was one of the most highly phosphorylated proteins after agonist treatment. Endothelin-1 produced an identical pattern of phosphorylation. Five of these substrates were also phosphorylated by phorbol-12-myristate-13-acetate, and 5 were also phosphorylated after treatment with ionomycin. In general, the protein-kinase-C-dependent phosphorylations were sustained, while those mediated by calcium were rapid. Since these experiments were performed in cultured, phenotypically modulated cells stimulated with agents that promote cellular hypertrophy or hyperplasia, this pattern of phosphorylation may be representative of that seen during the growth response.
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PMID:Angiotensin-II-and endothelin-induced protein phosphorylation in cultured vascular smooth muscle cells. 839 84

The physiological importance of protein kinase C during oligodendrocyte progenitor maturation was investigated by analyzing the effects of the protein kinase C activator phorbol 12-myristate 13-acetate (TPA) on the morphology, proliferation, and differentiation of oligodendrocytes at sequential stages of development. Monoclonal antibodies A2B5 and O4 were used to identify the A2B5+O4- and the A2B5+O4+ galactocerebroside- progenitor stages. Anti-galactocerebroside and anti-myelin basic protein were used to identify mature, post-mitotic oligodendrocytes. Proliferation was measured by bromodeoxyuridine incorporation. Within 24 hr after addition, TPA induced a down-regulation of the O4 antigen in OL progenitors, and an increase of expression of the intermediate filament protein vimentin, leading to a phenotypic reversion from the vimentin-A2B5+O4+ phenotype to the less mature vimentin+A2B5+O4- stage. Concomitantly, TPA induced an increase in the number of bromodeoxyuridine-labeled oligodendrocyte progenitors and extensive process elongation. The response of O4+ progenitors was transient. Even with continued exposure to TPA, by 4 days after TPA addition the reverted cells ceased proliferation, reacquired O4 immunoreactivity, became vimentin-negative, and began to express galactocerebroside and myelin basic protein, and to display the complex, highly branched morphology characteristic of terminally differentiated oligodendrocytes. These results indicate that modulation of protein kinase C activity by TPA induces a transient reversion of O4+ progenitors to less mature O4- cells, causing a transient inhibition of terminal differentiation. The relationship of these data to similar responses of the OL lineage to specific growth factors and implications for remyelination after pathologic injury are discussed.
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PMID:Transient reversion of O4+ GalC- oligodendrocyte progenitor development in response to the phorbol ester TPA. 842 32

Vertical slices of 6-day postnatal (P6) rat retina were cut at a thickness of 100 microns and cultured using the roller-tube technique. After 14-21 days in vitro there was significant distortion of normal retinal architecture, but localized areas of the slices showed the typical pattern of layering of mature retina. The following immunocytochemical markers were used to characterize the different retinal cell types: antibodies against protein kinase C (PKC), calcium binding protein (CabP 28kD), neurofilaments (NF), glia-specific antibodies (GFAP, vimentin), and transmitter-specific antibodies (GABA, TH). The expression of these markers was compared in P6 retina, adult retina, and slice culture. To further characterize the cultured cells, patch-clamp recordings were performed in combination with intracellular injection of Lucifer Yellow (LY). Transmitter- and voltage-gated membrane currents were recorded from morphologically identified neurons. The experiments show that a mammalian slice culture can be used to study differentiation and function of retinal cell types.
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PMID:Organotypic slice culture of the mammalian retina. 848 85

Using two types of anti-phosphopeptide antibodies which specifically recognize vimentin phosphorylated by protein kinase C (PKC) at two distinct PKC sites, we found that PKC acted as a mitotic vimentin kinase. Temporal change of vimentin phosphorylation by PKC differed form changes by cdc2 kinase. The mitosis-specific vimentin phosphorylation by PKC was dramatically enhanced by treatment with a PKC activator, 12-O-tetradecanoylphorbol-13-acetate (TPA), while no phosphorylation of vimentin by PKC was observed in interphase cells treated with TPA. By contrast, the disruption of subcellular compartmentalization of interphase cells led to vimentin phosphorylation by PKC. Cytoplasmic and nuclear membranes are fragmented and dispersed in the cytoplasm and some bind to vimentin during mitosis. Thus, targeting of activated PKC, coupled with the reorganization of intracellular membranes which contain phospholipids essential for activation, leads to the mitosis-specific phosphorylation of vimentin. We propose that during mitosis, PKC may phosphorylate an additional subset of proteins not phosphorylated in interphase.
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PMID:Mitosis-specific phosphorylation of vimentin by protein kinase C coupled with reorganization of intracellular membranes. 860 2

Administration of 0.3 microM mitomycin C (MMC) or 2.0 microM cis-diamminedichloroplatinum II (CDDP) decreased the growth activity and induced the differentiation of U-937 human promonocytic cells, as shown by nitroblue tetrazolium reduction and an increase in surface expression of the leukocyte integrins CD11b/CD18 and CD11c/CD18. Expression of these differentiation markers started to be significant at 48 hr of treatment. These concentrations resulted in little cell damage (determined by Trypan blue exclusion) and slightly induced apoptosis (determined by DNA degradation and changes in nuclear morphology). The treatments induced a transient increase in c-fos and c-jun mRNA levels, with maximum values at 1-6 hr; a transient increase in collagenase mRNA level, with a maximum value at 48 hr; and a progressive increase in vimentin and lamin A and C mRNA levels. These changes were qualitatively similar to those produced by 12-0-tetradecanoylphorbol 13-acetate. CDDP and MMC also caused a transient increase of total AP-1 binding activity, as determined by gel retardation assays. The drugs produced an early transient activation (3-6 hr) of membrane-bound protein kinase C, followed by a later activation (48 hr) of both the membrane and the cytosolic enzyme. These results suggest that protein kinase C and AP-1-dependent gene expression could be involved in myeloid cell differentiation by alkylating agents.
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PMID:Differentiation of U-937 promonocytic cells with mitomycin C or cis-diamminedichloroplatinum II. 863 94

Fostriecin is an antitumor drug in phase I clinical trials. We have recently shown that it is a potent inhibitor of protein phosphatases 1 and 2A in vitro, a property not previously described for an antitumor drug. We have investigated its effects on protein phosphorylation in baby hamster kidney cells. Fostriecin strongly stimulated the phosphorylation of a single protein, which we identified as the intermediate filament vimentin. Fostriecin also caused rounding of the cells and a reorganization of the vimentin filaments. These effects are similar to those of the known protein phosphatase 1 and 2A inhibitors okadaic acid and calyculin A, which are also tumor promoters. Fostriecin induced vimentin hyperphosphorylation mostly at two sites, which were sensitive to staurosporine and could be phosphorylated by protein kinase C in vitro. Fostriecin-induced vimentin hyperphosphorylation also occurred in cells that lack p34cdc2 kinase activity. These results suggest that protein kinase C plays a direct or indirect role in vimentin hyperphosphorylation during exposure to fostriecin. The results also provide strong evidence that fostriecin inhibits protein phosphatases 1 and 2A in vivo and raise the possibility that it may have tumor-promoting activity.
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PMID:The antitumor drug fostriecin induces vimentin hyperphosphorylation and intermediate filament reorganization. 864 Sep 45

The subcellular localization of protein kinase C (PKC)-delta was determined in HL60 cells differentiated toward monocytes/macrophages by treatment with TPA. PKC-delta was detected in the nucleus and cytoplasm of differentiated HL60 cells and, more specifically, associated with structures resembling intermediate filaments. Indirect immunostaining revealed that PKC-delta colocalized with vimentin in the cytosol and perinuclear region of these cells. Immunoprecipitation studies showed that PKC-delta was in an active (autophosphorylated) state in differentiated HL60 cells and that vimentin immunoprecipitated from these cells was also phosphorylated. Treatment of HL60 cells with the PKC-specific inhibitor chelerythrine decreased the phosphorylation of vimentin. These data suggest that vimentin is a substrate for PKC-delta and that this PKC isoenzyme may play a specific role in the regulation of shape change and cell adhesion during HL60 differentiation.
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PMID:Protein kinase C-delta associates with vimentin intermediate filaments in differentiated HL60 cells. 866 Sep 25

Calpains are Ca-activated neutral proteases present in all cells together with an endogenous inhibitor, calpastatin. Proposed substrates are; cytoskeletal proteins like microtubules and actin, protein kinases such as PKC and membrane-bound enzymes like Ca-ATPase and the Ca-channel. In lenses from different species calpains have been detected in decreasing amounts from the epithelium to the cortex to the nucleus. Several substrates for calpain in the lens have been demonstrated: crystallins, vimentin, actin, beaded filaments and MP26 among others. Both studies on animal models and capsulorhexis indicate that calpains are mainly involved in cortical cataract.
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PMID:Calpains in the human lens: relations to membranes and possible role in cataract formation. 872 65

Airway smooth muscle plays a principal role in the pathogenesis of asthma. Primary cultures are being used to investigate airway myocyte proliferation and cellular pathways regulating contraction. Airway smooth muscle cells (SMC) modulate from a contractile to a noncontractile phenotype in culture, but no systematic study of the concomitant changes in expression of cytocontractile and cytoskeletal proteins has been reported. We measured temporal changes in protein marker expression of canine tracheal SMC in primary culture, using specific antibodies and cDNA probes. Immunoblot analysis revealed that when cells became proliferative after 5 days of culture, the content of smooth muscle myosin heavy chain (sm-MHC), calponin, sm-alpha-actin, and desmin diminished by > 75%; myosin light chain kinase, h-caldesmon, and beta-tropomyosin had also decreased significantly (P < 0.05). Northern blots revealed that mRNA levels for sm-MHC and sm-alpha-actin were also significantly reduced in proliferative SMC. Conversely, immunoblotting demonstrated the content of non-muscle myosin heavy chain, l-caldesmon, vimentin, alpha/beta-protein kinase C (PKC), and CD44 homing cellular adhesion molecule (HCAM) increased one- to sixfold as cells became proliferative. The content of sm-MHC and sm-alpha-actin protein increased after confluence, suggesting that cultured airway SMC are capable of phenotypic plasticity. Marker protein contents were also compared, by immunoblot assay, between SMC dissociated from trachealis or pulmonary arterial media. Cytocontractile protein content was higher in the trachea, which shortens faster than the pulmonary artery. The identification of these markers provides tools for assessing the phenotype of airway SMC in culture and the airways of asthmatic patients.
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PMID:Markers of airway smooth muscle cell phenotype. 876 31

Bistratene A is a marine toxin which induces phosphorylation of cellular proteins. Our current evidence indicates that this occurs through activation of protein kinase C-delta. In fibroblasts bistratene A causes rounding up of the cells and a rapid disappearance of vinculin staining and actin stress fibers as detected by fluorescence immunohistochemistry. Phosphorylation of the focal adhesion protein, talin, is increased after bistratene A treatment and this is inhibited by calphostin C, a specific inhibitor of PKC. No changes in the phosphorylation status of vinculin, tubulin, or vimentin were observed in the presence of the toxin. Treatment with bistratene A caused a redistribution of PKC-delta from cytosolic and membrane compartments to the nuclear fraction. There was no effect on the subcellular distribution of any other PKC isoform. These results demonstrate that phosphorylation of talin is implicated in the disruption of actin microfilaments in fibroblasts by bistratene A and that this is most likely mediated by PKC-delta.
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PMID:Bistratene A causes phosphorylation of talin and redistribution of actin microfilaments in fibroblasts: possible role for PKC-delta. 898 16


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