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)

Serum-free cultures of PC 12 cells have been used as a model system for studying neuronal death occurring after neurotrophic factor deprivation. In this system, NGF rescues cells from death and prevents apoptotic DNA fragmentation. We report here that GM1 also promotes long-term survival of naive and NGF-pretreated PC 12 cells in serum-free medium and prevents internucleosomal cleavage of PC 12 cell DNA. In contrast to NGF, GM1 does not promote neurite outgrowth or somatic hypertrophy. The survival effects of GM1 are concentration dependent, with maximal activity at 30-50 microM. Optimal promotion of survival is obtained with multiple additions of GM1. Asialo-GM1 and sialic acid do not mimic these actions, indicating a requirement for the intact GM1 molecule. Prevention of serum-free PC 12 cell death is also obtained with di-, tri-, and tetrasialogangliosides. The ganglioside effects on survival and DNA fragmentation appear to be independent of macromolecular synthesis. GM1 is also effective under conditions in which cellular protein kinase C activity is downregulated by preexposure to high concentration of 12-O-tetradecanoylphorbol-13-acetate. Furthermore, GM1 promotes long-term survival of cultured rat sympathetic neurons after withdrawal of NGF. These findings complement prior observations that gangliosides protect cerebellar granule neurons from neurotoxicity caused by exposure to excitatory amino acids and extend the actions of gangliosides to rescue of neuronal cells deprived of neurotrophic factor support.
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PMID:Gangliosides rescue neuronal cells from death after trophic factor deprivation. 847 81

A vascular thrombotic lesion localized to the rat sensorimotor cortex was produced following intravenous injection of the photosensitive dye rose bengal, and its activation with a small beam of high-intensity white light focused to the skull overlaying the sensorimotor cortex. In the sensorimotor cortex at various times after the triggering event, two contiguous brain regions with different degree(s) of neuronal damage can be distinguished: (1) a primary thrombotic ischemic core where the majority of cells are dead and (2) a penumbra region surrounding the core lesion in which a slower progressive neuronal degeneration is occurring. Importantly, in both brain regions the neuronal degeneration is associated with the activation and persistent translocation of protein kinase C (PKC) as indicated by an increase in 4-beta-3H-phorbol-12,13-dibutyrate (3H-PDBu) binding. Moreover, the demonstration that in the area penumbra the neuronal degeneration and the persistent translocation of PKC can be inhibited by a pretreatment with dizocilpine (i.e., MK-801) indicates that the dynamics of the progression of the neuronal degeneration are maintained by glutamate accumulating in the extraneuronal fluids. MK-801 additionally prevents the transcriptional activation of several immediate-early genes (IEGs) (e.g., c-fos) and their cognate third nuclear messenger (i.e., c-Fos) expression present in the hemisphere ipsilateral to the lesion. On the other hand, LIGA4 and LIGA20 derivatives of GM1 lysoganglioside reduce the membrane translocation of PKC and the neuronal damage in the penumbra area, but fail to change the increase of IEG expression in the cortex ipsilateral to the lesion.
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PMID:Semisynthetic sphingolipids prevent protein kinase C translocation and neuronal damage in the perifocal area following a photochemically induced thrombotic brain cortical lesion. 850 19

Gangliosides are a family of glycolipids that are present at the cell surface of all mammalian cells. Patterns of gangliosides are different in gliomas than normal brain, and exogenously added gangliosides affect the growth of cultured glioma cells. Gangliosides inhibit the activities of several kinases, including protein kinase C (PKC) and cAMP-kinase. U-1242 MG cells (derived from a human malignant glioma) have receptors for platelet-derived growth factor (PDGF) that become phosphorylated on tyrosine when exposed to PDGF. Exposure of these cells to PDGF also causes an increase in intracellular calcium concentration ([Ca2+]i) and induces a translocation of PKC to the membrane. Preincubation of U-1242 MG cells with several species of gangliosides inhibits the increase in ([Ca2+]i) and PKC translocation in response to PDGF, but GM3 is much less effective than other species tested. This is due to a lack of activation of the receptor tyrosine kinase as monitored by phosphorylation of the receptor on tyrosine residues, but is not due to an inhibition of binding of PDGF to its receptors. The lack of activation of the PDGF receptor tyrosine kinase is due to an inhibition of dimerization of the receptor monomers by gangliosides GM1, GM2, GD1a, GT1b, but not GM3. Therefore, gangliosides may be involved in coordinating the activities of multiple trophic factors simultaneously acting on a cell by regulating the dimerization of their respective receptor monomers.
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PMID:Ganglioside modulation of the PDGF receptor. A model for ganglioside functions. 852 78

CMP-NeuAc:GM1 alpha 2,3-sialyltransferase (ST-IV) was purified to homogeneity from rat brain. Microsequencing of the tryptic peptides derived from the purified enzyme revealed two amino acid sequences homologous to the 14-3-3 proteins. A polyclonal antibody was raised against purified ST-IV. A 33 kDa protein was co-immunoprecipitated from rat brain extracts with the anti-(ST-IV) antibody as detected by Western blot analysis. This protein was identified as a subtype of 14-3-3 family by an anti-(14-3-3) antibody. Screening of a rat brain lambda gt11 library using the anti-(ST-IV) antibody resulted in the identification of a cDNA clone coding for the subtype of 14-3-3 protein. These results indicate an association of the 14-3-3 protein with the sialyltransferase. Since the 14-3-3 protein has PKC inhibitor activities and the activity of sialyltransferases is, at least in part, regulated by PKC, the association of the 14-3-3 protein with ST-IV may indicate a role for this protein in the post-translational regulation of the sialyltransferase activity through the processes of phosphorylation and dephosphorylation.
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PMID:Association of a 14-3-3 protein with CMP-NeuAc:GM1 alpha 2,3-sialyltransferase. 869 95

This series of studies has investigated the involvement of the NMDA receptor and the translocation of PKC in the seemingly unrelated phenomena of neuropathic pain and tolerance and dependence to narcotic analgesic drugs. This work has demonstrated that the NMDA receptor and PKC translocation are importantly involved in neuropathic pain and morphine tolerance or dependence and that these phenomena may be importantly interrelated. Neuropathic pain following nerve injury is a major chronic pain syndrome. Utilizing a rat model of painful peripheral mononeuropathy produced by CCI of the sciatic nerve, the authors have investigated central mechanisms of postinjury neuropathic pain. Behavioral and pharmacological studies indicate that thermal hyperalgesia and spontaneous pain behaviors observed in this model are attenuated by treatment with NMDA receptor antagonists. A consequence of NMDA receptor activation is calcium influx, which in turn can result in translocation of PKC from cytosol to membrane. Inhibitors of intracellular PKC translocation and activation block thermal hyperalgesia and spontaneous pain behaviors after CCI and also reduce the elevated spinal cord neural activity in CCI rats. Furthermore, spinal cord levels of membrane-bound PKC reliably increase in CCI rats as a result of translocation of PKC revealed by the [3H]PDBu autoradiographic assay. This increase in membrane-bound PKC is associated with postinjury neuropathic pain behaviors in CCI rats and both pain-related behaviors and membrane-bound PKC are reduced potently by GM1 ganglioside.
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PMID:The association of neuropathic pain, morphine tolerance and dependence, and the translocation of protein kinase C. 874 91

Gangliosides are known to be differentiation-inducing molecules in mammalian stem cells. We studied the interaction between the molecular structure of glycosphingolipids (GSLs) and their promoting mechanisms of the phagocytic processes in human polymorphonuclear leukocytes (PMN). The effect of various gangliosides from mammalian tissues on adhesion, phagocytosis, phagosome-lysosome (P-L) fusion and superoxide anion production was examined by human PMN using heat-killed cells of Staphylococcus aureus-coated with GSLs. Gangliosides GM3, GD1a, GD3 and GT1b showed a marked stimulatory effect on the phagocytosis and P-L fusion in a dose-dependent manner, while ganglioside GM1, asialo GM1 and neutral GSLs did not. The relative phagocytic rate of ganglioside GM3-coated S. aureus was the highest among the tested GSLs. Both P-L fusion rate and phagocytosis of S. aureus were elevated significantly when coated with ganglioside GD1a, GD3 or GT1b, and GT1b gave a five times higher rate than that of the non-coated control. These results suggest that the terminal sialic acid moiety is essential for the enhancement of phagocytosis and that the number of sialic acid molecules in the ganglioside is related to the enhancement of the P-L fusion process. On the other hand, the superoxide anion release from PMN was not affected by ganglioside GM2, GM3, GD1a or GT1b. Furthermore, to clarify the trigger or the signal transduction mechanism of phagocytic processes, we examined the effect of protein kinase inhibitors such as H-7, staurosporine (protein kinase C inhibitor), H-89 (protein kinase A inhibitor), genistein (tyrosine kinase inhibitor), ML-7 (myosin light chain kinase inhibitor), and KN-62 (Ca2+/calmodulin-dependent protein kinase II inhibitor) on ganglioside-induced phagocytosis. H-7, staurosporine and KN-62 inhibited ganglioside-induced phagocytosis in the range of concentration without cell damage, while H-89, genistein and ML-7 did not. Moreover, H-7 and KN-62 inhibited ganglioside-induced P-L fusion. These results suggest that protein kinase C and Ca2+/calmodulin-dependent protein kinase II may be involved in the induction of phagocytosis and P-L fusion stimulated by gangliosides.
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PMID:Stimulatory effect of gangliosides on phagocytosis, phagosome-lysosome fusion, and intracellular signal transduction system by human polymorphonuclear leukocytes. 933 83

Interferon-gamma (IFN-gamma)-induced, indoleamine dioxygenase-catalyzed tryptophan catabolism was studied in cultured human foreskin fibroblasts using the increase in cellular kynurenine synthesis as an index of gene expression. The time courses of the inhibition of IFN-gamma-induced kynurenine synthesis by actinomycin D and cycloheximide showed that the indoleamine dioxygenase gene was transcribed as early as 2 h and translated as early as 5 h after initiation of IFN treatment. Expression was completely inhibited by the Ser/Thr kinase inhibitor, H-7 (66 microM), during the first 2 h after IFN-gamma treatment. Prolonged pretreatment of cells with high concentrations of staurosporine (380 nM) or genestein (610 microM) inhibited expression by 38% and 53%, respectively. Genestein also inhibited expression when it was added to cultures between 8 and 24 h after IFN-gamma treatment. The expression of kynurenine synthesis was inhibited by A23817 during the first 4 h after IFN treatment by mechanisms that were independent of cyclooxygenase, calmodulin, and calcineurin. Exogenous gangliosides (bovine brain gangliosides and purified GM1) inhibited IDO expression throughout the first 24 h after IFN-gamma treatment by mechanisms that did not involve effects on Ca2+ channels. Other biologic response modifiers, including phorbol myristic acetate, arachidonic acid, lipopolysaccharide, analogs of cAMP and cGMP, W-7, and sphingosine, did not induce IDO in the absence of IFN-gamma, nor did they modulate IFN-gamma-induced expression. These results indicate that the expression of kynurenine synthesis is modulated at the transcriptional and posttranscriptional levels by protein tyrosine kinase and by a Ser/Thr kinase with properties distinctly different from those of conventional protein kinase C. The capacity for attenuation of this IFN-gamma-induced response over its entire time course by many effectors and through multiple cellular signaling pathways may represent a mechanism for fine-tuning the level of oxidative tryptophan metabolism to meet the needs of a particular cytostatic or antiproliferative response.
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PMID:Expression and regulation of interferon-gamma-induced tryptophan catabolism in cultured skin fibroblasts. 971 67

Cell differentiation is frequently accompanied by alterations in the composition of gangliosides in the plasma membrane resulting from a regulation of the enzyme activities involved. The regulation of CMP-NeuAc:GM1 alpha2-3-sialyltransferase (ST-IV) and UDP-GalNAc:GM3 N-acetylgalactosaminyltransferase (Gal-NAc-T) by the degree of enzyme phosphorylation was analyzed by determination of the enzyme activity on incubation of NG108-15 cells with various protein phosphatase inhibitors (okadaic acid and orthovanadate) or protein kinase activators (phorbol ester and forskolin). Incubation with okadaic acid, but not with orthovanadate, inhibited the ST-IV activity to 45% of that of control cells with t(1/2) = 60 min for the inactivation reaction. This indicates a rapid hyperphosphorylation of ST-IV due to the inhibition of a serine/threonine-specific phosphatase. A similar rate of inactivation was found on stimulation of protein kinase C with phorbol ester. In contrast to ST-IV, the activity of GalNAc-T was increased on stimulation of intracellular phosphorylation systems. The fastest activation of GalNAc-T was achieved with forskolin, yielding up to 160% of the initial activity within 30 min of effector incubation. Up-regulation of GalNAc-T in conjunction with down-regulation of ST-IV by stimulation of phosphorylation is suggested to serve as a physiological mechanism to increase the concentration of GM1, which was found to be elevated in correlation with the cell density. This assumption was corroborated by metabolic labeling studies with radioactive ganglioside precursors indicating an enhancement of the relative amount of a-series gangliosides subsequent to GM3 on phosphorylation stimulation. In particular, the biosynthesis of GM1 was specifically elevated within 2 h of incubation with forskolin. We conclude from the overall data that the ganglioside composition during the cell differentiation of NG108-15 cells can be specifically regulated by both protein kinase A- and protein kinase C-related phosphorylation systems.
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PMID:Regulation of ganglioside metabolism by phosphorylation and dephosphorylation. 972 22

An increasing body of evidence suggests that glycolipid domains are present on the plasma membrane surface of mammalian cells and play a key role in signal transduction. We have investigated the modulation of glycolipid-protein interaction consequent to a specific event occurring at the plasma membrane. For this purpose, a new photoactivable, radioactive derivative of GM1 ganglioside, carrying a phenyldiazirine fatty acid labelled with 125I, has been used with rat cerebellar granule cells in culture. Upon incubation of photoactivable GM1 with the cells followed by illumination, several proteins become radioactive and were detectable on the two dimensional-electrophoresis, which points to their interaction with the ganglioside. Upon addition of cytotoxic doses of glutamate, known to induce indirectly the activation of protein kinase C (PKC), one of the proteins crosslinked by photoactivable GM1 in control cells of molecular mass about 92 kDa and pI about 4, was not anymore detectable; this suggests its exclusion from the glycolipid domains. On the contrary, another protein, of about 15 kDa and pI 6.5, previously not crosslinked, was interacting with the ganglioside derivative after glutamate treatment. Comparable effects were exerted by phorbol-2-myristate-3-acetate, which directly induces the activation of PKC. These results show that PKC activation, a key step of inbound trans-membrane signalling, affects the interaction between glycolipids and proteins at the plasma membrane surface, possibly within a mixed domain. The dynamic modulation of ganglioside-protein interaction may affect the involvement of glycolipid domains in membrane-located events such as signal transmission and lipid/protein sorting.
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PMID:Glycolipid-protein interaction in the mechanism of signal transduction: studies with a photoactivable ganglioside analogue. 982 70

The pattern of expression of several protein kinase C (PKC) isoforms (alpha, betaI, delta, epsilon, eta, and zeta) during the course of hematopoietic development was investigated using primary human CD34(+) hematopoietic cells and stable cell lines subcloned from the growth factor-dependent 32D murine hematopoietic cell line. Each 32D cell clone shows the phenotype and growth factor dependence characteristics of the corresponding hematopoietic lineage. Clear-cut differences were noticed between erythroid and nonerythroid lineages. (1) The functional inhibition of PKC-epsilon in primary human CD34(+) hematopoietic cells resulted in a twofold increase in the number of erythroid colonies. (2) Erythroid 32D Epo1 cells showed a lower level of bulk PKC catalytic activity, lacked the expression of epsilon and eta PKC isoforms, and showed a weak or absent upregulation of the remaining isoforms, except betaI, upon readdition of Epo to growth factor-starved cells. (3) 32D, 32D GM1, and 32D G1 cell lines with mast cell, granulo-macrophagic, and granulocytic phenotype, respectively, expressed all the PKC isoforms investigated, but showed distinct responses to growth factor readdition. (4) 32D Epo 1.1, a clone selected for interleukin-3 (IL-3) responsiveness from 32D Epo1, expressed the epsilon isoform only when cultured with IL-3. On the other hand, when cultured in Epo, 32D Epo1.1 cells lacked the expression of both epsilon and eta PKC isoforms, similarly to 32D Epo1. (5) All 32D cell lines expressed the mRNA for PKC-epsilon, indicating that the downmodulation of the epsilon isoform occurred at a posttranscriptional level. In conclusion, the PKC isoform expression during hematopoiesis appears to be lineage-specific and, at least partially, related to the growth factor response.
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PMID:Lineage-restricted expression of protein kinase C isoforms in hematopoiesis. 994 60


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