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)

Protein ubiquitination has been implicated in ATP-dependent protein turnover and in a number of biological processes in eukaryotic cells. The ubiquitination activating enzyme, E1, and ubiquitin carrier protein, E2, are two essential enzymes in the protein ubiquitination machinery. Using purified E1 and E2 from rabbit reticulocytes and various protein kinases, which include cAMP-dependent protein kinase, protein kinase C, and protein tyrosine kinase, we demonstrated that E1 is phosphorylated by protein kinase C, with a stoichiometry of 0.65 mol of phosphate/mol of E1, and one of the E2 isoforms, E2(32kDa), is phosphorylated by protein tyrosine kinase to 2 eq of phosphate/mol of protein. Phosphorylation of E1 causes a 2-fold enhancement of its activity as monitored by ubiquitin-dependent ATP in equilibrium PPi exchange. When 1 eq of phosphate was incorporated into E2(32kDa), a 2.4-fold activation was also observed for its activity to catalyze the ubiquitination of histone H2A. The regulatory significance of this finding is discussed.
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PMID:Protein ubiquitination is regulated by phosphorylation. An in vitro study. 132 Nov 38

Hypothermia was first applied therapeutically as a local anesthetic and later was used to achieve organ protection during procedures necessitating circulatory interruption. Profound whole-body hypothermia, typically carried out in conjunction with extracorporeal bypass, has long been employed during cardiac and neurosurgical operative procedures. More recently, studies in small-animal experimental models of cerebral ischemia have provided persuasive evidence that even small decreases in brain temperature confer striking protection against ischemic neuronal injury. By contrast, small elevations of brain temperature during ischemia accelerate and extend pathologic changes in the brain and promote early disruption of the blood-brain barrier. Hypothermia retards the rate of high-energy phosphate depletion during ischemia and promotes postischemic metabolic recovery. More importantly, mild intraischemic hypothermia markedly attenuates the release of glutamate into the brain's extracellular space and significantly diminishes the release of dopamine. Similarly, the inhibition of calcium-calmodulin-dependent protein kinase II triggered by normothermic ischemia is prevented by hypothermia, as is the ischemia-induced translocation and inhibition of the key regulatory enzyme protein kinase C. Hypothermia also appears to facilitate the resynthesis of ubiquitin following ischemia. Studies of potential clinical importance have shown that moderate hypothermia is capable of attenuating ischemic damage even if instituted early in the postischemic period. In the setting of focal cerebral ischemia, moderate brain hypothermia reduces the infarct size (particularly in the setting of reversible middle cerebral artery occlusion); conversely, hyperthermia markedly increases the infarct volume. These studies underscore the importance of monitoring and regulating the brain temperature during experimental studies of cerebral ischemia to insure a consistent pathologic outcome and to avoid the false attribution of "pharmacoprotection" to drugs that reduce the body temperature. The measurement of brain temperature is now practicable in neurosurgical patients requiring invasive monitoring, and human studies have shown that cortical and cerebroventricular temperatures may exceed systemic temperatures. Mild to moderate decreases in brain temperature are neuroprotective in cerebral ischemia, while mild elevations of brain temperature are markedly deleterious in the setting of ischemia or injury. It is anticipated that controlled clinical trials of therapeutic brain temperature modulation will be undertaken over the next several years.
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PMID:Therapeutic modulation of brain temperature: relevance to ischemic brain injury. 138 56

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

Neuritic (senile) plaques are a hallmark of the pathology found in the brain of patients afflicted with Alzheimer's disease (AD). Neuritic plaques have been considered to be composed of an amyloid core surrounded by dilated neurites, although the use of anti-beta/A4-protein antibody revealed the presence of diffuse plaques without a nuclear-like central mass or surrounding paired helical filament (PHF)-containing neuritic components. The presence of diffuse plaques without PHF-containing neuritic components strongly suggests that the formation of amyloid precedes the degeneration of neurites that surround amyloid. Diffuse plaques are thus considered to be an early marker of AD pathology. In this article, we report that diffuse plaques, possible markers of early AD pathology, are immunostained with anti-protein kinase C(beta II) [anti-PKC(beta II)] antibodies. The PKC(beta II)-immunoreacting components of the diffuse plaques extend from neurons embedded in the plaques. Immunoelectron microscopy of diffuse and mature neuritic plaques shows that PKC(beta II)-like immunoreactivity in the plaques is closely associated with membranous structures of fine neuronal processes apposed to the amyloid fibers. These fine neuronal processes are distinct from classical neurites found typically in mature neuritic plaques. Furthermore, biochemical analysis demonstrates that PKC abnormalities, but not other AD markers (ubiquitin and A68), were found in the neocortex of clinically nondemented individuals with cortical plaques. Therefore, the PKC alteration in neurons might be involved in the early pathophysiology of AD.
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PMID:Protein kinase C alteration is an early biochemical marker in Alzheimer's disease. 188 May 47

The receptor tyrosine kinase Kit and Kit ligand (KL), encoded at the murine white spotting (W) and steel (Sl) loci, respectively, function in hematopoiesis, melanogenesis, and gametogenesis. To understand the mechanism of turnover of Kit in mast cells, mutant receptors generated in vitro were heterologously expressed in Wsb/Wsh mast cells lacking endogenous c-kit expression, and the effects of mutations on KL-induced internalization and ubiquitination/degradation of Kit were studied. Upon binding of KL, KL.Kit receptor complexes were rapidly internalized, and the turnover was accelerated by ubiquitin-mediated degradation. Inactivation of the Kit kinase resulted in a reduced rate of internalization of KL.Kit complexes, degradation of kinase-inactive receptor complexes was relatively slow, and receptor ubiquitination was absent. But abolishment of KL-induced receptor association and activation of phosphatidylinositol 3'-kinase and of tyrosine 821 autophosphorylation did not affect KL-induced internalization and ubiquitination/degradation of Kit. Furthermore, Kit receptors can be down-regulated by proteolytic cleavage induced by either activation of protein kinase C or by isopropyl alcohol. In summary, KL-induced internalization of KL.Kit complexes and ubiquitination/degradation require an active kinase. By contrast, proteolytic cleavage of Kit mediated by protein kinase C activation is independent of kinase activity.
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PMID:Mechanism of down-regulation of c-kit receptor. Roles of receptor tyrosine kinase, phosphatidylinositol 3'-kinase, and protein kinase C. 752 1

Bryostatins and phorbol esters acutely activate and subsequently down-regulate protein kinase C (PKC) by inducing its proteolysis via an unknown pathway. Here we show that treatment of renal epithelial cells with bryostatin 1 (Bryo) produced novel PKC-alpha species, which were larger than the native protein (80 kDa). The >80 kDa PKC-alpha species contained Ubi as indicated by immunostaining and accumulated in the presence of lactacystin, a selective inhibitor of proteolysis by the proteasome. In vitro experiments with 125I-ubiquitin and membranes from Bryo-treated cells showed that PKC-alpha became ubiquitinated by a reaction that depended on ATP and a cytosolic fraction. Lactacystin or a peptidyl aldehyde, Bz-Gly-Leu-Ala-leucinal, which inhibits certain proteinase activities of the proteasome, inhibited Bryo-evoked disappearance of PKC-alpha protein from the cells. Lacta preserved Bryo-induced 32P-labeled PKC-alpha indicating that the proteasome inhibitor spared activated enzyme from down-regulation in vivo. These findings show that Bryo induces the degradation of PKC-alpha by the ubiquitin-proteasome complex.
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PMID:Ubiquitination of protein kinase C-alpha and degradation by the proteasome. 870 57

We evaluated the possibility that distinct proteolytic pathways contribute to the down-regulation of a novel (epsilon) or conventional (alpha) isoform of protein kinase C (PKC) in nonimmortalized human fibroblasts. Inhibitors of calpains and other cysteine proteinases, vesicle trafficking, or lysosomal proteolysis did not affect the down-regulation of PKC-alpha or -epsilon produced by bryostatin 1 (Bryo). Lactacystin (Lacta) and certain terminal aldehyde tripeptides or tetrapeptides, which selectively inhibit the proteasome, preserved substantial PKC-alpha and -epsilon protein from down-regulation by Bryo or phorbol-12-myristate-13-acetate. Lacta preserved active kinase in vivo, as shown by the retention of Bryo-induced autophosphorylated PKC-alpha. Concomitant with down-regulation, Bryo produced PKC-alpha and -epsilon species that were larger than the native proteins (80 and 90 kDa, respectively). Western blot analysis showed that the larger PKC-alpha species were ubiquitinylated. Treatment with Bryo plus Lacta synergistically increased multiubiquitinylated PKC-alpha, as expected if Bryo induces ubiquitinylation of PKC-alpha and Lacta blocks its degradation. Bryo also produced a 76-kDa, nonphosphorylated form of PKC-alpha and an 86-kDa form of PKC-epsilon. Phosphatase inhibitors decreased production of 76- and 86-kDa PKC-alpha and -epsilon by Bryo and preserved 80- and 90-kDa PKC-alpha and -epsilon, respectively. Our results suggest that the down-modulation of PKC-alpha and -epsilon occurs principally via the ubiquitin/ proteasome pathway. Dephosphorylation seems to predispose PKC to ubiquitinylation.
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PMID:Bryostatin 1 and phorbol ester down-modulate protein kinase C-alpha and -epsilon via the ubiquitin/proteasome pathway in human fibroblasts. 905 99

Treatment of cells with tumor-promoting phorbol esters results in the activation but then depletion of phorbol ester-responsive protein kinase C (PKC) isoforms. The ubiquitin-proteasome pathway has been implicated in regulating the levels of many cellular proteins, including those involved in cell cycle control. We report here that in 3Y1 rat fibroblasts, proteasome inhibitors prevent the depletion of PKC isoforms alpha, delta, and epsilon in response to the tumor-promoting phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA). Proteasome inhibitors also blocked the tumor-promoting effects of TPA on 3Y1 cells overexpressing c-Src, which results from the depletion of PKC delta. Consistent with the involvement of the ubiquitin-proteasome pathway in the degradation of PKC isoforms, ubiquitinated PKC alpha, delta, and epsilon were detected within 30 min of TPA treatment. Diacylglycerol, the physiological activator of PKC, also stimulated ubiquitination and degradation of PKC, suggesting that ubiquitination is a physiological response to PKC activation. Compounds that inhibit activation of PKC prevented both TPA- and diacylglycerol-induced PKC depletion and ubiquitination. Moreover, a kinase-dead ATP-binding mutant of PKC alpha could not be depleted by TPA treatment. These data are consistent with a suicide model whereby activation of PKC triggers its own degradation via the ubiquitin-proteasome pathway.
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PMID:Activation of protein kinase C triggers its ubiquitination and degradation. 944 80

p62 is a recently identified ubiquitin-binding, cytosolic phosphoprotein that interacts with several signal transduction molecules including the tyrosine kinase p56(lck) and the protein kinase C-zeta. p62 is therefore suggested to serve an important role in signal transduction in the cell, although the physiological function of p62 remains undefined. Here we demonstrate by transient transfection assays that p62 stimulates the transcription of reporter genes linked to the simian virus 40 (SV40) enhancer. A putative p62-responsive element was localized to the B domain of the distal 72-base pair repeat of the SV40 enhancer. p62 was unable to bind this element in vitro, nor was it able to activate transcription when directly tethered to a promoter, suggesting that p62 stimulates transcription via an indirect mechanism. Stimulation of transcription mediated by p62 was dependent on its amino-terminal region, which is also necessary for interaction with cell surface signaling molecules. These findings indicate that p62 may link extracellular signals directly to transcriptional responses, and identify the SV40 enhancer as a downstream target for signal transduction pathways in which p62 participates.
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PMID:The p56(lck)-interacting protein p62 stimulates transcription via the SV40 enhancer. 1037 30

The intracellular signalling pathways controlling muscle protein synthesis and proteolysis are potential targets for anabolic/anti-catabolic therapy. In this review, we consider both the potentiation of the effect of anabolic hormones and suppression of the catabolic action of cytokines. Potential candidates, in particular isoforms of the protein kinase C family, and their role in the control of ribosomal action and the ubiquitin-proteasome proteolytic system are discussed.
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PMID:Potential intracellular targets for anabolic/anti-catabolic therapies. 1045 50


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