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)

Tumor necrosis factor (TNF-alpha) stimulates a number of signal transduction pathways in which phospholipases produce lipid second messengers. However, the immediate molecular targets of these messengers, in particular those of ceramide and arachidonic acid (AA) and their role in TNF signaling are not well defined. In this study we investigated the relationship of ceramide and AA in regulating an atypical PKC isozyme, PKC zeta. U937 cells responding to TNF-alpha treatment with NF kappa B activation displayed enhanced phosphorylation of PKC zeta, which is already detectable 30 s after stimulation. [14C]ceramide specifically binds to and regulates kinase activity of PKC zeta in a biphasic manner. Binding studies indicate high and low affinity binding with bmax values of 60 and 600 nM and Kd values of 7.5 and 320 nM respectively. At ceramide concentrations as low as 0.5 nM an up to 4-fold increase in autophosphorylation is obtained, which, at concentrations > 60 nM, again declines to basal levels. Interestingly, AA competes for ceramide binding and inhibits basal and ceramide-stimulated PKC zeta kinase activity at < 100 nM. Metabolism of [14C]ceramide in cells is slow and is inhibited in the presence of equimolar concentrations of lyso-phosphatidylcholine. Based on the bifunctional modulation of PKC zeta by the lipid messengers ceramide and AA, a model of TNF signal pathways is suggested in which PKC zeta takes a central position, acting as a molecular switch between mitogenic and growth inhibitory signals of TNF-alpha.
 ...
PMID:PKC zeta is a molecular switch in signal transduction of TNF-alpha, bifunctionally regulated by ceramide and arachidonic acid. 774 3

The maturation of epidermal keratinocytes is a tightly regulated, stepwise process which requires protein kinase C (PKC) activation. We investigated the effect of elevated extracellular Ca2+, a potent differentiation signal which increases cellular sn-1,2-diacylglycerol levels, on the PKC isozyme profile of cultured murine keratinocytes. Five PKC isozymes (alpha, delta, epsilon, zeta, and eta) were detected by immunoblotting. During Ca(2+)-induced differentiation, total cellular PKC alpha decreased, PKC epsilon and eta increased 3-5-fold, and the level of other PKC isozymes was relatively unchanged. PKC alpha underwent a progressive translocation from the soluble to the particulate fraction following elevation of extracellular Ca2+. The kinetics of PKC alpha translocation corresponded with the induction of keratinocyte differentiation markers. Both PKC delta and epsilon were selectively lost from the soluble fraction of keratinocytes exposed to elevated extracellular Ca2+, resulting in an increase in the proportion of these isoforms in the particulate fraction. PKC eta increased in both the soluble and particulate fractions, while PKC zeta did not change in amount or distribution during keratinocyte differentiation. Selective down-regulation of PKC isoforms by either 12-deoxyphorbol-13-phenylacetate or bryostatin 1 inhibited Ca(2+)-induced expression of differentiation markers at doses most specific for the down-regulation of PKC alpha. Taken together, these observations suggest that the induction of keratinocyte differentiation by Ca2+ results in the activation of specific PKC isozymes.
 ...
PMID:Specific protein kinase C isozymes mediate the induction of keratinocyte differentiation markers by calcium. 775 73

The purpose of this study was to determine if decreasing dietary protein from 24% (high protein) to 5% casein (low protein), substituting sucrose and cornstarch isocalorifically for casein, would modify the activity of protein kinase C (PKC) alpha and beta isoenzymes, as well as the expression of PKC alpha, beta, delta and zeta subtypes in the particulate, soluble and nuclear fractions of rat liver, and the development of gamma-glutamyltranspeptidase (GGT)-positive foci and nodules in the early stages (4, 7 and 60 days post-hepatectomy) of diethylnitrosamine-induced carcinogenesis promoted by 2-acetylaminofluorene in the diet plus partial hepatectomy (DEN-AAF-PH). In rats fed the 5% casein diet, body and liver weights decreased significantly compared with 24% casein-fed animals. However, the PKC total activity was unmodified. In 5% casein-fed rats, over-expression of PKC delta in the liver particulate fraction was detected at 7 and 60 days post-hepatectomy, with no significant PKC alpha and beta isoform activation. These animals showed only scattered GGT-positive hepatocytes at 60 days post-hepatectomy, with no appearance of hyperplastic foci or preneoplastic nodules. In contrast, rats fed the 24% casein diet demonstrated a progressive loss of PKC delta expression in the particulate fraction during tumour promotion, with activation and increased membrane association of PKC alpha and beta subtypes. These animals developed hyperplastic cell foci and preneoplastic nodules at 7 and 60 days respectively. Taken together, the results of this study suggest that overexpression of PKC delta in the liver particulate fraction of low protein-fed rats may play a specific role in inhibiting the development of hepatocellular focal lesions in the early stages of DEN-AAF-PH-induced carcinogenesis and confirm the role for nuclear PKC beta in promoting the selective growth of carcinogen-initiated hepatocytes in high protein-fed animals. No evidence for a role of PKC zeta in the carcinogenic process could be demonstrated.
 ...
PMID:Over-expression of protein kinase C delta is associated with a delay in preneoplastic lesion development in diethylnitrosamine-induced rat hepatocarcinogenesis. 776 90

Studies on the mechanism of dietary fat and energy modulation of skin carcinogenesis suggest that these diets may act through the cellular binding site of the phorbol ester tumor promoters, protein kinase C (PKC). High-fat diets increase the activity of PKC but have no impact on the steady-state protein levels. Energy restriction reduces the activity of PKC, presumably through reduction in the steady-state levels of particular isoenzymes (PKC alpha and PKC zeta). Phorbol-binding studies with epidermal cells from mice fed energy-restricted diets indicated a reduction of phorbol-binding sites in these cells. Investigations into lipid metabolism showed that both dietary fat and energy restriction increased epidermal cell diacylglycerol (DAG). The increase in DAG in cells from energy-restricted mice may be due to increased turnover of phosphatidylinositol, as was evident in the reduced phosphatidylinositol-4-phosphate and phosphatidylinositol-4,5-biphosphate and elevated inositol biphosphate and inositol triphosphate in these cells.
 ...
PMID:Dietary modulation of epidermal protein kinase C: mediation by diacylglycerol. 778 24

High extracellular glucose activates protein kinase C (PKC), a family of kinases vital to intracellular signaling. However, which PKC isoforms are involved and where in the cell they operate is unclear. We tested the hypothesis that only those PKC isoforms binding to diacylglycerol (DAG) are activated by high glucose. We also reasoned that the isoforms would translocate to different parts of the cell, where they presumably serve different functions. The PKC isoforms alpha, beta, delta, epsilon, and zeta were studied. Twenty mM glucose caused an increase in total PKC activity at six hours, which was maintained at 24 hours. High glucose decreased the angiotensin II-induced calcium signal. This effect was reversed by preincubating the cells with the PKC inhibitor staurosporine. Glucose induced a translocation of all PKC isoforms except PKC zeta by Western blot. Confocal microscopy showed that PKC alpha, beta, and epsilon were translocated into the nucleus. PKC delta showed strong association with cytoskeletal structures. The effects were sustained at 24 hours for PKC isoform beta and to a lesser extent for PKC delta and epsilon, but not for PKC alpha. Thus, PKC isoforms differ in their propensity to be activated by high glucose. Those isoforms binding to DAG are activated. Both cytoskeletal and nuclear signaling may be involved.
 ...
PMID:High glucose concentrations and protein kinase C isoforms in vascular smooth muscle cells. 778 2

The effect of phosphoinositides on the activity of protein kinase C (PKC) isotypes was investigated. PKC alpha, beta I, beta II, gamma, delta, epsilon, eta, and zeta were expressed in baculovirus-infected insect cells and purified by column chromatography. The calcium-activated PKC isotypes alpha, beta I, beta II, and gamma were not significantly activated by any of the phosphoinositides investigated (phosphatidylinositol-4-phosphate (PtdIns-4-P), PtdIns-3-P, PtdIns-4,5-P2, PtdIns-3,4-P2, and PtdIns-3,4,5-P3) when added in the presence of concentrations of phosphatidylserine that give maximal stimulation. The calcium-insensitive PKC isotypes delta, epsilon, and theta also showed little response to PtdIns-3-P, PtdIns-4-P, or PtdIns-4,5-P2 when these lipids were added in the presence of phosphatidylserine. In contrast, PtdIns-3,4-P2 and PtdIns-3,4,5-P3 caused a 5-15-fold stimulation of these enzymes compared with phosphatidylserine alone. 50% maximal stimulation of PKC epsilon by PtdIns-3,4,5-P3 occurred when this lipid was present at about 1% of the carrier PtdIns-4,5-P2 (about 100 nM). These lipids had little effect on baculovirus-expressed PKC zeta, which was constitutively active. A short chain version of PtdIns-3,4,5-P3, dioctanoyl-PtdIns-3,4,5-P3, activated PKC delta, epsilon, and eta in the absence of other lipids, whereas a short chain version of PtdIns-4,5-P2, dihexanoyl-PtdIns-4,5-P2, did not. Since PtdIns-3,4-P2 and PtdIns-3,4,5-P3 are nominally absent in unstimulated cells and appear within seconds to minutes of stimulation by various cell activators, these lipids could act as second messengers to activate PKC delta, epsilon, or eta in vivo.
 ...
PMID:Activation of protein kinase C family members by the novel polyphosphoinositides PtdIns-3,4-P2 and PtdIns-3,4,5-P3. 779 35

Protein kinase C zeta (PKC zeta) is an atypical PKC isoform that has recently been implicated in cell division and cell growth. However, there has been no morphologic evidence for the involvement of PKC zeta in mitogenic signal transduction. Here we use immunocytochemistry to demonstrate that PKC zeta co-localizes with microtubules in both interphase and metaphase cells of the shark rectal gland in primary culture. This co-localization is present after non-ionic detergent treatment and is disrupted by nocodazole. During mitosis, PKC zeta is associated with the mitotic apparatus and co-localizes with beta-tubulin in spindle microtubules, while entirely sparing astral microtubules. These findings provide the first evidence that PKC zeta is associated with the mitotic apparatus. The striking presence of PKC zeta in the central portion of the mitotic apparatus suggests a functional role for this kinase isoform in cell division.
 ...
PMID:Protein kinase C zeta is associated with the mitotic apparatus in primary cell cultures of the shark rectal gland. 779 44

Binding proteins to the pleckstrin homology domain of RAC protein kinase were screened by using glutathione S-transferase fusion protein system. Proteins in CHO cell extract of approximate molecular mass of 76 kD and 200 kD bound specifically to the pleckstrin homology domain of RAC protein kinase in vitro. The 76 kD protein was identified as protein kinase C zeta by immunoblot analysis. Studies of the association between the pleckstrin homology domain-truncated mutants and protein kinase C zeta indicated that the amino-terminal portion of the pleckstrin homology domain is essential for the binding and the whole structure of the domain is important for the efficient binding to protein kinase C zeta. The pleckstrin homology domain of RAC protein kinase was shown to recognize the regulatory domain of protein kinase C zeta. The protein-protein interaction between RAC protein kinase and protein kinase C through the pleckstrin homology domain might be important for the regulation of these protein kinases.
 ...
PMID:The pleckstrin homology domain of RAC protein kinase associates with the regulatory domain of protein kinase C zeta. 781 Dec 63

Recently this group found an endogenous substrate protein for Ca(2+)-independent novel protein kinase C (nPKC), i.e. KP-10 (pI 4.7/25,500 M(r)), in primary cultured mouse epidermal cells [Nishikawa, K. et al. (1992) Cell. Signal. 4, 757-776]. In the present study, the nPKC isozymes which phosphorylate KP-10 in these cells were determined. Western blot analysis revealed that PKC alpha, eta and zeta were present in epidermal cell 105,000 g supernatants and that the content of PKC zeta was much higher than those of PKC alpha and eta. Neither PKC beta, delta nor epsilon was detected in the 105,000 g supernatants. Phosphatidylserine and phorbol 12-myristate 13-acetate (PMA)-dependent KP-10 phosphorylating activity was immunoprecipitated by anti-PKC eta and zeta antibodies, but not by antiPKC alpha antibody. These results suggest that PKC eta and/or zeta phosphorylate KP-10 and play pivotal roles in intracellular signal pathways in intact epidermal cells.
 ...
PMID:KP-10, a novel protein kinase C substrate in intact mouse epidermal cells, is phosphorylated by novel protein kinase C eta and/or zeta. 781 86

Using Western blotting and immunofluorescence microscopy we detected the protein kinase C isoforms delta, epsilon and zeta in isolated cell nuclei from bovine cerebral cortex. Both protein kinase C (PKC) delta and PKC epsilon are present in higher concentrations in neuronal than in glial nuclei and are located inside the nucleus and at the nuclear envelope. There they give a punctate staining in immunofluorescence microscopy. PKC zeta is also present both in the nucleoplasm and at the nuclear envelope. PKC eta could not be detected in the cell nuclei and, even in the homogenate of cerebral cortex, this isoform is present only in very low concentrations. The antibody against PKC eta bound strongly to a nucleoplasmic protein with an apparent molecular mass of 99 kDa. The localization of non-conventional PKC isoforms at the cell nucleus strongly indicates that these isoforms are directly involved in the regulation of nuclear processes.
 ...
PMID:Localization of non-conventional protein kinase C isoforms in bovine brain cell nuclei. 782 40


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>