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

We have previously demonstrated that at least four isoforms of protein kinase C (PKC; alpha, delta, epsilon, and zeta) are expressed in neonatal rat ventricular myocytes and that development is associated with a decline in their expression. The mechanism(s) regulating PKC isoform expression in ventricular myocytes is completely unknown. The developmental decline in PKC expression occurs, in large part, during the first 2 weeks of postnatal life, while thyroid hormone levels are known to be progressively increasing. Accordingly, this study examined the influence of thyroid hormone on PKC isoform expression to determine whether thyroid hormone can be implicated as a potential physiological regulator of PKC gene expression during normal cardiac development. Hypothyroidism was induced in adult rats by surgical thyroidectomy; thyroid status was manipulated in cultured neonatal ventricular myocytes by growth in serum-free medium with varying triiodothyronine (T3) levels. In each case, hypothyroidism was verified by a 10- to 50-fold increase in steady state mRNA for beta-myosin heavy chain. In hypothyroid adult ventricular myocardium, there was a selective 60% increase in the expression of PKC epsilon protein that corresponded to an increase in maximally stimulated PKC enzyme activity with PKC epsilon substrate peptide (epsilon pep) but not with histone as substrate. Northern blot analysis revealed a 70% increase in PKC epsilon mRNA, indicating that the regulatory effects of thyroid hormone are mediated, at least in part, at the message level. In neonatal ventricular myocytes, there was a T3-dependent reduction in immunoreactivity for both PKC alpha and PKC epsilon that was associated with significant reductions in both histone- and epsilon pep-kinase activities. The concentration of T3 that half-maximally repressed PKC alpha and PKC epsilon expression was approximately 0.5 nmol/L. Thyroid hormone had no effect on PKC delta and PKC zeta expression in neonatal or adult ventricular myocytes. PKC isoform expression in cardiac fibroblasts was not influenced by variations in the thyroid hormone concentration during culture. These results provide evidence that thyroid hormone specifically represses PKC alpha and PKC epsilon in the neonatal heart and PKC epsilon in the adult heart. Thyroid hormone-induced changes in PKC may play an important permissive role in the modulation of autonomic responsiveness in ventricular cardiomyocytes.
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PMID:Thyroid hormone represses protein kinase C isoform expression and activity in rat cardiac myocytes. 878 72

Recent evidence suggests that the formation and permeability of tight junctions are actively regulated by second-messenger-generating systems involving G proteins and protein kinase C (PKC). A possible specific target for these regulatory proteins is the tight junction protein ZO-1. An extensive immunocytochemical study was performed in cultured epithelial monolayers of MDCK and Caco-2 cells to identify which isoforms of G proteins and PKC are present at or near zonula occludens complex. Antibodies against alpha-subunits of each one of the four major subfamilies were used for the localization of the G proteins. For the PKC localization, antibodies against eight different isoforms were used. In confluent monolayers, G alpha 12 and PKC zeta, were the only isoforms of these proteins at the cell borders. In subconfluent monolayers, G alpha 12 and PKC zeta were found at the plasma membrane only along the areas of lateral cell-cell contact. These isoforms formed a pattern of distribution very similar to the ZO-1 protein. The present findings indicate that G alpha 12 and PKC zeta may be part of the zonula occludens complex and may locally regulate formation and permeability of tight junctions.
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PMID:Identification of isoforms of G proteins and PKC that colocalize with tight junctions. 880 52

Vertebrate and invertebrate photoreceptors shed their photosensitive membrane on a daily basis. Although we have detailed knowledge of the morphology of the disc shedding and renewal process in vertebrate photoreceptors, and of the turnover of rhabdom in invertebrate photoreceptors, we know relatively little about the molecular mechanisms whereby these processes are triggered by light and/or by circadian efferent input to the retina. We have used the horseshoe crab, Limulus polyphemus, as a model system to unravel the molecular means by which the trigger light is communicated to the intracellular machinery responsible for the daily breakdown of the photosensitive membrane. Phorbol esters, potent and specific activators of protein kinase C (PKC), induce a robust burst of rhabdom shedding when injected subretinally into the compound lateral eye of Limulus. This occurs in the absence of the light trigger normally required to initiate shedding in the lateral eye at dawn, suggesting that PKC may play a role in the light triggering of rhabdom shedding. Diacylglycerol (DAG) analogs were also found to elicit rhabdom shedding in the lateral eye without a light trigger, but at uncharacteristically high concentrations. However, injecting inositol trisphosphate (InsP3) and DAG analog simultaneously results in a tenfold decrease in the concentration of DAG analog required to initiate a shedding event. Immunohistochemical screening for PKC in the lateral eye shows that two isozymes (PKC beta II and PKC zeta) are co-localized to the retinular cell rhabdom. Taken together, these data suggest that light triggers rhabdom shedding at dawn via a classical Ca(2+)-sensitive PKC, similar to PKC beta II, which is activated synergistically by the light-evoked production of DAG and InsP3.
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PMID:Dawn, diacylglycerol, calcium, and protein kinase C--the retinal wrecking crew. A signal transduction cascade for rhabdom shedding in the Limulus eye. 882 34

Relatively little is known about the substrate specificity of individual protein kinase C (PKC) isozymes, particularly with respect to physiologically relevant substrates. One class of prominent cellular substrates for PKC is represented by the myristoylated alanine-rich C kinase substrate, or MARCKS, protein. In the present study, we have used a baculovirus expression system to coexpress human MARCKS with eight different isozymes of PKC, to determine which isozymes are capable of phosphorylating MARCKS in intact cells. In Sf9 cells, coexpression of MARCKS with individual PKC isozymes led to the following increases in MARCKS phosphorylation: alpha, 3.6-fold; beta iota, 4.6-fold; beta mu, 2.7-fold; gamma, 4.8-fold; delta, 3.0-fold; epsilon, 4.3-fold; and eta, 4.9-fold. In most cases, stimulation of cells with a phorbol ester led to a slight increase (20-30%) in MARCKS phosphorylation. PKC zeta did not phosphorylate MARCKS to any appreciable extent above control. In addition, in vitro kinetic analysis of PKC zeta showed that it has a 1000-fold lower affinity for a synthetic peptide comprising the MARCKS phosphorylation site domain compared to mixed conventional PKC isozymes from rat brain. These data indicate that MARCKS is a substrate in intact cells for at least seven isozymes of PKC: alpha; beta iota; beta mu; gamma; delta; epsilon; and eta. The isozyme PKC zeta does not appear to phosphorylate MARCKS in vivo or with significant affinity in vitro. Thus, PKC zeta, which is not activated by phorbol esters or diacylglycerol, also appears to behave differently with respect to this class of important cellular PKC substrates.
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PMID:MARCKS phosphorylation by individual protein kinase C isozymes in insect Sf9 cells. 883 63

In this study, we demonstrated that epidermal growth factor (EGF) stimulated the phosphorylation of myelin basic protein (MBP), a mitogen-activated protein kinase (MAPK) substrate, in crude extracts of human dermal fibroblasts. Moreover, using a selective protein kinase C inhibitor, GF 109203X (3-[1-[3-(dimethylamino)propyl]-1 H-indol-3-yl]-4 (1 H-indol-3-yl)-1 H-pyrrole-2,5-dione monohydrochloride), we observed that protein kinase C was partially involved in the total MBP phosphorylation. To determine the role of protein kinase C in the MBP phosphorylation, we separated, using fast protein liquid chromatography, the proteins present in the fibroblast crude extracts; we thus detected two distinct MBP kinase activities. The first one was stimulated by EGF and corresponded to p42mapk and p44mapk isoforms; this stimulation was not modified by GF 109203X. The second MBP kinase activity was not stimulated by EGF and was due to two protein kinase C isoforms reacting with an anti-protein kinase C zeta antibody. These results show that, in human dermal fibroblasts, EGF stimulates p42mapk and p44mapk isoforms in a protein kinase C-independent manner.
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PMID:Protein kinase C-independent activation of mitogen-activated protein kinase by epidermal growth factor in skin fibroblasts. 883 23

This study was designed to test the hypothesis that induction of the preconditioned state results in a sustained translocation of protein kinase C (PKC) which accounts for the memory associated with preconditioning. Isolated rabbit cardiomyocytes were subjected to established preconditioning protocols using either adenosine or transient ischemia. At timed intervals during induction of preconditioning (PC), post-incubation or final sustained ischemia, cells were harvested, subjected to digitonin lysis and separated into cytosolic and particulate fractions. Samples were evaluated by Western blot analysis with monoclonal antibodies to alpha, epsilon, zeta and gamma PKC isozymes, and bands were qualified by densitometry. Internal controls for each experiment included oxygenated cardiomyocytes and cell with PKC translocation evoked by treatment with phorbol 12-myristate 13-acetate (PMA). For control oxygenated cells, the particulate fraction contained about 30% of PKC epsilon, 5-10% of PKC alpha and 60-70% of PKC zeta. Preconditioning with adenosine (100 microM) or 10 min ischemia had no significant effect on these percentages. Furthermore, the relative amounts of PKC isozymes associated with the particulate fraction of control and preconditioned cells did not differ after a postincubation in oxygenated buffer or during a final ischemic incubation. PMA and ingenol completely translocated the epsilon and alpha isoforms, while thymeleatoxin totally translocated PKC alpha but only partially (50%) translocated PKC epsilon. The distribution of PKC zeta between fractions was not affected by any drug. The protein phosphatase inhibitor calyculin A protected cells mimicking preconditioning. This protection was blocked by preincubation with the selective PKC inhibitor calphostin C but was largely retained if calphostin C was added only during the final ischemic period. It is concluded that PKC activity is required for preconditioning, but a sustained translocation of PKC above basal levels is not necessary for protection of rabbit cardiomyocytes in vitro.
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PMID:Translocation of PKC, protein phosphatase inhibition and preconditioning of rabbit cardiomyocytes. 884 35

The limited amount of available information regarding the developmental control of protein kinase C (PKC) isoform expression restricts our understanding of the role of these enzymes in normal physiology. Accordingly, this study investigated PKC isoform expression in selected tissues from fetal, neonatal, and adult rats. PKC beta immunoreactivity was prominent in brain tissue, whereas the expression of PKC alpha, PKC delta, PKC epsilon, and PKC zeta was found to be widespread. Although no developmental change in any PKC isoform was evident in liver, striking tissue-specific age-dependent differences in PKC isoform abundance were noted in other tissues. For example, age-dependent increases in PKC alpha, PKC beta, and PKC delta in brain contrasted with age-dependent decreases in PKC alpha and PKC delta in lung, kidney, and heart. Immunoreactivity for PKC epsilon was abundant in all fetal/neonatal tissues; PKC epsilon was detected in the adult brain, heart, and liver, but not the adult kidney and lung. Finally, PKC zeta was more abundant in fetal/neonatal than in adult brain, lung, kidney, and heart. These results indicate that the fetal/neonatal lung, kidney, and heart are enriched in PKC zeta, PKC alpha, PKC delta, and PKC epsilon, relative to the adult tissues. These age-dependent variations in the abundance of individual isoforms of PKC may critically influence tissue responsiveness to external stimuli. Moreover, the finding that PKC zeta is particularly abundant in fetal tissues as well as the liver, the only tissue included in this study which retains regenerative capacity in the adult animal, is consistent with the notion that PKC zeta may play a role in cell proliferation.
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PMID:Tissue-specific developmental regulation of protein kinase C isoforms. 886 31

Regulation of the Ca(2+)-independent protein kinase C (PKC) activity and isoforms by phorbol esters was investigated in rat cerebral cortex. Loss of soluble PKC eta immunoreactivity from the soluble fraction was dramatic with only a small increase in the membrane fraction. The kinetics of PKC epsilon and -delta translocation were slower than that for PKC eta, while phorbol esters had no effect on PKC zeta translocation. Despite the translocation of PKC delta, -epsilon and -eta from the soluble to the membrane fraction, both fractions showed a loss of PKC activity. These data indicate that the rates of translocation, inactivation and/or downregulation appear to be different not only among these Ca(2+)-independent isozymes, but also from that reported for the Ca(2+)-dependent PKCs. In addition, these results emphasize the importance of measuring both Ca(2+)-independent PKC activity and immunoreactivity in evaluating activation of these isoforms.
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PMID:Differential isoform-specific regulation of calcium-independent protein kinase C in rat cerebral cortex. 887 93

Insulin and 12-O-tetradecanoyl phorbol-13-acetate (TPA) induce both glucose uptake and translocation of protein kinase C (PKC) from cytosol to membrane in insulin-sensitive tissues as previously reported by several investigators. We examined insulin-mediated PKC beta I, beta II, and epsilon translocation from cytosol to cytoskeleton, and expression of PKC alpha, beta I, beta II, gamma, and epsilon isoforms using the reverse transcription polymerase chain reaction (RT-PCR) method during treatment with insulin for 240 min in rat adipocytes. Insulin-induced increases in PKC beta I, beta II, and epsilon were greater in the cytoskeleton fraction than those in the membrane fraction. Insulin induced time-dependent increases in PKC alpha, gamma, epsilon and zeta mRNA levels for up to 240 min (555%, 117%, 236% and 138% increase, respectively). TPA also induced time-dependent increases in PKC alpha and gamma (34% and 500% increase, respectively) but not in PKC zeta. However, PKC beta I mRNA was decreased for up to 60 min and then maintained at under the basal level during stimulation with insulin and TPA. On the other hand, PKC beta II mRNA was markedly increased for up to 240 min. These results suggest that insulin-regulated PKC alpha, gamma and epsilon mRNA levels and PKC beta mRNA alternative splicing may occur in rat adipocytes.
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PMID:Insulin regulated PKC isoform mRNA in rat adipocytes. 892 37

Protein kinase C (PKC) influences cellular sensitivity to cis-diamminedichloroplatinum(II) (cDDP). We have investigated whether the PKC signal transduction pathway is affected during the development of cellular resistance to cDDP. Activators of PKC, such as phorbol 12,13-dibutyrate (PDBu), enhanced the sensitivity of human small cell lung cancer H69 cells to cDDP by 2-fold but had no effect on the sensitivity of cDDP-resistant H69 cells (H69/CP) to cDDP. The maximum sensitization was achieved with 10 nM PDBu and blocked by down-regulation of PKC with higher concentrations of PDBu (1 microM) or bryostatin 1 (0.1 microM). PKC activity was decreased significantly in H69/CP cells compared to the drug-sensitive variant. A similar reduction in PKC activity was noted in ovarian carcinoma 2008 cells that were resistant to cDDP. A modest decrease in PKC activity was also observed in etoposide-resistant H69 (H69/VP-16) cells but not in Taxol-resistant H69 cells or bleomycin-resistant human head and neck carcinoma A-253 cells. H69 cells expressed conventional PKC alpha and-beta, novel PKC delta, atypical PKC zeta and-iota, and novel/atypical PKC mu. A decrease in cPKC alpha and-beta and an increase in nPKC delta were associated with the cDDP-resistant phenotype. The abundance of aPKC zeta or-iota was unaffected. H69/ VP-16 cells also displayed a reduction in cPKC beta and an increase in nPKC delta. Taxol-resistant H69 cells had no alteration in the expression of any of the PKC isozymes. Thus, a reduction in cPKCs and an increase in nPKC may be associated with cDDP resistance.
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PMID:Characterization of the protein kinase C signal transduction pathway in cisplatin-sensitive and -resistant human small cell lung carcinoma cells. 893 Apr


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