Regulation of α1-adrenoceptor-mediated contractions of uterine arteries by PKC: effect of pregnancy

2006 ◽  
Vol 291 (5) ◽  
pp. H2282-H2289 ◽  
Author(s):  
Hongying Zhang ◽  
DaLiao Xiao ◽  
Lawrence D. Longo ◽  
Lubo Zhang
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Western Blot ◽  
Subcellular Distribution ◽  
Response Curve ◽  
Uterine Artery ◽  
Uterine Arteries ◽  
Kinase C ◽  
Pkc Isozymes ◽  
Near Term

Protein kinase C (PKC) plays an important role in the regulation of uterine artery contractility and its adaptation to pregnancy. The present study tested the hypothesis that PKC differentially regulates α1-adrenoceptor-mediated contractions of uterine arteries isolated from nonpregnant (NPUA) and near-term pregnant (PUA) sheep. Phenylephrine-induced contractions of NPUA and PUA sheep were determined in the absence or presence of the PKC activator phorbol 12,13-dibutyrate (PDBu). In NPUA sheep, PDBu produced a concentration-dependent potentiation of phenylephrine-induced contractions and shifted the dose-response curve to the left. In contrast, in PUA sheep, PDBu significantly inhibited phenylephrine-induced contractions and decreased their maximum response. Simultaneous measurement of contractions and intracellular free Ca2+ concentrations ([Ca2+]i) in the same tissues revealed that PDBu inhibited phenylephrine-induced [Ca2+]i and contractions in PUA sheep. In NPUA sheep, PDBu increased phenylephrine-induced contractions without changing [Ca2+]i. Western blot analysis showed six PKC isozymes, α, βI, βII, δ, ε, and ζ, in uterine arteries, among which βI, βII, and ζ isozymes were significantly increased in PUA sheep. In contrast, PKC-α was decreased in PUA sheep. In addition, analysis of subcellular distribution revealed a significant decrease in the particulate-to-cytosolic ratio of PKC-ε in PUA compared with that in NPUA sheep. The results suggest that pregnancy induces a reversal of PKC regulatory role on α1-adrenoceptor-mediated contractions from a potentiation in NPUA sheep to an inhibition in PUA sheep. The differential expression of PKC isozymes and their subcellular distribution in uterine arteries appears to play an important role in the regulation of Ca2+ mobilization and Ca2+ sensitivity in α1-adrenoceptor-mediated contractions and their adaptation to pregnancy.

ERK MAP kinases regulate smooth muscle contraction in ovine uterine artery: effect of pregnancy

2002 ◽  
Vol 282 (1) ◽  
pp. H292-H300 ◽  
Author(s):  
Daliao Xiao ◽  
Lubo Zhang
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Uterine Artery ◽  
Map Kinases ◽  
Smooth Muscle Contraction ◽  
Isometric Tension ◽  
Uterine Arteries ◽  
Kinase C ◽  
Pregnant Sheep

The present study investigated the potential role of extracellular signal-regulated kinase (ERK) in uterine artery contraction and tested the hypothesis that pregnancy upregulated ERK-mediated function in the uterine artery. Isometric tension in response to phenylephrine (PE), serotonin (5-HT), phorbol 12,13-dibutyrate (PDBu), and KCl was measured in the ring preparation of uterine arteries obtained from nonpregnant and near-term (140 days gestation) pregnant sheep. Inhibiting ERK activation with PD-98059 did not change the KCl-evoked contraction but significantly inhibited the contraction to 5-HT in both nonpregnant and pregnant uterine arteries. PD-98059 did not affect PE-induced contraction in the uterine arteries of nonpregnant sheep but significantly decreased it in the uterine arteries of pregnant sheep. In accordance, PE stimulated activation of ERK in uterine arteries of pregnant sheep, which was blocked by PD-98059. PD-98059-mediated inhibition of the PE-induced contraction was associated with a decrease in both intracellular Ca2+ concentration and Ca2+ sensitivity of contractile proteins in the uterine arteries of pregnant sheep. PDBu-mediated contraction was significantly less in pregnant than in nonpregnant uterine arteries. PD-98059 had no effect on PDBu-induced contraction in nonpregnant but significantly increased it in pregnant uterine arteries. In addition, PD-98059 significantly enhanced PDBu-stimulated protein kinase C activity. The results indicate that ERK plays an important role in the regulation of uterine artery contractility, and its effect is agonist dependent. More importantly, pregnancy selectively enhances the role of ERK in α1-adrenoceptor-mediated contractions and its effect in suppressing protein kinase C-mediated contraction in the uterine artery.

scholarly journals Dysregulation of protein kinase C in adult depression and suicide: evidence from postmortem brain studies

2021 ◽  
Author(s):  
Ghanshyam N Pandey ◽  
Anuradha Sharma ◽  
Hooriyah S Rizavi ◽  
Xinguo Ren
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Protein Expression ◽  
Mrna Expression ◽  
Postmortem Brain ◽  
Cortical Region ◽  
Cytosol Fraction ◽  
Kinase C ◽  
Pkc Isozymes

Abstract Background Several lines of evidence suggest the abnormalities of protein kinase C (PKC) signaling system in mood disorders and suicide based primarily on the studies of PKC and its isozymes in the platelets and postmortem brain of depressed and suicidal subjects. In this study we examined the role of PKC isozymes in depression and suicide. Methods We determined the protein and mRNA expression of various PKC isozymes in the prefrontal cortical region [Brodmann area 9 (BA9)] in 24 normal control (NC) subjects, 24 depressed suicide (DS) subjects and 12 depressed non-suicide (DNS) subjects. The levels of mRNA in the prefrontal cortex (PFC) were determined by qRT-PCR and the protein expression was determined by Western blotting. Results We observed a significant decrease in mRNA expression of PKCα, PKCβI, PKCδ and PKCε and decreased protein expression either in the membrane or the cytosol fraction of PKC isozymes - PKCα, PKCβI, PKCβII and PKCδ in DS and DNS subjects compared with NC subjects. Conclusions The current study provides detailed evidence of specific dysregulation of certain PKC isozymes in the postmortem brain of DS and DNS subjects and further supports earlier evidence for the role of PKC in the platelets and brain of adult and teenage depressed and suicidal population. This comprehensive study may lead to further knowledge of the involvement of PKC in the pathophysiology of depression and suicide.

scholarly journals Protein Kinase C as a Therapeutic Target in Non-Small Cell Lung Cancer

2021 ◽  
Vol 22 (11) ◽  
pp. 5527
Author(s):  
Mohammad Mojtaba Sadeghi ◽  
Mohamed F. Salama ◽  
Yusuf A. Hannun
Keyword(s):  
Lung Cancer ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Predictive Biomarkers ◽  
Small Cell ◽  
Small Cell Lung ◽  
Kinase C ◽  
Pkc Isozymes

Driver-directed therapeutics have revolutionized cancer treatment, presenting similar or better efficacy compared to traditional chemotherapy and substantially improving quality of life. Despite significant advances, targeted therapy is greatly limited by resistance acquisition, which emerges in nearly all patients receiving treatment. As a result, identifying the molecular modulators of resistance is of great interest. Recent work has implicated protein kinase C (PKC) isozymes as mediators of drug resistance in non-small cell lung cancer (NSCLC). Importantly, previous findings on PKC have implicated this family of enzymes in both tumor-promotive and tumor-suppressive biology in various tissues. Here, we review the biological role of PKC isozymes in NSCLC through extensive analysis of cell-line-based studies to better understand the rationale for PKC inhibition. PKC isoforms α, ε, η, ι, ζ upregulation has been reported in lung cancer, and overexpression correlates with worse prognosis in NSCLC patients. Most importantly, PKC isozymes have been established as mediators of resistance to tyrosine kinase inhibitors in NSCLC. Unfortunately, however, PKC-directed therapeutics have yielded unsatisfactory results, likely due to a lack of specific evaluation for PKC. To achieve satisfactory results in clinical trials, predictive biomarkers of PKC activity must be established and screened for prior to patient enrollment. Furthermore, tandem inhibition of PKC and molecular drivers may be a potential therapeutic strategy to prevent the emergence of resistance in NSCLC.

scholarly journals Targeting Protein Kinase C in Glioblastoma Treatment

Biomedicines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 381
Author(s):  
Noelia Geribaldi-Doldán ◽  
Irati Hervás-Corpión ◽  
Ricardo Gómez-Oliva ◽  
Samuel Domínguez-García ◽  
Félix A. Ruiz ◽  
...  
Keyword(s):  
Stem Cells ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Combined Treatment ◽  
Primary Brain Tumor ◽  
Kinase C ◽  
Pkc Isozymes ◽  
New Generation ◽  
Effective Drugs

Glioblastoma (GBM) is the most frequent and aggressive primary brain tumor and is associated with a poor prognosis. Despite the use of combined treatment approaches, recurrence is almost inevitable and survival longer than 14 or 15 months after diagnosis is low. It is therefore necessary to identify new therapeutic targets to fight GBM progression and recurrence. Some publications have pointed out the role of glioma stem cells (GSCs) as the origin of GBM. These cells, with characteristics of neural stem cells (NSC) present in physiological neurogenic niches, have been proposed as being responsible for the high resistance of GBM to current treatments such as temozolomide (TMZ). The protein Kinase C (PKC) family members play an essential role in transducing signals related with cell cycle entrance, differentiation and apoptosis in NSC and participate in distinct signaling cascades that determine NSC and GSC dynamics. Thus, PKC could be a suitable druggable target to treat recurrent GBM. Clinical trials have tested the efficacy of PKCβ inhibitors, and preclinical studies have focused on other PKC isozymes. Here, we discuss the idea that other PKC isozymes may also be involved in GBM progression and that the development of a new generation of effective drugs should consider the balance between the activation of different PKC subtypes.

scholarly journals Mitogen-induced phosphorylation of human B-lymphocyte proteins. Relationship to protein kinase C activation

1989 ◽  
Vol 263 (1) ◽  
pp. 57-64 ◽  
Author(s):  
G R Guy ◽  
M Finney ◽  
R H Michell ◽  
J Gordon
Keyword(s):  
Protein Kinase C ◽  
B Cells ◽  
Protein Kinase ◽  
B Lymphocytes ◽  
Dose Response ◽  
Response Curve ◽  
Dose Response Curve ◽  
Beta Form ◽  
Kinase C ◽  
Hydrolysis Of

We have investigated the rapid phosphorylation of proteins in B-lymphocytes incubated with the tumour-promoting phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA), anti-Ig and combinations of TPA and the Ca2+ ionophore ionomycin. Two-dimensional electrophoretic analysis was used to identify the proteins phosphorylated in cells preincubated with [32P]Pi. TPA induced a characteristic pattern of labelled proteins, four of which (pp85, pp76, pp66 and pp63) showed a dose-dependent incorporation of 32P on serine residues. The phosphorylation of pp63 and pp66, in particular, correlated with the mitogenic dose-response curve. Addition of the Ca2+ ionophore ionomycin to B-cells also stimulated a characteristic incorporation of 32P into proteins, which included pp63 and pp66. With combined doses of TPA and ionomycin, these two proteins show an enhanced phosphorylation, which correlated well with the synergistic enhancement of proliferation shown by this combination of agents. Protein kinase C (PKC) was partially purified from B-cells and separated into alpha and beta subtypes. The activation of both PKCs was assessed with increasing doses of TPA and concentrations of Ca2+ of 0.1 microM and 2 microM. For both forms of PKC, in particular the beta form, higher concentrations of Ca2+ shifted the dose-response curve for TPA to the left and increased the maximum activation. Anti-Ig, which stimulated B-cells by cross-linking surface immunoglobulin and causing hydrolysis of PtdIns(4,5)P2, also caused increased phosphorylation of several proteins, which again included pp63 and pp66. These data suggest that PKC, particularly the beta form, is involved in the early part of the proliferation cascade for human B-lymphocytes. It is most probably activated in a synergistic manner by the increased Ca2+ and diacylglycerol levels which result from the earlier hydrolysis of PtdIns(4,5)P2.

scholarly journals Protein kinase C isozymes; predictors of progression free survival in NSCLC patients

2019 ◽  
Author(s):  
Ann Rita Halvorsen ◽  
Mads Haugland Haugen ◽  
Åsa Kristina Öjlert ◽  
Marius Lund-Iversen ◽  
Lars Jørgensen ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Protein Expression ◽  
Molecular Subtypes ◽  
Progression Free Survival ◽  
Free Survival ◽  
Kinase C ◽  
Pkc Isozymes ◽  
Pkc Β ◽  
Low Expression

Abstract Background Protein expression is deregulated in cancer, and the proteomic changes observed in lung cancer may be a consequence of mutations in essential genes. The purpose of this study was to identify protein expression associated with prognosis in lung cancers stratified by smoking status, molecular subtypes, and EGFR-, TP53- and KRAS-mutations. Methods We performed profiling of 295 cancer-relevant phosphorylated and non-phosphorylated proteins, using reverse phase protein arrays. Biopsies from 80 patients with operable lung adenocarcinomas were analyzed for protein expression and association with progression free survival (PFS) were studied. Results Spearman rank correlation analysis identified 56 proteins with significant association to PFS (p<0.05). High expression of protein kinase C (PKC)-α and the phosporylated state of PKC-α, PKC-β and PKC-δ, showed the strongest positive correlation to PFS, especially in the wild type samples. This was confirmed in gene expression data from 186 samples. Based on protein expression, unsupervised hierarchical clustering separated the samples into four subclusters enriched with the molecular subtypes TRU, PI or PP (p=0.0001). Subcluster 2 contained a smaller cluster (2a) enriched with samples of the subtype PP, low expression of the PKC isozymes, and associated with poor PFS (p=0.003) compared to the other samples. Subcluster 2a revealed increased expression of neuroendocrine markers, supporting the aggressive behavior. Low expression of the PKC isozymes in the subtype PP and a reduced relapse free survival was confirmed with the TCGA LUAD samples. Conclusion This study identified different proteins associated with PFS depending on molecular subtype, smoking- and mutational-status, with PKC-α, PKC-β and PKC-δ showing the strongest correlation. Cluster analysis detected a subgroup of samples enriched for samples of the PP subtype and poor PFS, which may benefit from a more aggressive treatment regimen.

scholarly journals Protein Kinase C Mediates the Mitogenic Action of Thrombopoietin in c-Mpl–Expressing UT-7 Cells

Blood ◽  
1998 ◽  
Vol 91 (3) ◽  
pp. 813-822 ◽  
Author(s):  
Ying Hong ◽  
Dominique Dumènil ◽  
Bernd van der Loo ◽  
Frédérique Goncalves ◽  
William Vainchenker ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Subcellular Distribution ◽  
Membrane Fraction ◽  
Induced Expression ◽  
Gm Csf ◽  
Kinase C ◽  
Pkc Isoforms ◽  
Mitogenic Action ◽  
Pkc Activation

Protein kinase C (PKC) has been implicated in signal transduction events elicited by several hematopoietic growth factors. Thrombopoietin (TPO) is the major regulator of megakaryocytic lineage development, and its receptor, c-Mpl, transduces signals for the proliferation and differentiation of hematopoietic progenitors. In this study we have examined the effect of TPO on the subcellular distribution of PKC (a measure of enzyme activation) in a growth factor-dependent pluripotent hematopoietic cell line that was engineered to express the c-Mpl receptor (UT-7/mpl). In addition, we have assessed the significance of this activation for the induction of both mitogenesis and differentiation. Using a PKC translocation assay, TPO was found to stimulate a time- and dose-dependent increase in the total content of PKC activity present in the membrane fraction of UT-7/mpl cells (maximum increase = 2.3-fold above basal level after 15 minutes with 40 ng/mL TPO, EC50 = 7 ng/mL). Accordingly, a decrease of PKC content in the cytosolic fraction was observed. Immunoblot analysis using PKC isotype-specific antibodies showed that TPO treatment led to a marked increase of the Ca2+/diacylglycerol-sensitive PKC isoforms α and β found in the membrane fraction. In contrast, the subcellular distribution of these isoforms did not change after treatment with granulocyte-macrophage colony-stimulating factor (GM-CSF). Exposure of UT-7/mpl cells to the selective PKC inhibitor GF109203X completely inhibited the PKC activity associated to the membrane fraction after TPO treatment, and blocked the mitogenic effect of TPO. In contrast, GF109203X had no effect on the TPO-induced expression of GpIIb, a megakaryocytic differentiation antigen. Downregulation of PKC isoforms α and β to less than 25% of their initial level by treatment with phorbol 12,13-dibutyrate also abolished the TPO-induced mitogenic response, but had no significant effect when this response was induced by GM-CSF. Taken together, these findings suggest that (1) TPO stimulates the activation of PKC, (2) PKC activation mediates the mitogenic action of TPO, and (3) PKC activation is not required for TPO-induced expression of megakaryocytic surface markers.

Protein kinase C isozymes and the regulation of diverse cell responses

2000 ◽  
Vol 279 (3) ◽  
pp. L429-L438 ◽  
Author(s):  
Edward C. Dempsey ◽  
Alexandra C. Newton ◽  
Daria Mochly-Rosen ◽  
Alan P. Fields ◽  
Mary E. Reyland ◽  
...  
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Specific Binding ◽  
Wnt Signaling Pathway ◽  
Cell System ◽  
Cell Responses ◽  
Kinase C ◽  
New Ideas ◽  
Pkc Isozymes ◽  
Lung Health

Individual protein kinase C (PKC) isozymes have been implicated in many cellular responses important in lung health and disease, including permeability, contraction, migration, hypertrophy, proliferation, apoptosis, and secretion. New ideas on mechanisms that regulate PKC activity, including the identification of a novel PKC kinase, 3-phosphoinositide-dependent kinase-1 (PDK-1), that regulates phosphorylation of PKC, have been advanced. The importance of targeted translocation of PKC and isozyme-specific binding proteins (like receptors for activated C-kinase and caveolins) is well established. Phosphorylation state and localization are now thought to be key determinants of isozyme activity and specificity. New concepts on the role of individual PKC isozymes in proliferation and apoptosis are emerging. Opposing roles for selected isozymes in the same cell system have been defined. Coupling to the Wnt signaling pathway has been described. Phenotypes for PKC knockout mice have recently been reported. More specific approaches for studying PKC isozymes and their role in cell responses have been developed. Strengths and weaknesses of different experimental strategies are reviewed. Future directions for investigation are identified.

ANG II-mediated inhibition of neuronal delayed rectifier K+ current: role of protein kinase C-α

2001 ◽  
Vol 281 (1) ◽  
pp. C17-C23 ◽  
Author(s):  
Sheng-Jun Pan ◽  
Mingyan Zhu ◽  
Mohan K. Raizada ◽  
Colin Sumners ◽  
Craig H. Gelband
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Phorbol Esters ◽  
Delayed Rectifier ◽  
Dependent Manner ◽  
Ang Ii ◽  
Mediated Effects ◽  
Kinase C ◽  
K Current ◽  
Pkc Isozymes

It was previously determined that ANG II and phorbol esters inhibit Kv current in neurons cultured from newborn rat hypothalamus and brain stem in a protein kinase C (PKC)- and Ca2+-dependent manner. Here, we have further defined this signaling pathway by investigating the roles of “physiological” activators of PKC and different PKC isozymes. The cell-permeable PKC activators, diacylglycerol (DAG) analogs 1,2-dioctanoyl- sn-glycerol (1 μmol/l, n = 7) and 1-oleoyl-2-acetyl- sn-glycerol (1 μmol/l, n = 6), mimicked the effect of ANG II and inhibited Kv current. These effects were abolished by the PKC inhibitor chelerythrine (1 μmol/l, n = 5) or by chelation of internal Ca2+ ( n = 8). PKC antisense (AS) oligodeoxynucleotides (2 μmol/l) against Ca2+-dependent PKC isoforms were applied to the neurons to manipulate the endogenous levels of PKC. PKC-α-AS ( n = 4) treatment abolished the inhibitory effects of ANG II and 1-oleoyl-2-acetyl- sn-glycerol on Kv current, whereas PKC-β-AS ( n = 4) and PKC-γ-AS ( n = 4) did not. These results suggest that the angiotensin type 1 receptor-mediated effects of ANG II on neuronal Kv current involve activation of PKC-α.

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