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1
Plammootil, Suma Mary. "Herstellung und Etablierung von 4-Hydroxytamoxifen aktivierbaren PKC[alpha]- [PKC alpha]-, PKC[beta]1- [PKC beta1] und PKCd--Fusionsproteinen [PKC delta-Fusionsproteinen]". [S.l.] : [s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=971703302.
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2
Snider, Adam K. "PKC gamma regulates connexin 57". Thesis, Manhattan, Kan. : Kansas State University, 2010. http://hdl.handle.net/2097/4128.
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Bahte, Svenja-Katharina Paula. "Identifikation neuer Bindungspartner von PKC- d [PKC-delta] mit Hilfe des Yeast-two-hybrid-Screens". [S.l.] : [s.n.], 2004. http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&doc_number=013081490&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA.
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4
Cheng, Sam Xian Jun. "Functional significance of phosphorylation of rat renal Na+,K+-ATPase by PKA and PKC /". Stockholm, 1998. http://diss.kib.ki.se/1998/91-628-2971-8.
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Quittau-Prévostel, Corinne. "Mutant D294G de la PKC[alpha] tumorigénèse humaine : la PKC[alpha], un nouveau suppresseur de tumeur". Montpellier 1, 1997. http://www.theses.fr/1997MON1T005.
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ZINI, SILVIA. "PKC: Paffard Keatinge-Clay architetto itinerante". Doctoral thesis, Università IUAV di Venezia, 2015. http://hdl.handle.net/11578/278352.
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Worthmann, Kirstin [Verfasser]. "Die Rolle der atypischen Protein Kinase C Isoformen PKC[lambda]/[iota] und PKC[zeta] in Podozyten / Kirstin Worthmann". Hannover : Technische Informationsbibliothek und Universitätsbibliothek Hannover, 2011. http://d-nb.info/1012625508/34.
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8
Cabrerizo, Benito Yolanda. "Studies on a PKC-PLD-MAPK pathway". Thesis, University College London (University of London), 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.399767.
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Kostelecky, B. D. "An investigation of PKC isoform functional specificity". Thesis, University College London (University of London), 2009. http://discovery.ucl.ac.uk/18705/.
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Protein kinase C (PKC) isozymes are vital signalling proteins in many intracellular processes including cell survival, proliferation and migration. As such, changes in their expression levels have been linked to many types of cancer. The various PKC family members provoke differential responses in cancer highlighting the need for study of individual isoforms. This investigation of PKC has aimed to determine how kinase domain structure, regulatory region interactions and binding partners confer functional specificity to individual PKC isoforms. X-ray crystallographic, biochemical and biophysical studies have been employed to explore the architecture of these PKC interactions. A panel of recombinant PKC kinase domains has been cloned, expressed and purified to characterise their maturation, activities and structures. Kinetic constants have been determined for several PKC kinase domains in various phosphorylation states. Additionally, inhibition by novel low molecular weight inhibitors provided by collaborators at Cancer Research Technologies (CRT) has been probed. The PKCζ kinase domain has been crystallised with one of the CRT inhibitors and the structure determined at 2.8Å resolution. A panel of PKC isoform regulatory regions has also been expressed and purified. The results presented here show it is possible to reconstitute an intact PKC holoenzyme complex after expression of the domains as individual polypeptides. The protocols and materials developed during this thesis project will be further used in the laboratory with the aim of crystallising a PKC holoenzyme complex. This thesis also presents the crystal structure of PKCε-binding partner 14-3-3 bound to an asymmetric PKCε di-phosphorylated peptide determined at 2.2Å resolution. The PKCε di-phosphorylated peptide in the crystal structure was derived from the PKCε V3 variable region containing one consensus 14-3-3-phospho-binding motif and one divergent 14-3-3-binding motif. A thermodynamic analysis of the interaction between 14-3-3 and the PKCεV3 di-phosphopeptide reveals an increased affinity more than two orders of magnitude greater than the singly phosphorylated species. Together, the results of this study provide a multifaceted examination of PKC functional specificity by isoform-specific low molecular weight inhibitors, regulatory domains and binding partner interactions and provide a solid platform for exploring further aspects of PKC regulation.
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Peel, N. R. "Dissecting compartmentalised atypical PKC controls in cell migration". Thesis, University College London (University of London), 2014. http://discovery.ucl.ac.uk/1419046/.
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Atypical Protein Kinase C (aPKC) isoforms are essential regulators of polarised cell behaviour and in migrating NRK cells translocate to the leading edge in a complex with the exocyst and KIBRA. Engineered delivery of upstream signals to the plasma membrane places leading edge ERK activation downstream of aPKC and demonstrates partial sufficiency in regulating cell migration and adhesion. This model system provides the opportunity to probe the leading edge to better understand events downstream of aPKC. Multiple screening approaches have identified cytoskeletal and translation processes as putative targets of this pathway. Based on in silico candidate screening it is shown that multi-site phosphorylation of Parvin alpha is important for focal adhesion maturation. These phosphorylation events are triggered following acute focal adhesion turnover, which can be blocked by aPKC and MEK inhibition. Based upon proteomic approaches, a novel role for the putative aPKC/ERK substrate Cdc42 effector protein 1 (Cdc42ep1) has been identified. siRNA knockdown of Cdc42ep1 phenocopies aPKC loss; focal adhesions enlarge and turnover less efficiently. This impacts on polarized cell motility as knockdown prevents cell orientation and efficient wound closure. Finally, a novel role for aPKC is reported in relation to leading edge translation. Active translation at the leading edge is reduced following aPKC and MEK inhibition and compartmentalised distribution of translation factors is modulated following pathway intervention. This includes the eukaryotic translation initiation factor 3A (eIF3A), one hit identified by proteomic screening. eIF3A interacts with the exocyst and localises to the leading edge in an aPKC-dependent fashion. In addition, eIF3A is shown to regulate polarised migration and adhesion maturation. The data presented in this thesis illustrate combined screening and validation to delineate compartmentalised signalling events. Localised aPKC/exocyst/ERK activity is necessary for cytoskeletal controls and the polarized delivery and activation of translation machinery at the leading edge.
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Gumpert, Nicolas Maximilian. "Funktionale Bedeutung der Protein Kinase C - d [C - delta] (PKC - d) [(PKC - delta)] in der Reorganisation der zytoskelettären Architektur humaner Keratinozyten". [S.l.] : [s.n.], 2000. http://deposit.ddb.de/cgi-bin/dokserv?idn=964885824.
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Qian, Yu. "Analyser le gène PKC-2 chez Caernorhabditis elegans et crible les mutants contre sérotonine chez le C. elegans souche pkc-2 (ok328)". Phd thesis, Université Claude Bernard - Lyon I, 2009. http://tel.archives-ouvertes.fr/tel-00712129.
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La myopathie de Duchenne est une maladie génétique qui se caractérise principalement par une dégénérescence progressive des muscles squelettiques dont la cause est l'absence de dystrophine fonctionnelle dans les muscles. A ce jour, il n'existe toujours pas de traitement efficace contre ces maladies. Comme le plus grand gène connu chez l'Homme, la dystrophine code pour une protéine de 427kDa. La protéine connecte l'actine avec le DAPC (Dystrophin Associated Protein Complex) dans les muscles striés. Pour l'instant, il y a 3 hypothèses concernant le mécanisme du DMD. L'absence de la dystrophine peut supprimer le lien physique entre les protéines structurales de la membrane basale (laminines) et les protéines structurales du cytosquelette (filaments intermédiaires et actine), ou la distribution et la fonction des canaux ioniques, ou des voies de signalisation nécessaires à la survie du muscle. Caenorhabditis elegans ne possède qu'un homologue du gène de la dystrophine humaine, le gène dys-1. La protéine DYS-1 présente 37% d'homologie avec la dystrophine humaine. Le double mutant dys-1(cx18) ; hlh-1(cc561) présente une forte dégénérescence musculaire. Comme le sarcomère de C. elegans ressemble au sarcomère de mammifère, C. elegans est modèle pertinent d'étude la maladie. En vue de comprendre la raison du DMD chez les mammifères et chez les vers, le groupe L. SEGALAT a effectué des cribles pour identifier les molécules et les gènes qui peuvent supprimer la dégénérescence musculaire. On a trouvé un gène pkc-2 qui est capable de supprimer la dégénérescence musculaire chez C. elegans. La protéine PKC-2 est l'orthologue de la Protein Kinase C Alpha (PKC) humaine et appartient à la famille du serine/threonine protéine kinase. Afin d'étudier la fonction du gène pkc-2, on a analysé l'expression du gène avec les construits différents in vivo et a utilisé la technique de double-hybride dans la levure. De plus, le crible par EMS (éthane méthyle sulfonâtes) a identifié une molécule sérotonine (5-HT) qui est un neuromédiateur, et supprime partiellement la dégénérescence musculaire des doubles mutants dys-1; hlh-1. La sérotonine a aussi un effet fort sur le mutant pkc-2(ok328), puisqu'elle provoque un phénotype blister. Ça nous permet de rechercher le lien entre la signalisation sérotoninergique et pkc-2. Le crible génétique peut contribuer à la connaissance du rôle pkc-2. [...]. Elle sert aussi de plate-forme de voie de signalisation intracellulaire. L'identification de Y59A8A.3 propose la possibilité que pkc-2 modifie la filamin A par l'intermédiaire de la filamin A interacting protéine 1. Le crible génétique par EMS pour rechercher des suppresseurs de l'effet blister de la sérotonine sur les mutants pkc-2(ok328) a donné 8 candidats sur 5000 F1s : cx253, cx254, cx259, cx263, cx267, cx268, cx270, cx276. Les mutations ont été localisées sur les chromosomes par SNP mapping avec une souche de C. elegans très polymorphe, mais le temps a manqué pour leur identification exacte. L'expérience valide notre approche à étudier le lien entre la signalisation sérotoninergique et pkc-2. En résumé, le but de la thèse était de rechercher la fonction du gène pkc-2 dans les mécanismes moléculaires conduisant à la nécrose musculaire en absence de dystrophine. Les résultats présentés dans la thèse apportent des réponses aux questions fondamentales sur pkc-2 et aussi demandent des expériences supplémentaires afin de élucider plus avant les mécanismes de la dégénérescence musculaire dystrophine-dépendante.
13
Aaltonen, V. (Vesa). "PKC and neurofibromin in the molecular pathology of urinary bladder carcinoma:the effect of PKC inhibitors on carcinoma cell junctions, movement and death". Doctoral thesis, University of Oulu, 2007. http://urn.fi/urn:isbn:9789514285899.
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Abstract
This study examined the role of tumor suppressor neurofibromin and Protein kinase C (PKC) in urinary bladder cancer, and the effect of PKC inhibitors on cancer cell behaviour.
Tumor suppressor protein neurofibromin is a product of the NF1 gene, a mutation of which causes the most common hereditary tumor syndrome, type 1 neurofibromatosis. NF1 gene mutations and changes in expression have been demonstrated in malignancies, unrelated to type 1 neurofibromatosis. The best known function of neurofibromin is its Ras GTPase accelerating function. Thus, it functions as a Ras inactivator. This study demonstrated for the first time that the NF1 gene is expressed in normal and malignant urinary bladder epithelium and in cultured bladder carcinoma cells in mRNA and at the protein level. Furthermore, neurofibromin expression is decreased during bladder carcinogenesis. It can be speculated that this may lead to increased Ras activity in urinary bladder cancer.
The PKC family is composed of several different isoenzymes which are responsible for a number of important intracellular events and cellular functions. Many of these are also important in cancer development and progression. The results demonstrate changes in expression of PKC α and βI isoenzymes in urinary bladder carcinoma. Furthermore, the results relate the increased expression of isoenzymes to increased PKC enzyme activity and the high proliferation rate of the cancer cells. In addition, this study utilizes small molecular inhibitors of PKC isoenzymes in order to study the effect of the inhibition of these isoenzymes on cancer cell behaviour in vitro and in vivo. The study mainly focuses on the function of PKC α and βI isoenzymes and on the effects of inhibition of these by using Go6976. The results show that Go6976 inhibits cancer cell growth, migration and invasion in vitro, and tumor growth in a mouse model. The use of Go6976 induces changes in desmosomes and adherens junctions, and in focal adhesions and hemidesmosomes. The results also show that Go6976 functions as a cell cycle checkpoint abrogator and increases the cytotoxicity of two classical chemotherapeutic agents, doxorubicin and paclitaxel. In the future, it may be possible that Go6976 or related drugs could be used in clinical cancer treatments.
14
Hessabi, Tarik. "Über die Rolle von PKC epsilon während der Wundheilung". [S.l.] : [s.n.], 2005. http://deposit.ddb.de/cgi-bin/dokserv?idn=977243265.
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Garratt-Lalonde, Michelle. "The role of atypical PKC iota in glioblastoma multiforme". Thesis, University of Ottawa (Canada), 2003. http://hdl.handle.net/10393/26484.
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Glioblastoma multiforme, a high grade malignant astrocytoma, is the most common and mortal intracranial tumor in adults. The median survival time for glioblastoma patients remains from 9--12 months despite aggressive treatment programs. These high-grade central nervous system tumors bear genetic and molecular aberrations that result in innate chemoresistance to commonly used chemotherapeutic agents.
The main focus of this thesis is on exploring signaling events downstream of phosphoinositide 3-kinase (PI3-K) in glioblastoma multiforme in attempts to discover molecular targets that may be highly specific and thus less toxic therapeutic targets. The PI3-K pathway is constitutively activated in glioblastoma. The Protein Kinase C family of serine/threonine kinases is activated downstream of PI3-K. Our focus is placed on a member of the atypical protein kinase C subfamily called, atypical PKC iota.
We finally began examining the role of atypical PKC iota and invasion in U87MG glioblastoma cells using scratch/wound assays. (Abstract shortened by UMI.)
16
Ettinger, Susan Lorraine. "Cytokine-induced activation of PKC isoenzymes in hemopoietic cells". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp03/NQ27139.pdf.
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Nakagawa, Rinako. "Role of PKC during B cell development and transformation". Thesis, University of Glasgow, 2006. http://theses.gla.ac.uk/9056/.
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The objective of this thesis is to determine the role of specific PKC isotypes during B cell development and transformation. B cell generation systems were validated both in vitro and in vivo, by coculturing haematopoietic progenitor cells (HPCs) on the calvanial cell line, 0P9, or by adoptively transferring HPCs into recombinase-activating gene 1-deficient (RAG-1-/-) mice, respectively. In both cases, mature B cells were generated as determined by analysing surface B cell marker expression. Coupling of these in vitro and in vivo B cell generation systems with a retroviral gene transfer technique, plasmids-encoding PKC mutants in the retroviral vector MIEV were stably expressed in foetal liver (FL)-derived HPCs from wild type mice and cultured to assess the ability of individual PKC isoforms to modulate the development or transformation of B cells. Of note, expression of a plasmid-encoding dominant negative PKCalpha (PKCalpha-KR) in HPCs and placement in B cell generation system in vitro or in vivo resulted in the generation of a population of cells that displayed an enhanced proliferative capacity. Analysis of PKCalpha-KR-expressing cells in vitro revealed that these cells incorporated BrdU significantly more than the MIEV control, and unexpectedly upregulated cell cycle regulators, p21waf-1 and p27kip-1. Of surprise, PKCalpha-KR-expressing cells phenotypically resemble human B cell chronic lymphocytic leukaemia (CLL) cells. Expression of constitutively active PKCalpha, PKCalpha-CAT, or dominant negative PKCalpha, PKCalpha-KR in HPCs caused significant decrease in cell number. CLL is characterised by the accumulation of long-lived phenotypically mature B cells with the distinctive phenotype: CD19hi, CDS+, CD23+, IgMdim, which are deficient in apoptosis and have undergone cell cycle arrest in the G0/G1 phase. Closer analysis of PKCalpha-KR-expressing cells uncovered that these cells undergo cell cycle arrest in the absence of growth factors and stroma and consistent with their ability to escape growth factor withdrawal-induced apoptosis, exhibited elevated levels of Bcl-2 and Mcl-1 expression. Upon stimulation with IL-7, PKCalpha-KR-expressing cells showed explosive proliferation, suggesting that IL-7 is a proliferation factor for these cells. In accordance with this, IL-7R expression was upregulated in these cells, which may contribute to the increased sensitivity to IL-7. Mice injected with wildtype PKCalpha-KR-HPCs bore solid intraperitonial tumours at the injection site and the cells from both tumour and spleen showed CLL-like phenotype. Interestingly, splenocytes from these mice were cycling whereas the tumour cells were arrested at the G0/G1 stage, probably reflecting the two phases of this disease, a quiescent stage and an extensive proliferative stage, respectively. The expansion of the leukaemic cells was halted when they were cultured on 0P9-DL1, 0P9 cells with ectopic expression of Notch ligand, DL1, suggesting that Notch signalling mediates tumour suppression in CLL cells.
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Guerra, Gustavo Petri. "A melhora da memória induzida por espermidina envolve a fosforilação da pkc, pka e creb em hipocampo de ratos". Universidade Federal de Santa Maria, 2011. http://repositorio.ufsm.br/handle/1/4431.
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Coordenação de Aperfeiçoamento de Pessoal de Nível SuperiorThe endogenous poliaminas, putrescine, spermidina and spermine are aliphatics amines that are present in high concentrations in the central nervous system (SNC). The action of the poliamines involves the modulation of several ionic channels, including the subtype of glutamatergic N-methyl-D-aspartate receptor (NMDA). The processes mediated by NMDA receptor include synaptic plasticity and formation of neural circuitry. It is believed that these plasticities happening in some cerebral areas specifies, as the hippocampus, are critical for the learning and memory processes. It is described that spermidine (SPD), as well as the protein kinase are directly involved with processes of formation of the memory. Therefore, we investigated the involvement of the Ca2+ dependent (PKC) and cAMP-dependent (PKA) protein kinase in the facilitatory effect induced by SPD on the memory of males Wistar rats. For that, the rats were bilaterally cannulae in the hippocampus, after the surgical recovery, the animals were trained in the inhibitory avoidance task and injected (0.5 μL) bilaterally in the hippocampus. A subset of the animals was euthanized 30 or 180 min after injections and activity of PKC, PKA and cAMP response element-binding protein (CREB), in the hippocampus, was determined for Western blot. The other animals had a testing session, 24 h pos-training in the inhibitory avoidance apparatus. The post-training administration of the 3-[1-(Dimethylaminopropyl)indol-3-yl]-4-(indol-3-yl)maleimide hydrochloride [GF 109203X, 2.5 ρmol intrahippocampal (ih)], inhibitor of PKC, N-[2-bromocinnamylamino ethyl]-(5-isoquinoline sulfonamide) [H-89, 0.5 ρmol intrahippocampal (ih)], PKA inhibitor or arcaine (0.02 nmol ih), the antagonist of the NMDA receptor polyamine-binding site prevented memory improvement induced by SPD (0.2 nmol ih). The SPD (0.2 nmol), in the hippocampus, facilitated PKC 30 min, PKA and CREB phosphorylation 180 min after administration, and increased translocation of the catalytic subunit of PKA into the nucleus. GF 109203X, (2.5 ρmol) prevented the stimulatory effect of SPD on PKC, PKA and CREB phosphorylation. Furthermore, arcaine (0.02 nmol) and H-89 (0.5 ρmol) prevented the stimulatory effect of SPD on PKA and CREB phosphorylation 180 min after administration. None of the drugs studies altered the locomotor activity of the animals. These results suggest that the facilitatory effect of the memory induced by the ih administration SPD involves the cross talk between PKC and PKA/CREB, with PKC activation follow by PKA/CREB pathways activation in rats.
As poliaminas endógenas, putrescina, espermidina e espermina, são aminas alifáticas que estão presentes em altas concentrações no sistema nervoso central (SNC). As poliaminas modulam diversos canais iônicos, incluindo o subtipo de receptor glutamatérgico N-metil D-aspartato (NMDA). Os processos mediados pelo receptor NMDA incluem plasticidade sináptica e formação de circuitos neurais. Acredita-se que estas plasticidades ocorrendo em algumas regiões cerebrais específicas, como o hipocampo, são críticas para os processos de aprendizado e memória. Está descrito que a espermidina (SPD), assim como as proteínas quinase, esta diretamente envolvida com os processos de formação da memória. Assim, investigamos o envolvimento das proteínas quinases dependente de AMPc (PKA) e dependente de Ca2+ (PKC) sobre a melhora da memória induzida por SPD em ratos. Para isso, ratos Wistar machos foram canulados bilateralmente no hipocampo e após a recuperação cirúrgica treinados na tarefa de esquiva inibitória. Imediatamente após o treino os animais receberam através das cânulas (0,5 μl/sítio) a administração de N-[2-bromocinamilamino etil]-(5-isoquinolina sulfonamida) [H-89, 0,5 ρmol intrahipocampal (ih)], inibidor da PKA, 3-[1-(Dimetilaminopropil)indol-3-il]-4-(indol-3-il)maleimida hidrochloride [GF 109203X, 2,5 ρmol (ih)], inibidor da PKC, arcaína (0,02 nmol, ih), antagonista do sítio de ligação das poliaminas no receptor NMDA ou SPD (0,2 nmol, ih). Um grupo de animais foi eutanasiado 30 ou 180 minutos após a administração das drogas e a atividade da PKC, PKA e o elemento ligante responsivo ao AMPc (CREB), no hipocampo, foi determinada por Western blot. Os outros animais foram submetidos à sessão de teste, 24 horas depois do treino na esquiva inibitória. A administração de H-89, GF 109203X ou arcaína preveniu a melhora da memória induzida por SPD. A SPD (0,2 nmol) aumentou a fosforilação da PKC 30 min, da PKA e do CREB 180 min após a injeção e aumentou a translocação da subunidade catalítica da PKA do citosol para o núcleo. GF 109203X, (2,5 ρmol) preveniu o efeito estimulatório da SPD sobre a fosforilação da PKC, PKA e CREB. Além disso, arcaína (0,02 nmol) e H- 89 (0,5 ρmol) preveniram o efeito estimulatório da SPD sobre a fosforilação da PKA e CREB 180 min depois da injeção. Nenhuma das drogas alterou a atividade motora dos animais. Estes resultados sugerem que o efeito facilitatório da memória induzido pela administração ih de SPD envolve um cruzamento entre PKC e PKA/CREB, com a ativação inicial da PKC, seguida da ativação da cascata PKA/CREB em ratos. Assim, poderemos determinar um possível mecanismo de ação da espermidina nos processos de formação da memória, e desta forma, fornecer subsídios para o desenvolvimento de fármacos.
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Dykes, Ava Caudill. "Diverse roles of PKC[alpha] in vascular smooth muscle contraction". Huntington, WV : [Marshall University Libraries], 2006. http://www.marshall.edu/etd/descript.asp?ref=680.
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Theses (Ph. D.)--Marshall University, 2006.Title from document title page. Includes abstract. Document formatted into pages: contains xiii, 122 p. including illustrations. Bibliography: Chap.I. p.28-33; Chap. II. p. 82-86; Chap. III p.115-116.
20
Brandt, Dominique. "Über die Rolle von PKC bei der Reorganisation des Zytoskeletts". [S.l. : s.n.], 2003. http://deposit.ddb.de/cgi-bin/dokserv?idn=968536875.
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Hall, Kellie Joann. "The Regulation and Role of Novel PKC Isoforms in Platelets". Thesis, University of Bristol, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.486072.
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Platelets are central to physiological haemostasis and respond to stimulation by a variety of soluble and insoluble agonists. Most platelet activatory agonists couple to activation of protein kinase C (PKC) isoforms, including PKC8 and PKCe, members of the novel PKC family. So far the role of PKC8 in platelets has been fairly well characterised although its regulation in platelets, particularly by phosphorylation, is less well understood. Conversely the role of PKCe is less well understood due to a lack of selective inhibitors. This thesis aimed to investigate the regulation ofPKC8 by tyrosine phosphorylation and the role ofPKCe in platelets to improve our understanding of the signalling pathways leading to platelet activation. PKCo was found to be phosphorylated on T~11 and T~65 following thrombin stimulation of human platelets, downstream ofSrc family kinases and phospholipase C signalling. PKCo required membrane recruitment and allosteric modulation (by DAG or PMA) for tyrosine phosphorylation to occur. Tyrosine phosphorylation of PKCo was not required for membrane recruitment of the kinase but was able to potentiate the kinase activity. The presence of the two identified phosphorylation sites in the hinge region (fy(3l1) and the kinase domain (f~6~ suggests that phosphorylation of these sites may stabilise the active conformation ofthe kinase. The role ofPKCe in platelet functional responses is less well characterised than that of PKCo. Using platelets from PKCe-l- mice it was f~und that PKCe negatively regulated integrin activation and a-granule release downstream of GPVI signalling. Interestingly PKce positively regulated thrombin-induced integrin activation however this effect was not seen when using the PAR4 agonist AYPGKF. PKCe was found to positively regulate dense granule secretion downstream of PAR4 but negatively regulate it downstream of TxA2 although the mechanism by which this occurred was not investigated. The findings from this study suggest that PKCe plays a distinct role in platelet activation in an agonist-specific manner.
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Clelland, Lyndsay Jacquelyn. "Role of ROK and PKC in Permeabilized Rabbit Femoral Artery". VCU Scholars Compass, 2007. http://hdl.handle.net/10156/1581.
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Rao, Sudha. "Identification and characterisation of a novel form of PKC-zeta". Thesis, King's College London (University of London), 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.312797.
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Scott, Hannah Elizabeth. "PKC-δ, its C2 domain and breast cancer cell lines". Thesis, University of Nottingham, 2012. http://eprints.nottingham.ac.uk/12668/.
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Protein kinase C δ (PKC-δ) is a novel member of the PKC family of serine-threonine kinases. PKC-δ structure is widely conserved within the PKC family and has a catalytic region and regulatory region. The regulatory region has two main sub domains C1 and C2. Although several studies have investigated the role of the C1 domain, little is known about the function of the C2 domain, however there is some evidence that it acts as a protein interaction domain. PKCs are involved in a wide variety of cellular functions within cancer. PKC-δ has been demonstrated to have a particular involvement with the apoptotic processes of a cancer cell. A pro-apoptotic role for PKC-δ has been identified, whereby tyrosine phosphorylation of particular residues induces translocation to the nucleus, alongside a similar translocation event for caspase-3. In the nucleus, caspase-3 cleaves the regulatory and catalytic regions to form a free catalytic domain that is uninhibited by the regulatory portion. This free catalytic region causes the induction of the apoptotic pathway. Conversely an anti-apoptotic role has also been identified for PKC-δ. This was found in MDA-MB-231 cells, which have a ras mutation. Due to this mutation in these cells, ERK1/2 phosphorylation is high. Without PKC-δ activity the high phosphorylation levels induce apoptosis. PKC-δ acts on a pathway to reduce ERK1/2 phosphorylation, thus facilitating cell survival. This study aimed to investigate the role of the PKC-δ C2 domain within breast cancer cells. Through use of these techniques, the role of the C2 domain was examined in order to consider its utility as a drug target to treat breast cancer. •Constructs were developed of pIRESneo2 vector with myc-tagged C2 domain and myc-tagged PKC-δ sequences •Breast cancer cell lines, MDA-MB-468, MDA-MB-231 and MCF-7, were stably transfected with a vector control and myc-δC2 construct. MDA-MB-231 and MCF-7 were also transfected with myc-PKC-δ. •Cell lines developed were examined for alterations due to the presence of the C2 domain or PKC-δ over-expression As the C2 domain is proposed to be a protein interaction domain, we hypothesized that over-expression of this domain would interfere with endogenous PKC-δ interactions, through competitive inhibition, and thus we could identify C2 domain roles. The effect on the cells of the endogenous PKC-δ would be opposed by the C2 domain. Thus the role of endogenous PKC-δ could also be clarified for a particular situation - it would be the opposite of the effects induced by the myc-δC2 on the cells. In the MDA-MB-468 stable cell lines, immuno-fluorescence examination of the myc-δC2 cells showed the myc-δC2 was localised at the ends of actin protrusions from the bulk of the cell. The myc-δC2 expressing cells had a more extensive cytoskeleton than the Vector control cells, possibly suggesting improved attachment to a surface. An experiment examining this illustrated that the myc-δC2 cells appeared to attach in a shorter time period. This implies that the role of the endogenous PKC-δ is to discourage cell attachment and promote an invasive phenotype, this is in agreement with the literature. During sub-culture of the MDA-MB-468 cell lines it became apparent that the myc-δC2 cells were growing at an increased rate over the Vector cell lines. This was quantified and indeed the myc-δC2 cells did increase in cell number more than the Vector cells. This was also the case with the MDA-MB-231 cells but not with the MCF-7 cells. Growth is a balance of proliferation and apoptosis. This effect indicates that PKC-δ is pro-apoptotic, or anti-proliferative. MCF-7 cells lack caspase-3 and thus pro-apoptotic effects of PKC-δ would be affected in this cell line. As the myc-δC2 did not have an effect in these cells we examined apoptosis to see if these effects could be attributed to differences in apoptosis. The MDA-MB-468 cells expressing myc-δC2 had higher viability than the Vector cells. This fits with the cell number data, indicating that a lower level of apoptosis has led to a greater cell number, and advocates a pro-apoptotic role for PKC-δ. This was not the case in MDA-MB-231 cell lines where Vector cells had higher viability. This agrees with the literature describing PKC-δ displaying an anti-apoptotic role in this cell line, but does not fit with the cell number data. Thus, differences in cell number are likely due to effects on proliferation, although this was not investigated. MCF-7 cells showed no differences indicating the apoptotic program of these cells is indeed affected by the lack of caspase-3. Serum starvation is a commonly used method to induce apoptosis. MDA-MB-468 cell lines were serum starved in order to examine the effects. The apoptosis profile was altered and myc-δC2 cells showed lower viability than the Vector cells, indicative of an anti-apoptotic effect of PKC-δ. An anti-apoptotic effect is observed in MDA-MB-231 cells, where the effect was proteasome dependent. This was also the case in this situation. The anti-apoptotic effect is related to levels of phosphorylated ERK1/2, where high levels are pro-apoptotic. The phosphorylation status was examined and illustrated a much higher level of phosphorylation in myc-δC2 cells over Vector cells when starved. This indicates myc-δC2 is inhibiting the de-phosphorylating role of PKC-δ in these apoptotic cells. Thus it appears that the C2 domain acts as a ‘sensor’ to serum status, appropriating PKC-δ effects in apoptotic pathways according to the serum status, the method of which is unknown. This study has highlighted the importance of the PKC-δ C2 domain in breast cancer apoptosis. The effects appear to require a fully active PKC-δ pro-apoptotic pathway, and are dependent on the serum status of the cells. Further investigation would be required to identify a level of serum for use in vitro that is relevant to an in vivo tumour situation. If low levels are more relevant to a clinical state then it may be possible to target the C2 domain with drugs to allow induction of apoptosis. The differences between the cell lines clearly show that the phenotypic analysis of tumours would be vital to identifying whether such treatment would be applicable, as effects of any drug would vary greatly across tumour types. MDA-MB-468 and MDA-MB-231 are both triple negative cell lines (i.e. they do not express progesterone, oestrogen or HER2 receptors); however the strong differences seen in this case indicate further phenotypic analysis would be essential.
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FABRE, SERGE. "Conception et synthese d'inhibiteurs de la proteine kinase c (pkc)". Clermont-Ferrand 2, 1993. http://www.theses.fr/1993CLF21572.
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A travers la conception et la synthese de nouveaux inhibiteurs de la pkc, nous avons voulu mettre en evidence la correlation existant entre pouvoir inhibiteur sur la pkc et la suppression de differentes reponses biologiques resultant de l'activation de l'enzyme, telles la vasoconstriction ou la proliferation cellulaire, dans le but de mettre a jour d'eventuels principes actifs utilisables en therapeutique antihypertensive ou anticancereuse. L'ouvrage comporte trois volets, en plus d'une partie experimentale. La premiere partie est une etude bibliographique tres complete, presentant des generalites sur la pkc (structure, fonctions physiologiques) et un expose exhaustif des differents types d'inhibiteurs connus jusqu'a present. La deuxieme partie presente le travail de synthese proprement dit, c'est-a-dire la conception et la synthese de nouveaux inhibiteurs de la pkc, capables d'interagir avec le site de fixation de l'atp sur la pkc. Ces inhibiteurs ont ete inspires de deux types de structures decrites dans la litterature: d'une part des structures indolocarbazoles entrant dans la composition de certains metabolites secondaires bacteriens actifs sur la pkc, mais egalement des indolomaleimides de synthese, nettement plus specifiques que les drogues precedentes. Enfin, la troisieme partie a trait aux tests biologiques realises sur les molecules preparees qui evaluent leur caractere inhibiteur vis-a-vis de la pkc et de la pka (recherche de la specificite), puis leur interet en tant que vasodilatateurs et agents antiproliferatifs
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Mayanglambam, Azad. "Regulation of Protein Kinases (Syk and PKC zeta) in platelets". Diss., Temple University Libraries, 2010. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/91635.
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PhysiologyPh.D.
Platelets are crucial components of the hemostatic machinery of the body. When the endothelial continuity is disrupted due to injury or atherosclerotic plaque rupture, one of the earliest responses to arrest the bleeding is the adhesion of circulating platelets to the exposed subendothelial collagen matrix. Subsequent intracellular signaling mediated downstream of various receptor systems leads to alpha IIb beta 3 activation, thromboxane generation, ADP release, etc., culminating in platelet clot or thrombus formation. The protein kinase family of enzymes mediates a significant number of these intracellular signaling events that culminate in platelet activation. These enzymes can be broadly classified into two classes- tyrosine kinases and serine/threonine kinases. Syk (spleen tyrosine kinase) is an important non-receptor tyrosine kinase present in platelets and plays an important role downstream of GPVI-FcR gamma chain receptor complex activation. We studied the effects of curcumin (diferuloylmethane), which is the active ingredient found in the herbal remedy and food spice turmeric, on the GPVI-mediated platelet activation. We have found that it significantly inhibits the kinase activity of Syk without affecting its phosphorylation. Pre-incubating the platelets with curcumin for only a minute resulted in a concentration-dependent inhibition of aggregation and secretion, with approximately 75% inhibition observed at 50 mM curcumin. Additionally, the activation-dependent phosphorylation of tyrosines 753/759 on PLC gamma2 and phosphorylation of tyrosine 191 on the transmembrane scaffold protein LAT, were inhibited (p<0.05). However, the phosphorylation of the activation loop tyrosines 525/526 on Syk and of the tyrosine 145 on intracellular adaptor molecule SLP-76 were not significantly affected. Furthermore, the inhibitory action of curcumin on the catalytic activity of Syk was independent of any of its effects on the thromboxane generation because all our studies were performed using aspirin-treated platelets. PKC zeta is an atypical member of the PKC family of serine/threonine kinases. In this study, we have confirmed that it is expressed in human platelets and is constitutively phosphorylated at the activation loop threonine 410 as well as the turn motif threonine 560, which is an autophosphorylation site. Phosphorylation at these two residues has been shown to be important for its kinase activity. Furthermore, agonist-mediated platelet aggregation under stirring condition results in dephosphorylation of the Thr410 residue, which can be prevented by blocking integrin alpha IIb beta 3 by its antagonist SC-57101 (p<0.01). The dephosphorylation of Thr410 can also be prevented by okadaic acid, a Ser/Thr protein phosphatase inhibitor, at concentrations above 100 nM. However, in PP1c gamma null mice, we did not observe any effect on the dephosphorylation, suggesting that other isoforms of PP1 or other classes of the phosphatases could be responsible for this phenomenon, at least in these knockout mice. The basal phosphorylation of Thr560, however, remained unaffected by agonist stimulation, integrin activation, integrin blockade, okadaic acid treatment and in the PP1c gamma null mice. It can be speculated that PKC zeta may be constitutively active under basal resting conditions and acts as a negative regulator of platelet activation or functional responses. The Thr560 autophosphorylation signal alone may not be sufficient to sustain its full enzymatic activity.
Temple University--Theses
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Roberts, Sarah Anne. "An investigation of protein kinase C in Swiss 3T3 cells using phorbol esters". Thesis, University College London (University of London), 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.369190.
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Trachsel, Sébastien Auguste Charles. "Selective responses (Actin polymerization, shape changes, locomotion, pinocytosis) to the PKC-inhibitor Ro 31-8220 suggest thath PKC discriminately regulates functions of human blood lymphocytes /". [S.l : s.n.], 1996. http://www.ub.unibe.ch/content/bibliotheken_sammlungen/sondersammlungen/dissen_bestellformular/index_ger.html.
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Cozzi, Sarah-Jane. "Molecular targets of anticancer PKC activators in the treatment of melanoma /". [St. Lucia, Qld.], 2005. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe19185.pdf.
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Tränkle, Jens. "Mechanismen der Signalübertragung durch PKC und Rho in Hefe und Säugern". [S.l. : s.n.], 2003. http://deposit.ddb.de/cgi-bin/dokserv?idn=968798187.
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Humphries, Michael Jason. "PKC[delta] and apoptosis : analysis of the role of tyrosine phosphorylation /". Connect to full text via ProQuest. IP filtered, 2005.
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Thesis (Ph.D. in Cell and Developmental Biology) -- University of Colorado, 2005.Typescript. Includes bibliographical references (leaves 155-180). Free to UCDHSC affiliates. Online version available via ProQuest Digital Dissertations;
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Burstin, von Vivian Annaluise. "PKC isozymes in the control of fate of prostate cancer cells". Diss., lmu, 2011. http://nbn-resolving.de/urn:nbn:de:bvb:19-127021.
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Al-Kushi, Abdullah Glil. "Pathological changes in mesostriatal neurons in a PKC-gamma mutant rat". Connect to e-thesis, 2007. http://theses.gla.ac.uk/149/.
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Thesis (Ph.D.) - University of Glasgow, 2007.Ph.D. thesis submitted to the Division of Neuroscience and Biomedical Systems, Institute of Biomedical and Life Sciences, University of Glasgow, 2007. Includes bibliographical references.
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Rourke, Bryan. "Characterization of the activation of PKC Apl II in Aplysia californica". Thesis, McGill University, 2014. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=121492.
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PKC Apl II, a novel PKC in Aplysia californica, is required for reversal of depression, the cellular analog of behavioral dishabituation. The neurotransmitter 5HT activates PKC Apl II in sensory neurons and can induce the reversal of depression. Here we investigated the ability of 5HT to activate PKC Apl II and the molecular pathway involved. Reversal of depression can occur at concentrations as low as 1.6 μM. We observed that activation of PKC Apl II, as measured by membrane enrichment, can occur at similar concentrations (1 μM). Furthermore we observed differences in membrane enrichment in the processes compared to the cell bodies when sensory neurons had formed a synapse with a motor neuron but not in isolated sensory neurons. The receptor activated by 5HT upstream of PKC Apl II is currently unknown. We tested the ability of the Aplysia 5HT4Apl, B2 and B4 receptors to measure the activation of PKC Apl II in a heterologous cell system. The B receptors are unique to Aplysia and are related to the biogenic amine receptors. Neither receptor was able to activate PKC Apl II as measured by translocation. The ligand or purpose of the Aplysia B receptors remains unclear. Despite not being present in sensory neurons 5HT4Apl was able to activate PKC Apl II. Previous work has shown that genistein blocks PKC Apl II activation and reversal of depression. However was not clear which target of genistein was responsible. Using pharmacological inhibitors we confirm that genistein as acting on a tyrosine kinase. Furthermore we provided evidence that the receptor tyrosine kinase FGFR is involved in PKC Apl II activation. This suggests that the 5HT receptor responsible for PKC Apl II activation transactivates FGFR in Aplysia sensory neurons.Chez l'Aplysie de californie, la nouvelle PKC Apl II est importante pour inverser la dépression synaptique qui est sous-jacente à la déshabituation chez l'animal. Nos études précédentes avaient démontré que la sérotonine (5HT) activait la PKC Apl II dans les neurones sensoriels. De plus, des concentrations de 5HT aussi faibles que 1 μM pouvaient inverser la dépression synaptique. Dans la présente thèse, nous avons investigué la translocation de la PKC Apl II en réponse à la 5HT. En premier lieu, nous avons démontré que l'activation de la PKC Apl II, tel que mesurée par la translocation à la membrane plasmique, avait aussi lieu à des concentrations de 1 μM 5HT. De plus, nous avons observé des différences dans la translocation de la PKC Apl II à la membrane dans les prolongements par rapport aux corps cellulaires lorsque les neurones sensoriels formaient une synapse avec le neurone moteur. Le récepteur activé par la 5HT en amont de la PKC Apl II demeure inconnu. Nous avons donc cloné les récepteurs B2 et B4 de l'Aplysie et testé leur capacité à activer la PKC Apl II dans une lignée cellulaire soit les cellules Sf9. Les récepteurs B sont uniques à l'Aplysie et ressemblent aux récepteurs d'amines biogènes. Tel que mesuré par la translocation, les récepteurs B2 et B4 n'ont pas activé la PKC Apl II en réponse à la 5HT. Des travaux antérieurs ont montré que la génistéine bloquait l'activation de PKC Apl II et l'inversion de la dépression synaptique. Cependant, le récepteur précis ciblé par la génistéine n'était pas connu. En utilisant des inhibiteurs pharmacologiques, nous avons confirmé que la génistéine bloquait une tyrosine kinase. De plus, nous avons démontré que le récepteur tyrosine kinase de la famille des récepteurs de facteur de croissance des fibroblastes (FGFR) était impliqué dans l'activation PKC Apl II suggérant que la 5HT pouvait transactiver le récepteur FGFR dans les neurones sensoriels de l'Aplysie pour inverser la dépression synaptique.
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Al-kushi, Abdullah G. "Pathological changes in mesostriatal neurons in a PKC-gamma mutant rat". Thesis, University of Glasgow, 2008. http://theses.gla.ac.uk/149/.
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The AS/AGU rat originated as a recessive mutation (agu) in a closed colony of Albino Swiss (AS) rats. The mutation is in the gene coding for the gamma isoform of protein kinase C. It is characterized by movement impairments and progressive dysfunction of the nigrostriatal dopaminergic (DA) and raphe striatal serotonergic (5-HT) systems. The movement impairments including rigidity of the hind limbs, a staggering gait, a tendency to fall over every few steps, a slight whole body tremor and difficulty in initiating movements. The dysfunction in both systems is characterised by a failure to release DA or 5-HT within the striatum and cell loss within the substantia nigra pars compacta (dopaminergic cells) and the dorsal raphe nuclei (5-HT+ve cells). In this study, three experiments were carried out to examine the possible pathological responses of midbrain cell groups to the agu mutation in the gene coding for protein kinase C-gamma (PKC-γ). Experiment 1 was carried out to examine levels of two groups of molecules in the midbrain cell groups using quantitative immunofluorescence microscopy of cell bodies or their surrounding neuropil (a) those molecules giving information about the capacity of midbrain aminergic cell bodies to synthesis transmitters; tyrosine hydroxylase (TH) in the dopaminergic neurons and serotonin (5-HT) in the serotonergic neurons (b) those which have been found to occur in human neurodegenerative conditions such as Parkinson’s disease: ubiquitin, parkin and α-synuclein (Lewy body proteins). Immunofluorescence levels of tyrosine hydroxylase (in dopaminergic cells of the SNC) and serotonin (in 5HT+ve cells of the dorsal raphe nuclei) were both significantly increased in AS/AGU (mutant) compared to the AS (control) rats aged 6 months and older. TH and 5-HT immunofluorescence levels were both significantly decreased in the striatum in the AS/AGU (mutant) compared to the AS (control) rat aged 12 months. Ubiquitin immunofluorescence show a gradual increase with age in AS and AS/AGU rats and the increase was much greater in the mutant in every region except the oculomotor and pontine nuclei. Parkin immunofluorescence show increases in the mutant within the SNC and the dorsal raphe nucleus and this increase was significant at older ages. Alpha-synuclein does not occur in the cell bodies of the substantia nigra or VTA but outside in the neuropil. Alpha-synuclein immunofluorescence levels progressively increased with age in both strains in the SN and VTA and were higher in the mutant. The levels of those molecules (ubiquitin, parkin and alpha-synuclein) do not differ in the striatum of mutants compared to controls. Experiment 2 examined SNC cell bodies to look for possible strain differences in cell size or ultrastructure or any sign of cell death using light and transmission electron microscopy. The diameter (maximum and minimum) of the SNC cells and nuclei were measured in toluidine blue paraffin wax and immunoperoxidase DAB staining for TH sections. Cell diameter was reduced in the AS/AGU mutant compared to the AS control. No obvious ultrastructural differences were seen in nigrostriatal neurons of both strains. The volume fractions of mitochondria and rough endoplasmic reticulum were significantly higher in the mutant. No Lewy bodies were present. Experiment 3 examined TH+ve nigrostriatal dopaminergic terminals in the dorsal caudate-putamen to determine whether there are (a) differences in the percentages and numbers of TH+ve terminals and (b) differences in synaptic vesicles numbers. In 12-month AS/AGU mutant, there are reduction in TH+ve terminals (40%) together with a reduction in vesicle numbers (40%) in such terminals where in 3-month AS/AGU mutant, the reduction in TH+ve terminals was more (50%) and a reduction in vesicles numbers by three quarters. TH-ve terminals are also reduced in numbers in 12 months aged AS/AGU mutant rats. In 12-month AS/AGU rats, there were significantly reduced numbers of synaptic terminals in the striatum compared to AS controls. This applied to both dopaminergic terminals (which make up 15% of the total) and to non-dopaminergic terminals. In 3-month AS/AGU rats, there is a reduction in terminal numbers, but this is restricted to the dopaminergic terminals only: non-dopaminergic ones are unaffected.
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Omri, Samy. "Etude du rôle de la PKC Zeta dans la rétinopathie diabétique". Paris 5, 2010. http://www.theses.fr/2010PA05T033.
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La rétinopathie diabétique (RD) est la première cause de cécite chez les patients de moins de 60 ans. La formation d'oedème due à une altération des barrières oculaires et l'inflammation sont souvent associées à cette pathologie. Au cours du diabète, la PKC zeta joue un rôle prépondérant à différents niveaux ; comme le transport du glucose, la résistance à l'insuline, et la migration des macrophages au cours de l'inflammation oculaire. Mon travail a porté sur l'étude du rôle de la PKC zeta dans les mécanismes moléculaires impliqués dans ces altérations au cours du diabète de type 2 chez le rat Goto Kakizaki. Mes résultats ont conduit; 1°) a La caractérisation de la membrane limitante externe (OLM) comme une troisième barrière rétinienne avec la présence de jonctions serrées. La rupture de cette barrière, au cours de la RD est associée à la perte des cônes ; 2°) a La mise en évidence d'une forme courte de la PKC zeta et de son rôle dans la rupture de la barrière hémato-rétinienne externe (EPR); 3°) à la mise en évidence de l'existence d'un passage trans-cellulaire de la microglie activées à travers l'EPR. L'activité de la PKC zeta joue un rôle clé dans ce trafic, confirme par l'administration de son inhibiteur spécifique. L'ensemble de ces résultats montre que l'activation prolongée de la PKC zeta est deletere et participe aux altérations observées au cours de la RD. L'utilisation de son inhibiteur spécifique semble être protecteur de ces barrieres et limiter les processus inflammatoires. Le contrôle de l'activité prolongée de la PKC zeta par l'utilisation de son inhibiteur spécifique pourrait être un véritable outil thérapeutique de cette pathologieDiabetic retinopathy (DR) is the leading cause of blindness in patients younger than 60 years. The formation of edema due to ocular barriers alterations and inflammation are often associated with this pathology. In diabetes, the PKC zeta plays a role at different levels such as the transport of glucose, insulin resistance, and migration of macrophages in ocular inflammation. My work has focused on studying the role of PKC zeta in the molecular mechanisms involved in these alterations on Goto Kakizaki rats model of diabetes type 2. My results have demonstrated: 1°) the characterization of the outer limiting membrane (OLM) as a third retinal barrier with the presence of tight junctions. The rupture of this barrier during RD is associated with the loss of cones. 2 °) We evidenced a short form of PKC zeta and its role in the outer retinal barrier disruption (EPR). 3°) We evidenced a trans-cellular passage of activated microglia through the EPR. Taken together, the activity of PKC zeta plays a key role in this traffic, confirmed by the administration of its specific inhibitor. All these results show that prolonged activation of PKC zeta" is deleterious and contributes to the alterations observed in the DR. The use of its specific inhibitor may protect ocular barriers and decreased the inflammation. Control of prolonged activity of PKC zeta by using its specific inhibitor may be a therapeutic strategy for this pathology
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de, Souza Figueiroa Marina. "Efeito do extrato aquoso do chá verde e suas catecinas puras sobre a produção de testosterona pelas células de Leydig de rato in vitro". Universidade Federal de Pernambuco, 2008. https://repositorio.ufpe.br/handle/123456789/2139.
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Previous issue date: 2008Faculdade Intergrada do Recife
Este estudo investigou os efeitos agudos do extrato aquoso do chá verde (GTE) e dos seus constituintes polifenóis (-)-epigalocatecina-3-galato (EGCG) e (-)-epicatecina (EC) sobre a produção de testosterona basal e estimulada, em células de Leydig de ratos in vitro. Células de Leydig purificadas foram incubadas por 3 horas com GTE, EGCG ou EC e com o precursor da testosterona androstenediona, na presença ou ausência de ativadores da proteína quinase A (PKA) e da proteína quinase C (PKC). O GTE e a EGCG, mas não a EC, inibiram ambas as produções de testosterona, basal e quinaseestimuladas. Células pré-tratadas por 15 minutos com GTE ou EGCG e recuperadas por 1 hora foram submetidas a tratamento com gonadotrofina coriônica humana (hCG), hormônio liberador de gonadotrofinas (LHRH), 22OHColesterol ou androstenediona. Nestas condições o efeito inibitório do GTE/EGCG em suas maiores concentrações utilizadas (69,2 e 100 μg/mL, respectivamente) sob a produção de testosterona estimulada por hCG/LHRH ou 22OHColesterol se manteve, enquanto que a produção de testosterona estimulada pela androstenediona retornou para os níveis do controle, indicando que o efeito inibitório sob a função da enzima 17β-hidroxidesidrogenase (17β-HSD) foi reversível. Nestas mesmas condições de pré-tratamento, porém utilizando menores concentrações de GTE/EGCG (13,8 e 20 μg/mL, respectivamente) observou-se que o efeito inibitório destes polifenóis sobre a produção de testosterona estimulada pelo 22OHColesterol foi revertida e até excedeu os níveis do controle, indicando que o efeito inibitório dos polifenóis sob a função da enzima de clivagem da cadeia lateral (P450scc) em mitocôndrias foi reversível. Conclui-se que os efeitos inibitórios do GTE podem ser explicados, pelo menos em parte, pela ação da EGCG, seu principal componente, e que a presença do grupo galato em sua estrutura parece ser importante para sua alta eficácia na inibição da síntese de testosterona. Os mecanismos envolvidos nos efeitos do GTE e da EGCG são provavelmente diversos e envolvem a inibição das cascatas de sinalização da PKA/PKC, assim como a inibição da função das enzimas P450scc e 17β-HSD
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Nguyen, Loan Thi Kim. "Role of PKC-mediated phosphorylation on p53 localization and function in neuroblastoma". Thesis, University of Ottawa (Canada), 2006. http://hdl.handle.net/10393/27279.
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Neuroblastoma (NB) is the most common solid tumour in paediatrics, arising from primitive neural crest cells. The tumour suppressor protein, p53 is inactivated in NB through aberrant cytoplasmic localization, thus contributing to its tumourigenicity and multidrug resistance. Regulation of the p53 response pathway occurs through phosphorylation, however there may be dysregulation of p53 as NB contains abnormally high expression of PKCs. We investigated the role of PKC-mediated phosphorylation as a mechanism responsible for the p53 cytoplasmic sequestration in NB cell lines, [MR-32 and SHSY5Y. A pharmacological approach utilizing protein kinase inhibitors including H7, Bisindolyamide I (BisI), and Go6976 were tested on their ability to relocalize p53 and reintroduce function. All the inhibitors were able to relocalize p53, however, only the general kinase and PKC inhibitors H7 and BisI, respectively were able to induce a decrease in cell proliferation and cell cycle accumulation as demonstrated by flow cytometric analysis. The conventional PKC isoform inhibitor Go6976 had no effect on p53 function albeit able to relocalize p53. To further substantiate the effects with H7 and BisI as being p53-dependant, increased expression of Bax and p21 proteins served as a hallmark of p53 function. Antibody-mediated inhibition of PKC allowed us to identify the PKC isozymes involved in p53 regulation. Inhibition of PKCalpha resulted in accumulation and nuclear relocalization of p53. Furthermore substantiating p53 as a PKC substrate in vivo, serine residue phosphorylation of p53 decreased upon PKCalpha inhibition. We found that two independent PKC phosphorylation events and isoforms are responsible for regulation of p53 relocalization and activation. Specifically for NB, PKC inhibition can initiate and active the p53 response pathway. Electrospray ionization was used to monitor p53 peptide phosphorylation in vitro . Spectra revealed that phosphorylation variants ranging from mono- to tri-phosphorylated peptides can be detected. Thus, ESI was verified as an effective method of monitoring in vitro phosphorylation of p53 peptides.
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Bird, Rebecca Jane. "Novel areas of crosstalk between the cyclic AMP and PKC signalling pathways". Thesis, University of Glasgow, 2010. http://theses.gla.ac.uk/2117/.
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Mediation of biological functions occurs via tightly regulated signal transduction pathways. These complex cascades often employ crosstalk with other signalling pathways to exert strict control to allow for correct cellular responses. The cyclic AMP signalling pathway is involved in a wide range of cellular processes which require tight control, including cell proliferation and differentiation, metabolism and inflammation. Protein Kinase C (PKC) signalling is also involved in the regulation of many biological functions, due to the wide range of PKC isoforms, and there is emerging evidence that there are critical points of crosstalk between these two central signalling pathways. The aims of this research, therefore, are to identify the molecular basis underlying this pivotal cross-communication. The identification of the complex formed by Receptor for activated C Kinase 1 (RACK1), a scaffold protein for PKC, and the cyclic AMP-specific phosphodiesterase PDE4D5 demonstrated a potential area of crosstalk between the cyclic AMP and PKC signalling pathways although the function of the complex remained largely unknown. In this thesis I have outlined a role for RACK1 binding to PDE4D5 to control the enzymatic activity of the phosphodiesterase. Although RACK1 does not affect the intracellular localisation of PDE4D5, it does afford structural stability to PDE4D5, providing protection against denaturation. Furthermore, interaction with RACK1 facilitates high affinity binding of PDE4D5 to cyclic AMP and increases phosphodiesterase sensitivity to inhibition by rolipram, a PDE4-specific inhibitor that is a therapeutic treatment for depression and Alzheimer’s disease. Additionally, RACK1-bound PDE4D5 was found to be activated by PKCα, providing a route of negative regulation by PKC on cyclic AMP in HEK293 cells. The discovery of EPAC (Exchange Protein directly Activated by Cyclic AMP) has opened up the field of cyclic AMP research, providing an alternative route for the cyclic AMP signalling originally thought to occur solely through Protein Kinase A (PKA). Recent investigations have linked cyclic AMP signalling via EPAC to the control of inflammation, through the induction of Suppressor of Cytokine Signalling 3 (SOCS-3) to inhibit IL-6 signalling. Here I have further delineated this pathway in COS1 to show that induction of SOCS-3 by EPAC requires phospholipase C (PLC) ε. Investigation into downstream effectors of PLC action lead to the identification of PKCα and PKCδ as essential components of this pathway, further elucidating a mechanism by which cyclic AMP can affect inflammation and revealing a point of crosstalk between the two signalling pathways. Further elaborating on the identification of PKC isoforms α and δ as crucial components in the control of cytokine signalling by cyclic AMP via EPAC, investigations into the effect of cyclic AMP on PKC α and δ activation and autophosphorylation, and on downstream effectors, were carried out. It was revealed that cyclic AMP had no influence on PKCδ activity, although a role for cyclic AMP signalling through EPAC on the activation and autophosphorylation of PKCα was identified. Additionally, phosphorylation of the downstream kinase ERK was found to occur independently of PKC activation and required the presence of EPAC1 in COS1 cells. The work presented in this thesis therefore begins to delineate a novel pathway in which the cyclic AMP and PKC pathways work together to afford cell regulation, including the regulation of gene expression, through novel areas of crosstalk.
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Pandey, Pratima. "Role of Protein Kinase C (PKC) Isoforms in Regulation of Filopodia Dynamics". Bowling Green State University / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=bgsu1451317928.
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Jama, Abdulrahman M. "Lipin1 regulates skeletal muscle differentiation through the PKC/HDAC5/MEF2c:MyoD -mediated pathway". Wright State University / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=wright1533311098994136.
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Janoshazi, Agnès. "Study of activation process of protein kinase C (PKC) in living cells". Université Louis Pasteur (Strasbourg) (1971-2008), 2008. http://www.theses.fr/2008STR13064.
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Li, Chenwei. "PKC[alpha] translocation and actin remodeling in contracting A7r5 smooth muscle cells". Huntington, WV : [Marshall University Libraries], 2002. http://www.marshall.edu/etd/descript.asp?ref=62.
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Thesis (Ph. D.)--Marshall University, 2002.Title from document title page. Document formatted into pages; contains xi, 136 p. with illustrations. Includes abstract. Includes bibliographical references (p. 120-136).
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Bull, Natalie D. "Modulation of rat retinal glutamate transporters by PKC : physiological and ischaemic outcomes /". [St. Lucia, Qld.], 2002. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe16813.pdf.
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Bom, Vinícius Leite Pedro. "A importância da proteína fosfatase sitA na adesão, integridade da parede celular, biofilme e virulência de Aspergillus fumigatus". Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/17/17131/tde-20072016-092319/.
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Aspergillus fumigatus é um fungo patogênico oportunista capaz de infectar pacientes imunocomprometidos causando eventualmente infecções disseminadas difíceis de serem controladas e com alta taxa de mortalidade dos indivíduos infectados.. Para um melhor entendimento de como esse fungo age no hospedeiro é importante saber como as vias de sinalização que regulam esses fatores de virulência são orquestradas. Proteínas fosfatases são centrais em uma grande variedade de vias de transdução de sinal. Neste trabalho, nós caracterizamos a proteína fosfatase 2A SitA, a proteína homóloga de Sit4 em Saccharomyces serevisiae. O gene sitA não é essencial e por isso fomos capazes de construir um mutante nulo em A. fumigatus. A cepa ?sitA apresenta aumento na fosforilação da MpkA, é mais sensível à agentes que causam dano na parede celular, tem um aumento na quantidade de ?-1,3 glicano e quitina, e também tem problemas na adesão e formação de biofilme. O mutante ?sitA é mais sensível a vários metais e íons, como MnCl2, CaCl2, LiCl, entretanto é mais resistente à ZnSO4. O mutante ?sitA é avirulento em modelo de aspergilose pulmonar invasiva em camundongos. Esses resultados revelam que a fosfatase SitA está envolvida na via de integridade da parede celular de A. fumigatus possivelmente modulando a atividade de PkcA/MpkAAspergillus fumigatus is an opportunistic pathogenic fungus able to infect immunocompromised patients causing eventually disseminated infections that are difficult to be controlled, and lead to high mortality rates. It is important to understand how are orchestrated the signalling pathways that regulate these factors involved in virulence. Protein phosphatases are central to numerous signal transduction pathways. Here we characterize A. fumigatus protein phosphatase 2A SitA, the S. cerevisiae Sit4p homologue. The sitA gene is not an essential gene and we were able to construct an A. fumigatus null mutant. The ?sitA strain had increased MpkA phosphorylation, was more sensitive to cell wall damaging agents, had increased ??1,3?glican and chitin, and was impaired in biofilm formation. The ?sitA strain is more sensitive to several metals and ions such as MnCl2, CaCl2, and LiCl, however, it is more resistant to ZnSO4. The ?sitA strain was avirulent in a murine model of invasive pulmonary aspergillosis. These results stress the importance of A. fumigatus SitA as a possible modulator of PkcA/MpkA activity and its involvement in the cell wall integrity pathway
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Kumar, Varun. "Protein Kinase C Signaling in Neurodegeneration". Kent State University / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=kent1455721051.
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L'Ériger, Karine. "Régulation transcriptionnelle du récepteur P2X[indice inférieur 7] et son rôle dans le trafic membranaire du transporteur à glucose Glut2 dans les cellules épithéliales intestinales". Mémoire, Université de Sherbrooke, 2009. http://savoirs.usherbrooke.ca/handle/11143/4034.
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Le récepteur ionotropique P2X[indice inférieur 7] (P2X[indice inférieur 7]R) est impliqué dans divers rôles physiologiques tels la prolifération, l'apoptose, la réponse inflammatoire et le trafic membranaire dans plusieurs types cellulaires. Cependant, peu est connu quant aux rôles physiologiques du P2X[indice inférieur 7]R dans les cellules épithéliales intestinales (CEIs). Dans la littérature scientifique, le P2X[indice inférieur 7]R est connu pour activer la protéine kinase Dl (PKD1/PKC[mu]) qui est impliquée dans le transport des protéines membranaires. Comme l'un des rôles physiologiques majeurs des CEIs est le transport et l'absorption du glucose, le transporteur à glucose de type 2 (Glut2) a été ciblé afin d'étudier son transport membranaire suite à l'activation du P2X[indice inférieur 7]R. Glut2 est un élément clé dans le métabolisme du glucose par les CEIs. Une hypothèse stipulant que le P2X[indice inférieur 7]R serait impliqué dans le trafic membranaire de Glut2 par une voie dépendante de la PKD1/PKC[mu] a été émise. Les objectifs majeurs de l'étude étaient de déterminer le profil d'expression du P2X[indice inférieur 7]R selon le stade de différenciation des CEIs, d'élucider les mécanismes moléculaires régulant l'expression du P2X[indice inférieur 7]R, d'étudier la signalisation intracellulaire affectant l'expression membranaire de Glut2 induite par l'activation du P2X[indice inférieur 7]R. D'abord, le profil d'expression du P2X[indice inférieur 7]R en fonction de la différenciation des CEIs a été déterminé par immunofluorescence indirecte sur des sections de jéjunum de souris normales et par immunobuvardage de type western sur des lysats de cellules Caco-2/15 prolifératives et différenciées. Ensuite, la signalisation induite par l'activation du P2X[indice inférieur 7]R a été étudiée en stimulant des cellules IEC-6 avec de l'ATP ou du BzATP, deux agonistes du P2X[indice inférieur 7]R, et en prétraitant les cellules avec de l'oATP, un antagoniste du P2X[indice inférieur 7]R. Différents inhibiteurs pharmacologiques tels le UO126 (MEK1/2) et la rottlerine (PKC[delta]) ont été utilisés pour déterminer l'ordre des protéines dans les voies de signalisation. Également, différents chélateurs de calcium, comme le BAPTA-AM et l'EGTA, ont été utilisés pour étudier la dépendance des voies trouvées au calcium. L'expression de Glut2 à la membrane plasmique suite à la stimulation du P2X[indice inférieur 7]R a été étudiée par immunofluorescence indirecte et par biotinylation des protéines membranaires de surface. Finalement, la régulation transcriptionnelle du P2X[indice inférieur 7]R dans les cellules HEK 293T et Caco-2/15 a été étudiée par des essais luciférase qui permettent de visualiser l'interaction entre le promoteur du P2X[indice inférieur 7]R et des facteurs de transcription cibles comme Cdx-2, GATA-4, HNF-4[alpha], C/EBP[alpha] et C/EBP[bêta]. Les résultats obtenus démontrent que l'expression du P2X[indice inférieur 7]R augmente en fonction de l'état de différenciation des cellules Caco-2/15, ce qui coïncide avec sa localisation dans les deux tiers supérieurs de la villosité de jéjunum de souris normales. Aussi, l'activation du P2X[indice inférieur 7]R amène une augmentation de la phosphorylation des protéines PKD1/PKC[mu], PKC[delta], ERK1/2, MEK1/2, SAPK/JNK, p90RSK et CREB. Également, la PKC[delta] est en amont des protéines MEK1/2 et ERK1/2 qui elles-mêmes sont en amont de la PKD1/PKC[mu]. Cette voie PKC[delta]/MEK/ERK/PKD est également indépendante du calcium extracellulaire et intracellulaire. Aussi, il y a internalisation et diminution de l'expression membranaire de Glut2 suite à l'activation du P2X[indice inférieur 7]R par le BzATP. Finalement, le P2X[indice inférieur 7]R est régulé au niveau transcriptionnel par les facteurs de transcription HNF-4[alpha], C/EBP[alpha] et C/EBP[bêta] mais pas par Cdx-2 et GATA-4. En résumé, les résultats démontrent que le P2X[indice inférieur 7]R est impliqué dans l'internalisation et la diminution de l'expression membranaire de Glut2 par un mécanisme qui semble dépendant de la voie PKC[delta]/MEK/ERK/PKD calcium-indépendante.
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Chihabi, Kutibh. "Protein Kinase Mzeta (PKM-ζ) Regulates Kv1.2 Dependent Cerebellar Eyeblink Classical Conditioning". ScholarWorks @ UVM, 2017. http://scholarworks.uvm.edu/graddis/719.
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Learning and memory has been a topic that has captured the attention of the scientific and public communities since the dawn of scientific discovery. Without the faculty of memory, mammals cannot experience nor function in the world; among homosapiens specifically, language, relationships, and personal identity cannot be developed (Eysenck, 2012). After all, some philosophers such as John Locke argued we are nothing but a collection of past memories in which we have developed and improved upon (Nimbalkar, 2011).
Understanding the cellular mechanisms behind learning, and the subsequent formation of memory, has been a topic that has garnered scientific interest for many decades. One particular kinase that has been at the center of attention in the last decade is the serine/threonine kinase PKM-ζ, an N-terminal truncated form of PKC-ζ that renders it constitutively active (Hernandez et al., 2003). PKM-ζ has long been implicated in a cellular correlate of learning, long-term potentiation (LTP). Inhibition of PKM-ζ with Zeta-inhibitory peptide (ZIP) has been shown in many brain structures to disrupt maintenance of AMPA receptors, irreversibly disrupting numerous forms of learning and memory that have been maintained for weeks.
The voltage-gated potassium channel Kv1.2 is a critical modulator of neuronal physiology, including dendritic excitability, action potential propagation, and
neurotransmitter release. While expressed in various mammalian tissues, Kv1.2 is most prevalent in the cerebellum where it modulates both dendritic excitability of Purkinje cells (PCs) and basket cell (BC) inhibitory input to PCs. Because PCs are the main computational unit of the cerebellar cortex and provide its sole output (Napper et al., 1988; Harvey et al., 1991), regulation of synaptic Kv1.2 is predicted to have a major role in cerebellar function. Pharmacological inhibition of Kv1.2 in cerebellar PC dendrites increases excitability (Khavandgar et al., 2005), while its inhibition in BC axon terminals increases inhibition to PCs (Southan & Robertson, 1998). Interestingly, two prior studies have demonstrated that PKC-ζ, an atypical Protein Kinase C, is able to phosphorylate and bind cerebellar Kvβ2, a Kv1.2 auxiliary subunit. (Gong et al., 1999; Croci et al., 2003).
Delay eyeblink conditioning (EBC) is an established model for the assessment of cerebellar learning. Despite being highly expressed in the cerebellum, no studies have examined how regulation of cerebellar PKM-ζ may affect cerebellar-dependent learning and memory nor have they examined the possible effect PKM-ζ may have on Kv1.2. The goal of this dissertation was to determine whether PKM-ζ could modulate EBC in a Kv1.2 dependent manner. Through the use of microscopy techniques we have shown that PKM-ζ is highly expressed in the cerebellar cortex, primarily in the PC, and by the use of pharmacological manipulations, it was found that PKM-ζ has an important role in regulating the acquisition of EBC. Through the use of biotinylation, flow cytometry, and behavioral manipulations, it was determined that PKM-ζ regulates Kv1.2 during eyeblink conditioning. These studies provided the first evidence that PKM-ζ has a role for learning and memory in the cerebellum, and the first evidence of PKM-ζ regulating a voltage-gated ion channel rather than a ligand-gated ion channel such as AMPA receptors.
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Saville, Stephen Paul. "Analysis of yeast proteins with immunological or sequence similarities to mammalian PKC isozymes". Thesis, University of Leicester, 1998. http://hdl.handle.net/2381/30311.
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When this project began, its principal aims were the isolation and characterisation of additional members of the yeast PKC family, which were believed to exist on the basis of biochemical data obtained in our laboratory, and others worldwide. One such gene, PKC2, was identified in our laboratory (Simon et al., 93) and a thorough functional analysis of its respective peptide product, Pkc2p was to have formed a major part of this project. In November 1994, a paper was published which cast serious doubts on the authenticity of the PKC2 gene (Levin et al., 94). In order for this study to continue, it was necessary to verify the existence of PCK2 . Nucleotide sequencing of all the recombinants purportedly used to generate the PKC2 open reading frame failed to reveal any of the hallmark sequences which allowed its categorisation as a member of the PKC family. Nevertheless, the weight of biochemical evidence suggested that other PKC-like proteins did exist in yeast. In an attempt to identify the protein(s) responsible for these activities, an immunological screen was performed using polyclonal antisera known to recognise mammalian PKC isoforms. This screening failed to detect any such proteins but cross-reactivity was observed with the product of the YOR080w open reading frame. A thorough functional analysis of the YOR080w gene product, implicates the protein in the normal progression of the yeast cell cycle, with the defect manifesting itself at the spindle assembly checkpoint.
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Schreier, Juliane [Verfasser]. "Role of PKCε in RNA granule formation and protein translation / Juliane Schreier". Berlin : Freie Universität Berlin, 2013. http://d-nb.info/104162090X/34.
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