Dissertationen zum Thema „Cl11“
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Duncan, Peter I. „Characterisation of the murine CLK1 dual-specificity kinase“. Thesis, University of Ottawa (Canada), 1997. http://hdl.handle.net/10393/10402.
Der volle Inhalt der QuelleTibbles, Katherine L. „Regulation of Clb1 during meiosis in Saccharomyces cerevisiae“. Thesis, University of Warwick, 2013. http://wrap.warwick.ac.uk/60444/.
Der volle Inhalt der QuelleLange, Jenny. „Neuron-glia interactions in infantile neuronal ceroid lipofuscinosis (CLN1 disease)“. Thesis, King's College London (University of London), 2016. https://kclpure.kcl.ac.uk/portal/en/theses/neuronglia-interactions-in-infantile-neuronal-ceroid-lipofuscinosis-cln1-disease(ceed9c8f-f40d-4796-be7b-e799fe88b431).html.
Der volle Inhalt der QuelleNelvagal, Hemanth Ramesh. „Spinal cord pathology in CLN1 disease : a novel therapeutic target“. Thesis, King's College London (University of London), 2017. https://kclpure.kcl.ac.uk/portal/en/theses/spinal-cord-pathology-in-cln1-disease(8b1dc3ed-dfd9-442d-a427-43ded0d82a6a).html.
Der volle Inhalt der QuelleGARSUAULT, SOPHIE. „Degradation et fonction de cln1 identification de sequences en cis responsables de la degradation et de la fonction de cln1, une cycline g1 de saccharomyces cerevisiae“. Paris 6, 1998. http://www.theses.fr/1998PA066496.
Der volle Inhalt der QuelleZou, Meilin. „Haplotypes of cleistogamous flowering gene cly1 and association with temperature stress“. Thesis, Zou, Meilin (2017) Haplotypes of cleistogamous flowering gene cly1 and association with temperature stress. Honours thesis, Murdoch University, 2017. https://researchrepository.murdoch.edu.au/id/eprint/37942/.
Der volle Inhalt der QuelleAigner, Christian [Verfasser], und Franz [Akademischer Betreuer] Bracher. „Entwicklung neuer CLK1-Inhibitoren mit antiviraler Aktivität / Christian Aigner ; Betreuer: Franz Bracher“. München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2017. http://d-nb.info/1138566160/34.
Der volle Inhalt der QuelleDurkan, Anne Maria. „The expression of CX₃CL1 (fractalkine) in renal tubular epithelial cells and the regulation of CX₃CL1 by stimulation of the thromboxane prostanoid receptor“. Thesis, University of Edinburgh, 2012. http://hdl.handle.net/1842/24546.
Der volle Inhalt der QuelleHedden, J. J. „The role of Clp1 and Pcf11 in transcription and pre-mRNA 3’-end processing“. Thesis, University College London (University of London), 2012. http://discovery.ucl.ac.uk/1369193/.
Der volle Inhalt der QuelleIsosomppi, Juha. „Molecular and cell biology of infantile (CLN1) and varaint late infantile (CLN5) neuronal ceroid lipofuscinoses“. Helsinki : University of Helsinki, 2003. http://ethesis.helsinki.fi/julkaisut/laa/haart/vk/isosomppi/.
Der volle Inhalt der QuellePescheteau, Clémentine. „Conception et synthèse d’inhibiteurs duaux de DYRK1A et CLK1, kinases impliquées dans la maladie d’Alzheimer“. Electronic Thesis or Diss., Orléans, 2021. http://www.theses.fr/2021ORLE3203.
Der volle Inhalt der QuelleAlzheimer's disease is the most common form of dementia worldwide. To date, no effective treatment exists despite many ongoing research projects. New therapeutic strategies have emerged, targeting protein kinases involved in neurodegeneration and neuroinflammation, processes leading to diseases of the central nervous system. DYRK1A and CLK1 have been identified as interesting targets against some neuropathologies, and are particularly involved in Alzheimer's disease. In order to design powerful and selective inhibitors of these two kinases, we have synthesized original heterocyclic molecules with aromatic [5-5] and [6-5] core rings. We first continued our team’s studies on imidazo[2,1-b][1,3,4]thiadiazoles and we created a library of original compounds which revealed interesting activities against DYRK1A and CLK1. We optimized the access routes to the most promising dual inhibitors, and their biological evaluations carried out by our collaborators allowed us to identify a molecular hit that will be studied in vivo. We then explored other molecular series by modulating the scaffold of our compounds. Access to the bicycle [1,2,4]triazolo[3,4-b][1,3,4]thiadiazole has been studied to design analogs of our structures. An efficient synthetic methodology of imidazo[1,2-d][1,2,4]thiadiazoles was then developed to reach a variety of molecules with high value potential. Furthermore, the [1,2,4]triazolo[4,3-b]pyridazine scaffold was used, and pharmacomodulations of its substituents allowed us to refine the structure-activity relationships of the designed inhibitors. Finally, innovative structures were developed, such as selective inhibitory macrocycles of our two kinases of interest
Sako, Yukiya. „Development of an orally available inhibitor of CLK1 for skipping a mutated dystrophin exon in Duchenne muscular dystrophy“. Kyoto University, 2017. http://hdl.handle.net/2433/226771.
Der volle Inhalt der QuelleLagrange, Thierry. „Evolution, structure et expression du gène nucléaire rpl21 codant pour la protéine ribosomique plastidiale cL21 d'épinard“. Grenoble 1, 1993. http://www.theses.fr/1993GRE10152.
Der volle Inhalt der QuelleHanemian, Mathieu. „Rôle de la protéine CLV1 dans la sensibilité d'Arabidopsis thaliana à la bactérie phytopathogène Ralstonia solanacearum“. Toulouse 3, 2012. http://thesesups.ups-tlse.fr/2754/.
Der volle Inhalt der QuelleThe molecular mechanisms associated to disease development caused by the phytopathogenic bacteria Ralstonia solanacearum are poorly understood. Search for mutants altered in their response to the pathogen led to the identification of some susceptibility genes including targets of virulence factors as well as plant components required for pathogen fitness. The CLAVATA1 (CLV1) gene, extensively studied for its role in plant development, encodes a receptor-like kinase with a leucin-rich repeat extracellular domain. This protein plays indeed a key role in maintaining a pool of stem cell within the shoot apical meristem. The clv1 mutation leads to an increased resistance to R. Solanacearum, associated with a decrease of in planta bacterial growth. The aim of my PhD work was the understanding of the mechanisms underlying the increased resistance conferred by the clv1 mutation in using different approach (molecular, genetic and transcriptomic). We have been able to demonstrate the implication of the NF-YA transcription factor family, controlled by microRNA miR169, in the increased resistance of these mutants. These results demonstrate that the CLV1 protein is a required component for the establishment of the disease caused by R. Solanacearum. And illustrate the wide diversity of functions fulfilled by receptors kinases
Esvan, Yannick. „Conception et synthèse de nouveaux composés hétéroaromatiques inhibiteurs potentiels de kinases“. Thesis, Clermont-Ferrand 2, 2016. http://www.theses.fr/2016CLF22743.
Der volle Inhalt der QuelleIn 1950’s protein kinases were found to play a critical role in cell signaling, rising strong research potential for this enzyme family. Initially investigated for their implications in cancerogenesis they were more recently found to be involved in a wide variety of diseases including neurodegenerative pathologies. Herein will be presented two research projects that offer bright new perspectives for the inhibition of kinases involved whether in neurodegenerative diseases or cancers.First, the design and synthesis of new pyrido[3,4-g]quinazoline derivatives will be described as well as their protein kinase inhibitory potencies toward five CMGC family members (CDK5, CK1, GSK3, CLK1 and DYRK1A) that are known to play a potential role in Alzheimer’s disease. The interest for this original tricyclic heteroaromatic scaffold as modulators of CLK1/ DYRK1A activity was validated by nanomolar potencies. CLK1 co-crystal structures with two inhibitors revealed the binding mode of these compounds within the ATP-binding pocket and led to the synthesis of new diversely substituted pyrido[3,4-g]quinazolines.Then the synthesis of a new derivative of the staurosporine aglycon (K252c), in which the lactam ring was replaced by a pyrazole moiety, will be depicted. The resulting indolopyrazolocarbazole inhibited Pim isoforms 1–3 whereas it did not impair the activity of two known targets of K252c, protein kinase C isoforms α and γ . The lead compound exhibited same cytotoxic activity as K252c toward both human leukemia and colon carcinoma cell lines (K562 and HCT116), strongly suggesting that this new scaffold deserves further investigations for treatment of malignancies associated with kinases activities
Dikfidan, Aytac [Verfasser], und Ilme [Akademischer Betreuer] Schlichting. „Structural and functional characterization of Clp1, a eukaryotic RNA‐specific polynucleotide kinase / Aytac Dikfidan ; Betreuer: Ilme Schlichting“. Heidelberg : Universitätsbibliothek Heidelberg, 2013. http://d-nb.info/1177809524/34.
Der volle Inhalt der QuellePlace, Matthieu. „Méthodologies de synthèses d'hétérocycles bicycliques (6-5) et (5-5). Application à la conception d'inhibiteurs de kinases impliquées en oncologie et dans les maladies du système nerveux central“. Thesis, Orléans, 2017. http://www.theses.fr/2017ORLE2056.
Der volle Inhalt der QuelleSince the early 2000s, precise knowledge of kinome has induced the emergence of novel therapies targeting kinases involved in several kinds of pathologies in oncology and nervous central systems disorders.In order to target original kinases of interest identified in this work, we have developed diversity-oriented synthesis to create new high-valuable heterocycles. We have focused our efforts on the design and functionalization of [6-5] or [5-5] fused ring bicycles. Those chemical species representing a great pathway tocreate competitive inhibitors of ATP; the natural substrate of kinases.First-of-all, we have worked on imidazo[1,2-b]pyridazines and then on [1,2,4]triazolo[4,3-b]pyridazinesscaffolds, to create more active and selective HASPIN kinase inhibitors, a new hot-target in oncology.Then, we have pursued previous laboratory studies on imidazo[2,1-b][1,3,4]thiadiazoles. Based on a well-built methodology, we have synthesized severals DYRK1A and CLK1 kinases inhibitors involved in neurodegenerative disorders, as Alzheimer’s disease. Thus, through original imidazothiadiazoles analogues,we have proposed synthetic methodologies to design these novel heterocycles allowding esay pharmacomodulations.These medicinal chemistry projects have been undertaken to improved knowledge of structure-activityrelashionship, and providing novel strong inhibitors of HASPIN, DYRK1A or CLK1 kinases
Faist, Benjamin [Verfasser], und J. [Akademischer Betreuer] Kämper. „Mechanismus der Clp1-vermittelten Inhibition der bW- und Rbf1-Funktion in Ustilago maydis / Benjamin Faist ; Betreuer: J. Kämper“. Karlsruhe : KIT-Bibliothek, 2017. http://d-nb.info/1139360442/34.
Der volle Inhalt der QuelleWhite, Gemma. „The role of fractalkine (CX₃CL1) and its receptor (CX₃CR1) in vascular biology“. Thesis, University of Oxford, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.670108.
Der volle Inhalt der QuellePinter, Niko [Verfasser], Kai [Akademischer Betreuer] Heimel, Kai [Gutachter] Heimel und Gerhard [Gutachter] Braus. „Analysis of Clp1-dependent UPR modulation in Ustilago maydis / Niko Pinter ; Gutachter: Kai Heimel, Gerhard Braus ; Betreuer: Kai Heimel“. Göttingen : Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2019. http://d-nb.info/1188464884/34.
Der volle Inhalt der QuelleChen, Chun-Ti. „Regulation of the Cdc14-like Phosphatase CLP1 in Schizosaccharomyces pombe and Identification of SID2 Kinase Substrates: A Dissertation“. eScholarship@UMMS, 2009. https://escholarship.umassmed.edu/gsbs_diss/449.
Der volle Inhalt der QuelleFortenbacher, Julia [Verfasser], und J. [Akademischer Betreuer] Kämper. „Charakterisierung des Proteinkomplexes Clp1 mit bE/bW und seine Auswirkung auf die pathogene Entwicklung in Ustilago maydis / Julia Fortenbacher ; Betreuer: J. Kämper“. Karlsruhe : KIT-Bibliothek, 2019. http://d-nb.info/1202076750/34.
Der volle Inhalt der QuelleDahlmann, Cordula [Verfasser]. „Retinaler Phänotyp dreier Mausmodelle für die neuronale Ceroidlipofuszinose : (CLN1-knockout Mausmodell, CLN3Δex7/8-knock-in Mausmodell und CLN6-knockout Mausmodell) / Cordula Dahlmann“. Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2013. http://d-nb.info/1031097074/34.
Der volle Inhalt der QuelleGuyon, Clotilde. „Contrôle post transcriptionnel des transcrits des auto-antigènes induits par AIRE dans le thymus“. Thesis, Sorbonne Paris Cité, 2016. http://www.theses.fr/2016USPCB138/document.
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Ziegler, Yvonne [Verfasser], Volker [Akademischer Betreuer] Lipka und Thomas [Akademischer Betreuer] Teichmann. „The role of the putative receptor-like cytoplasmic kinase CLR1 in chitin signalling / Yvonne Ziegler. Betreuer: Volker Lipka. Gutachter: Volker Lipka ; Thomas Teichmann“. Göttingen : Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2016. http://d-nb.info/1081543574/34.
Der volle Inhalt der QuelleHieber, Marie-Lisa [Verfasser]. „Die prognostische Bedeutung der TP53-Mutation für Ansprechen und Überleben von CLL-Patienten : Analyse im Rahmen der prospektiven CLL11-Studie (Clb vs. RClb vs. GClb) / Marie-Lisa Hieber“. Ulm : Universität Ulm, 2018. http://d-nb.info/1166757110/34.
Der volle Inhalt der QuelleKwag, Doo Young [Verfasser], und Michael [Akademischer Betreuer] Hallek. „Disease-specific complications of chronic lymphocytic leukemia in binet stage a patients : analysis of immunodeficiency, autoimmune constellations and infections in the CLL1-protocol / Doo Young Kwag. Betreuer: Michael Hallek“. München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2012. http://d-nb.info/1029040273/34.
Der volle Inhalt der QuelleSchmitt, Christian [Verfasser], und Rolf W. [Akademischer Betreuer] Hartmann. „Development of new lead-like dual inhibitors of the cdc2-like kinase 1 (Clk1) and dual specificity Y-phosphorylation regulated kinases 1A and 1B (Dyrk1A and Dyrk1B) / Christian Schmitt. Betreuer: Rolf W. Hartmann“. Saarbrücken : Saarländische Universitäts- und Landesbibliothek, 2014. http://d-nb.info/1056906855/34.
Der volle Inhalt der QuelleDa, Silva Sophie. „Identification des gènes CiSTM et CiCLV1p chez Cichorium intybus : implicatio potentielle dans les modifications d'identité cellulaire au cours des phases précoces de l'embryogenèse somatique et du développement des embryons zygotiques et de la graine“. Lille 1, 2004. https://ori-nuxeo.univ-lille1.fr/nuxeo/site/esupversions/fb7d2815-c338-4560-bd04-b5e881028bde.
Der volle Inhalt der QuelleLes génotypes embryogène K59 et non embryogène C15 ont été choisis comme génotypes à réponse extrême, selon leur capacité à produire les différentes figures cytologiques observées. La dernière partie de la thèse a été consacrée à l'étude des profils d'expression des gènes CiSTM et CiCLV1p au cours de l'embryogenèse zygotique et au cours de l'embryogenèse somatique par RT PCR en temps réel. Ces résultats ont été comparés aux fenêtres de développement de l'embryon zygotique et aux profils de réactivation des génotypes sélectionnés. Au cours de l'embryogenèse zygotique, une induction importante de l'expression des gènes CiSTM et CiCLVlp a été corrélée à la mise en place d'un dôme méristématique entre les cotylédons. Au cours de l'embryogenèse somatique, les transcrits des gènes CiSTM et CiCLV1p sont accumulés de façon différentielle lors du passage de certaines cellules en cours de réactivation vers l'état réactivé. Ces résultats suggèrent une implication des gènes CiSTM et CiCLV1p dans les mécanismes de changement d'identité cellulaire chez la chicorée,que ce soit au cours de l'embryogenèse zygotique ou au cours de l'embryogenèse somatique
Monaghan, Richard. „A novel nuclear role for the mitochondrial hydroxylase Clk-1“. Thesis, University of Manchester, 2012. https://www.research.manchester.ac.uk/portal/en/theses/a-novel-nuclear-role-for-the-mitochondrial-hydroxylase-clk1(8de582a1-bfe3-4421-bfbf-75f9229a13b1).html.
Der volle Inhalt der QuelleAndreou, Tereza. „Nuclear localisation of Clk-1 : a novel regulator of mitochondrial to nuclear signalling“. Thesis, University of Manchester, 2015. https://www.research.manchester.ac.uk/portal/en/theses/nuclear-localisation-of-clk1-a-novel-regulator-of-mitochondrial-to-nuclear-signalling(11ce8f0a-0e9e-40ae-840f-7805f2abede6).html.
Der volle Inhalt der QuelleBarnes, Robert. „A nuclear role for the respiratory enzyme CLK-1 in regulating reactive oxygen species, the mitochondrial unfolded protein response and longevity“. Thesis, University of Manchester, 2016. https://www.research.manchester.ac.uk/portal/en/theses/a-nuclear-role-for-the-respiratory-enzyme-clk1-in-regulating-reactive-oxygen-species-the-mitochondrial-unfolded-protein-response-and-longevity(9a41f8d6-d11d-4102-b250-7b20091f4ded).html.
Der volle Inhalt der QuellePinter, Niko. „Analysis of Clp1-dependent UPR modulation in Ustilago maydis“. Doctoral thesis, 2019. http://hdl.handle.net/21.11130/00-1735-0000-0003-C12F-F.
Der volle Inhalt der QuelleYeh, I.-Hsin, und 葉怡欣. „Characterization of putative metastasis-related proteins enriched from comparative analysis of lung adenocarcinoma cell lines CL1-0 and CL1-5 secretomes“. Thesis, 2013. http://ndltd.ncl.edu.tw/handle/72804496264841341863.
Der volle Inhalt der Quelle國立陽明大學
醫學生物技術暨檢驗學系
101
Adenocarcinoma, the most frequent type of lung cancer, is one of the most common diseases around the world and a major health problem in Taiwan. Based on microscopic morphologies, lung cancers can be classified as non-small cell lung cancer (NSCLC) (85%) and small cell lung cancer (SCLC) account (15%). The major therapeutic methods for lung cancer include surgical resection, radiation therapy, chemotherapy, and target therapy. Lung cancer has often spread to other areas of the body when it is diagnosed. Metastasis-related proteins may serve as potential diagnostic markers or targets for cancer intervention. In this study, we used two NSCLC cell lines, a low-metastatic CL1-0 and the highly metastatic CL1-5 for the identification of such proteins. Of the 82 candidates identified in our previous proteomic analyses, I performed further Ingenuity Pathways Analysis (IPA) and literature and selected fifteen candidate genes to validate their expression in these two cell lines by semi-quantitative RT-PCR. We found eight candidates had higher mRNA levels in CL1-5 than in CL1-0. To examine whether the proteins are associated with NSCLC metastasis, we have knocked down the expression eight candidate genes with shRNA, and perform wound healing assay to examine the effect of silencing these genes on the cell migration abilities. In addition, immunofluorescence staining indicated the alteration of beta-actin and cell morphology after knocking down Candidate #19, Candidate #7, Candidate #18 and Candidate #42 of the eight candidates. The role of these genes in metastasis of lung cancer deserve further investigation. Keywords: Non-small cell lung cancer, Proteomics, Cancer metastasis, Secretome
Wang, Chung-yao, und 王重堯. „Phosphoproteome Analysis of Lung Cancer Cell Line CL1-5“. Thesis, 2008. http://ndltd.ncl.edu.tw/handle/30877637547436967369.
Der volle Inhalt der Quelle國立成功大學
環境醫學研究所
97
Lung cancer is one of the most common causes of cancer death in the world. Although the total annual number of cases has declined, probably due to the decreased trend in cigarette consumption, the incidence and mortality rate of lung cancer have increased at an alarming rate in the female population and in developing countries. Cancer metastasis and invasion are the most crucial steps in the cancer progress, occurring via a series of biologic activities including the interaction of tumor cells with the surrounding environment. These steps are the major causes of treatment failure and cancer deaths. Therefore, understanding the mechanisms that regulate progress of tumor cells is important for development of novel therapies to control cancer. Based on recent researches, evidences indicate that the changed protein phosphorylation result in altered invasive and metastatic properties of tumor cells. For example, Phosphorylated FAK was seen in invasive ovarian carcinoma, but not in the normal cells. Here, we used metal affinity based enrichment coupled with LC-MS/MS analysis, qualitatively but comprehensively defined the phosphoproteome of this lung cancer cell lines CL1-5. Cancer cell lysates were digested and phosphopeptides were enriched by self-packing titanium dioxide (TiO2) microcolumn. The enrichment protocol was based on a recently published method. After enriched by TiO2 microcolumn, eluted peptides were subjected to LC-MS/MS analysis and the raw data were searched against Swiss-Prot database. Although phosphopeptide enrichment has been set up, a process to reduce the false-positive phosphopeptides identification by current database search tools is needed. Commonly accepted MS/MS data filtering criteria are not suitable for data analysis with post-translational modifications such as phosphorylation. Thus, we manual validated all the MS/MS spectra to exclude low confidence identities. A total of 719 phosphorylaed peptides, assigned to 274 proteins, were identified in this study. Those identified phosphorylation events may provide novel information for not only mechanistic aspects of lung cancer but also potential drug targets for hampering the cancer metastatic processes.
Ziegler, Yvonne. „The role of the putative receptor-like cytoplasmic kinase CLR1 in chitin signalling“. Doctoral thesis, 2015. http://hdl.handle.net/11858/00-1735-0000-0028-8698-6.
Der volle Inhalt der QuelleLiu, Yu-Lin, und 劉玉琳. „The Role of NAD(P)H:Quinone Oxidoreductase 1 (NQO1) in β-Lapachone-Mediated Cell Death on Non-Invasive and Invasive Human Lung Adenocarcinoma cells (CL1-1 and CL1-5)“. Thesis, 2005. http://ndltd.ncl.edu.tw/handle/06503226907624730615.
Der volle Inhalt der Quelle國立陽明大學
解剖暨細胞生物學研究所
93
β-Lapachone, the product of a tree (Tabebuia avellanedae) from South America, has been known to exhibit anti-parasitic, -tumor and -virus effects. The aim of the present study was to elucidate the mechanisms by which β-lapachone exerts its cytotoxicity to non-invasive (CL1-1) and invasive human lung adenocarcinoma cells (CL1-5). Exposure of CL1-1 and CL1-5 cells to β-lapachone resulted in survival inhibition and apoptosis. This increase in apoptosis was associated with a decrease of mitochondrial membrane potential suggesting that β-lapachone treatment destroyed mitochondrial function. Furthermore, the induction of calcium influx in β-lapachone-treated cells following 1h treatment might induce ER stress for cytotoxicity. On the other hand, inhibition of PI3K/Akt pathway was also found. However, all of these events were dependent upon NAD(P)H: quinone oxidoreductase (NQO1) activity. Counteracting NQO1 activity with dicumoral prevented cell death induced by β-lapachone. Therefore, our results implied that β-lapachone-mediated cytotoxicity against non-invasive and invasive human lung adenocarcinoma cells (CL1-1 and CL1-5) might occur through the activation of NQO1 that might induce the intracellular calcium imbalance and mitochondrial dysfunction and inhibit PI3K/Akt signaling pathway.
Chang, Kung-Yan, und 張工彥. „Studies of ALA Photodynamic Effects on Mitochondria and Related Biological Responses in CL1-5 Cells“. Thesis, 2003. http://ndltd.ncl.edu.tw/handle/74242193490507297284.
Der volle Inhalt der Quelle國立臺灣大學
口腔生物科學研究所
92
Photodynamic therapy (PDT) is based on the selective retention of a photosensitizer by tumor tissue and the subsequent irradiation of this tissue with light. 5-aminolevulinic acid (5-ALA), a pro-drug of photosensitizer, is metabolized in mitochondria to protoporphyrin IX (PpIX) which selectively accumulates to greater extent in cancer cells. Using CL1-5 Human lung adenocarcinoma, we demonstrated that the production of PpIX occurs in mitochondria under fluorescence microscopy. After ALA-PDT, we observed morphological changes of cell and breakdown of mitochondrial membrane potential. This was followed by chromosome condensation and caspase-3 activation which result in 10% cell death. Besides, there was significant number of cells which could not be detached from the dish by trypsin compared to control cells without ALA-PDT. This reduced trypsin detachment accompanies F-actin reorganization. N-acetyl-cysteine (NAC), free radical scanvanger, inhibited PDT-induced resistance to trypsinization and F-actin reorganization. After 5 times ALA-PDT (5-PDT) growth rate and the ability of invasion and migration in CL1-5 were significantly decreased. These data indicate that the PDT-induced mitochondrial photo-damage are critical in decreasing mitochondrial membrane potential, which leads to morphological changing, F-actin reorganization, apoptotic death, and decreased growth rate and invasion during PDT with ALA.
Li, Rung-Chi, und 李容奇. „Mechanism of COX-2-mediated anti-apoptotic effects in human lung adenocarcinoma cell line CL1“. Thesis, 2000. http://ndltd.ncl.edu.tw/handle/85080070357411740503.
Der volle Inhalt der Quelle國立臺灣大學
毒理學研究所
88
Apoptosis profoundly influences a wide variety of physiological processes. Thus, dysregulation of apoptosis has been implicated in several human diseases, ranging from cancer to immunity, AIDS and neurological disorders. Recently, emerging evidence show that resistance to apoptosis becomes an important mechanism in regulating the invasive ability of malignant tumors. Here we demonstrated that a human lung cancer CL1-5 cells with higher invasive ability exhibited remarked resistance to apoptosis; in contrast, another lower invasive subline CL1-0 was susceptible to apoptosis. Immunoblot analysis showed that cyclooxygenase(Cox)-2 and Mcl-1 proteins were consistently elevated in CL1-5 cells. This prompted us to hypothesize a closely functional interaction between Cox-2 and Mcl-1. To address this, we treated CL1-0 cells with PGE2, a product of Cox-2, and examined the cellular response to apoptosis. PGE2 treatment rendered CL1-0 cells became resistance to UV-elicited apoptosis and induced the increased expression of Mcl-1. We further transiently transfected Cox-2-expressing plasmid along with an indicator vector, pCMV-bgal, into CL1-0 cells. After 48-hr transfection, Cox-2 transfected CL1-0 cells exhibited more viable cells following exposure to b-lapachone or UV when compared to vector control cells. Furthermore, we co-transfected the anti-sense Mcl-1 and COX-2 plasmids into CL1-0 and demonstrate that anti-sense Mcl-1 could decrease the Cox-2-caused viable blue cells. Again we found that overexpression of Cox-2 in CL1-0 cells led to an up-regulation of Mcl-1. Pretreatment with phosphatidylinositol 3-Kinase (PI 3-K) inhibitors, LY294002 and Wortmannin, effectively inhibited PGE2-mediated up-regulation of Mcl-1 in CL1-0 cells. In line with the observation, when Cox-2-transfected cells were further transfected a dominant-negative mutant of PI 3-K, DN-p85, the Cox-2-mediated Mcl-1 expression was blocked. In contrast to mock cells we found COX-2 overexpressing cells exhibited highly Akt phosphorylation, one major target of PI 3-K, which was abolished by pretreatment of LY294002 and Wortmannin, too. To investigate these observations completely, we established CL1-0 cells which stably expressed cox-2 gene. Pretreatment of LY294002 and Wortmannin disrupted COX-2 transfectants-caused Mcl-1 protein level induction and Akt phosphorylation. And CL1-0/COX-2 pure clone had higher PI 3-K phosphorylation than CL1-0 cell line. We further examined the invasive ability of CL1-0/COX-2 using matrix gel in vitro invasion assay and Metalloproteinase zymography assay. In conclusion, the present study demonstrates that Cox-2 plays a key role in regulating the invasive ability of human adenocarcinoma cells by suppressing cellular apoptosis. The mechanism underlying Cox-2 prevents apoptosis which is mediated by up-regulation of Mcl-1 with a PI 3-K-dependent pathway.
Ma, Haou-Tzong, und 馬豪聰. „Inosine Monophosphate Dehydrogenase Inhibitor Regulates Expression of Fucosyltransferase 8 in lung cancer cell line CL1-5“. Thesis, 2015. http://ndltd.ncl.edu.tw/handle/23357738560152345903.
Der volle Inhalt der QuelleLiu, Pei-Yi, und 劉佩宜. „Study on the mechanisms of Pipoxolan inhibiting the migration in CL1-5 human lung adenocarcinoma cells“. Thesis, 2012. http://ndltd.ncl.edu.tw/handle/n75z24.
Der volle Inhalt der Quelle中國醫藥大學
藥學系碩士班
100
Pipoxolan is a commonly prescribed smooth muscle relaxant in Taiwan. Clinical use is to alleviate symptoms such as muscle spasms induced disease or pain. Our previous studies have shown that pipoxolan induce apoptosis and arrest the cell cycle at the G0/G1 phase in human leukemia cancer cells. HL-60 cells were arrested in the G0/G1 phase via the induction of p53⁄p21 by pipoxolan. Apoptosis was associated with an increased Bax/Bcl-2 ratio, cytochrome c release, cleavage of procaspases -9, -3 and hydrolysis of poly(ADP-ribose) polymerase (PARP) and high levels of ROS were produced early in the drug treatment, but the effects on the migration and invasion of human lung cancer cells have not been reported. Lung cancer is one of the most common malignancies in most countries including Taiwan and its metastasis is the major cause of death. The major reason of its high mortality rate is cancer metastasis, the hardest part of cancer treatment. The aim of our study is to investigate the effect of pipoxolan inhibiting the migration in highly migratory CL1-5 lung adenocarcinoma cells. The data demonstrated that CL1-5 cells were treated with pipoxolan (5.2, 12.9 and 25.8 μM) for 24h having the inhibitory effects of migration by wound scratch assay and transwell assay. The gelatin zymography assay indicated that pipoxolan inhibited the activity of matrix metalloproteinases 2 (MMP-2) and MMP-9 in a concentration-dependent manner. Western blotting analysis indicated that pipoxolan suppressed the phosphorylation of JNK1/2, p38, Rac-1, MMP-2 and -9 protein expressions, thereby inhibiting CL1-5 cells migration. In conclution, pipoxolan significantly inhibited CL1-5 human lung adenocarcinoma cells migration through inactivation of the JNK and p38 MAPK signaling pathway and decrease the activities of MMP-2 and -9.
Tsai, You-Wei, und 蔡有緯. „A dual-functional inhibitor causes apoptosis and inhibits metastasis of lung cancer cell line CL1-5“. Thesis, 2019. http://ndltd.ncl.edu.tw/handle/6n444z.
Der volle Inhalt der Quelle國立臺灣大學
生化科學研究所
107
Lung cancer has a high mortality rate and often metastasizes to other organs. The cell line used in the study was CL1-5, which is a non-small cell lung cancer (NSCLC). According to previous studies, cancer cells can be killed through blocking the interaction between CCT-β and β-tubulin by I-Trp. The small molecule compound-845 used in this study was screened among a series of bactericidal compounds synthesized by NHRI and is the most potential to kill CL1-5 cells. In addition, its structure is composed of a functional group which is similar to the reversible inhibitors of CCT-β: β-tubulin complex previously simulated by computer and a side chain of I-Trp. It has been found that compound-845 would induce ER stress in CL1-5 cells, which in turn leads to the release of intracellular calcium ion and apoptosis. Furthermore, analyzed by wound healing assay and transwell assay, it has been found that compound-845 would inhibit the migratory and invasive ability of CL1-5 cells. Moreover, compound-845 would inhibit EMT, AKT/β-catenin and integrin signaling pathway investigated by western blot, thereby inhibiting CL1-5 cell metastasis. In conclusion, this study reveals that this dual-functional inhibitor compound-845 probably has anti-tumor and anti-metastasis ability against human lung cancer.
Lin, Yu-Cun, und 林俞村. „Cathepsin S expression and its effects in human lung adenocarcinoma CL1 cells after glutathione reductase (GR) siRNA transfection“. Thesis, 2011. http://ndltd.ncl.edu.tw/handle/62964664938735317371.
Der volle Inhalt der Quelle國立清華大學
生物科技研究所
100
CL1-X (1~5) cells as a lung-cancer metastasis cell model were established through Matrigel-coated Transwell-membrane in cell culture insert (in each well of 24-well micro-titer dish) after 72-h selection and 5 consecutive procedures from CL1-0 human lung adenocarcinoma in the laboratory of Dr. P. C. Yang from National Taiwan University Hospital. Their invasive abilities through basement membrane matrix showed a 4- to 6- fold increase over that of the parental cells. Nevertheless, not all characters for their genetic instabilities were known for many years. Recently, data from our laboratory indicated that endogenous and exogenous cathepsin S (CTSS) protease activity in CL1-3 increased 5~7-fold and 2~3-fold, respectively, in comparison with those in CL1-0 parental cells. Measurement on several anti-oxidative molecules resulted in about one-half glutathione reductase (GR) activity (P<<0.01), less glutathione (GSH) (P<0.01), more GSH transferase (GST) (P<0.03), slightly more Glutathione peroxidase (GpX) activity (P=0.06-0.09) in CL1-3 cells having relatively more invasive (higher CTSS) abilities. To understand the causes of decreased GR and increased CTSS activity in CL1-3 cells after invasive ability selection from parental CL1-0 cells, gene manipulation and GR-siRNA transfection in CL1-0 cells to produce similar phenomenon as CL1-3 cells was conducted in this study. GR-siRNA (#2, #3 and #5 different sequence, from Academia Sinica) and puromycin gene containing lentivirus vectors were transfected into CL1-0 cells. Clones containing low GR activity and high CTSS activity were selected. In Exp. I, among 68 clones picked from puromycin containing medium, 48 clones (>70%) had GR activity lower than 18.1 U/mg protein (close to background of CL1-3 cells). Among them, 19 clones (28%) showed lower than 0.53-fold of parental GR activity. Ten (relative lower GR, < 0.4-fold) of these 19 clones were chosen to further examine their CTSS activities. Only one clone, #3-16 (GR-siRNA #3 transfected) from all selected clones showed one-fifth GR activity (very low) and 1.64-fold endogenous CTSS activity in comparison with that in CL1-0-mock cells. In Exp. II, vectors containing GR-siRNA#5 and puromycin gene were transfected into CL1-0 cells. Among 77 clones picked from puromycin containing medium, 38 clones (49.4%) had 1.1~2.0-fold of parental CTSS activity. Six clones among these high CTSS clones contained more than 1.5-fold of parental CTSS activity and less than one-half (0.16~0.38-fold) of parental GR activity (close to background of CL1-3 cells). Cell migration ability examination by means of wound healing assays and Boyden chamber assays was determined in clones 3-13, 3-16, 5-04 from Exp. I, clone 5-29 from Exp. II and parental CL1-0 cells, respectively. The results indicated that those clones from GR-knock down manipulation and high-CTSS selection have better cell migration abilities. Clone 3-13 [1.64-fold CTSS, 0.22-fold GR] and clone 5-29 [2.0-fold CTSS, 0.38-fold GR] showed 1.5-fold and 16-fold of parental cell migration ability. Therefore, clones containing higher CTSS activity (1.5~2.0-fold) and cell migration abilities than parental cells had been obtained from genetic manipulation to lower down GR activity in parental CL1-0 cells. In the second part of this study, CTSS inhibitors, L-trans-epoxysuccinyl- L-leucylamido (4-guanidino) butane (E-64), N-Ethylmaleimide (NEM) and phenylmethanesulfonyl fluoride (PMSF) were applied in CL1-3 cells. E-64 reduced 50% CTSS activity at 5 nM in vitro and 10 μM in vivo. In addition, NEM reduced 50% CTSS activity at 800 μM in vitro. However, there was no significant inhibition on CTSS activity after PMSF treatment. Therefore, E-64 was a considerable potent inhibitor. Although clone 3-13 had 0.22-fold of parental GR activity, clone 3-13 showed slightly SRB viability difference from parental CL1-0 cells after H2O2 exposure for 4 h. In contrast, CL1-3 cells, containing 0.5-fold GR activity of parental CL1-0 cells, showed significant different sensitivity to H2O2 (4 h at 25~50 μM dose or 1~4 h at 40 μM), from CL1-0 cells. CL1-3 cells have 6~7-fold of parental CTSS activity. Whether higher CTSS activity in CL1-3 cells further increased H2O2 sensitivity (in comparison with clone 3-13 cells) remained to be further investigated.
Shu-Ming und 莊書銘. „Characterize the effect of slit2 protein fragments on cell growth and migration in CL1-5 lung cancer cell line“. Thesis, 2008. http://ndltd.ncl.edu.tw/handle/51905152541360802314.
Der volle Inhalt der Quelle中山醫學大學
醫學分子毒理學研究所
96
Our laboratory established suppressive subtractive cDNA libraries from tissues of a female lung adnocarcinnoma. After serial databases analysis, we identified slit2 gene whose expression level is highly repressed in lung cancer. Slit2 is a 200 kDa secreted glycoprotein. Its role in axon repellent and cell migration were extensively studied in different systems. Recent studies pointed that slit2 possesses tumor suppressor activity, however other report showed that slit2 has ability to induce angiogenesis. Therefore, the role of slit2 in carcinogenesis remains clarified. The expression of slit2 in lung cancer cell lines is very low except in the CL1 series cell line. The low invasive cell line CL1-0 expresses high level of slit2 while slit2 expression in high invasive cell line CL1-5 is very low. Since slit2 showed distinct biological activity in cell migration, and since slit2 expression is negatively correlated with invasive potential in CL1 series cell line, we thus use CL1 series cell line to study the role of slit2 in lung cancer. Our previous studies showed that overexpression of full length slit2 in CL1-5 reduce cell growth, which can be counted by increased in G1 phase cell population and decreased in S phase cell population. Furthermore, overexpression of slit2 decreased in vitro invasive ability of CL1-5 cell. In this study, we aimed to identify the domain of slit2 which confers inhibition of cell growth and/or invasion. To achieve this, we generated slit2-N terminal and slit2-C terminal fragments based on the reported cleavage site of slit2 in neuron system. Expression of slit2-C terminal fragment in CL1-5 showed similar growth repression activity compared with the full length slit2. In our system, we were unable to detect the cleavage product of overexpressed slit2. Nevertheless, it is interesting to investigate whether the cleavage of slit2 is important for its responsible function in CL1-5 or not. Our result showed that a non-cleavable slit2 showed similar growth inhibitory ability as the cleavable slit2. Therefore, the growth inhibitory ability of slit2 does not require cleavage at the reported cleavage site. Interestingly, overexpression of full length slit2 inhibited CL1-5 migration activity in wound healing assay, and this ability is retained in overexpressed slit2-C terminal fragment, while slit2-N terminal only slightly or did not inhibit cell migration. This result is rather surprising, since the ability to affect cell migration by slit2 in most system was referred to the slit2-N terminal domain. Invasive ability of cancer cell is often used to rank its malignancy. Thus, we are currently investigating the effect of slit2-N terminal and C terminal fragments in cell invasion. Once the function of each slit2 domain was confirmed, we will generate deletion mutations to narrow down the effective domain(s). Ultimately, we are hoping to identify small peptide fragment(s) which may inhibit cell growth or invasion.
Hui-Yi und 張彗怡. „Characterize the effect of Osteopontin splice variants on cell growth and invasion in CL1-5 lung cancer cell line“. Thesis, 2009. http://ndltd.ncl.edu.tw/handle/69850174392788003831.
Der volle Inhalt der Quelle中山醫學大學
醫學分子毒理學研究所
97
Osteopontin (OPN) is a glyco-phosphoprotein independently discovered by investigators from diverse scientific backgrounds and implicated in a broad array of physiological and pathological processes. OPN exists both intra- and extracellularly and in numerous post-translational isoforms. OPN is subject to alternative splicing, which yields 3 messages, osteopontin-a (full-length), osteopontin-b (exon 5-) and osteopontin-c (exon 4-). High level of OPN expression has been found in a number of cancer types including breast, prostate, colon, head and neck, and hepatic cancers and lung cancer. Strong association of OPN expression with tumor metastasis has been established in various transformed cell lines, animal tumor models, and human cancers. These findings suggest that OPN is a key extracellular molecule involved in tumor development and progression. However, OPN splice variants have not been extensively evaluated in lung cancer. This study aimed to explore the roles of various splice forms of osteopontin in cell growth and invasion in lung cancer cell lines. The expression of OPN in lung cancer cell lines is very low except in the CL1-0,H460 and H1355 cell lines. The low invasive cell line CL1-0 expresses high level of OPN while OPN expression in high invasive cell line CL1-5 is very low. In this study, we tested the effect of OPN splice variants on growth and invasion in CL1-5 and A549 lung cancer lines. Our data showed that CL1-5 cells stably expressed OPN with deletion of exon 4 (OPN-exon4- ) or exon 5 (OPN-exon5-) had similar growth activity compared with vector control, while exogenous full-length OPN had the ability to inhibit cell growth. Interestingly, stable expression of exogenous OPN-exon4- enhanced in vitro invasive ability of CL1-5 cell compared to vector control, while OPN-exon5- did not change invasive ability. Unexpectedly, overexpression of full-length OPN inhibited CL1-5 invasion ability, and this ability is retained in contioned medium treatment. This result is rather surprising, since most studies showed that OPN enhanced, but not inhibited cell invasion. In summary, overexpression of full-length OPN reduced lung cancer cell growth and inhibited cell invasion. Overexpression of OPN-exon4- enhanced CL1-5 cell invasive ability, while OPN-exon5- has little effect on lung cancer cell growth and invasion. It is important to resolve which isoform of OPN is/are overexpressed in lung cancer and its microenvironment. Since OPN becomes a noticeable target for cancer therapy, it is important to explore the functional role of OPN splice variants in tumor growth and metastasis, and to dissect signaling pathways that involved in these mechanisms.
LIN, YI-WEN, und 林以雯. „The Study of Anti-Cancer Effect of Ligusticum chuanxiong Hort. Extract on Human Lung Cancer Cell Line CL1-5“. Thesis, 2017. http://ndltd.ncl.edu.tw/handle/83344848217820500484.
Der volle Inhalt der Quelle大葉大學
分子生物科技學系碩士班
105
Lung cancer mortality rates are the highest in the world at present disease, cancer deaths occur mainly due to cancer. There are currently many studies using natural medicine cancer metastasis and proliferation. Effect is a Traditional Chinese herb, effects have been developed to inhibit liver cancer, hyperplasia of pancreatic cancer, skin cancer, breast cancer, and promote apoptosis, but in the lung cancer study is unknow. We used lung cancer cells with high metastasis CL1-5 as a test template, with different concentrations of extracts of Ligusticum chuanxiong Hort., Ferulic acid, Tetramethylpyrazine cell lines and analyze some of the functional analysis, also used gene chips to compare different concentration effect of ferulic acid on lung cancer cell line CL1-5 gene expression after , and then through the DAVID functional annotation tool analysis downstream signal path.Results showed that Ligusticum chuanxiong Hort. extract and the biological activity of ferulic acid and tetramethylpyrazine in inhibition of lung cancer cell Proliferation, Migration, Mobility, Cell cycle, while also promoting Apoptosis. Ferulic acid can promote FAS signaling to achieve apoptosis effect; promote P21 signal CDK4/6, CDK2 was inhibited up to cell cycle inhibition in G0/G1Phase through inhibition of VEGF signaling that angiogenesis was inhibited; dampen TRAF2/5 and metastasis inhibition. These experiments have confirmed that extracts of Ligusticum chuanxiong Hort. and their biological activity of ferulic acid and tetramethylpyrazine in inhibition of lung cancer cell proliferation and metastasis, can also promote apoptosis. Key words: lung cancer, Ligusticum chuanxiong Hort., cell cycle, apoptosis, metastasis
Kuo, Chin-Jung, und 郭瑾融. „A non-covalent small inhibitor blocking β-tubulin:CCT-β complex induces apoptosis and suppresses migration and invasionin CL1-5 cells“. Thesis, 2019. http://ndltd.ncl.edu.tw/handle/yj45b7.
Der volle Inhalt der Quelle國立臺灣大學
生化科學研究所
107
Previously, we reported the protein-protein interaction (PPI) between β-tubulin and CCT-β complex as a potential anti-cancer chemotherapeutic target. Through virtual screening, a compound 3112210 from Sigma-Aldrich compound bank was identified to be a reversible inhibitor of the PPI by docking into hot spots on this PPI interface of β- tubulin. In this study, 3112210 was tested on a highly metastatic non-small cell lung cancer (NSCLC) cell line, CL1-5. The co-IP experiments showed that, in 3112210-treated cancer cells, β-tubulin and CCT-β complex was disrupted. Furthermore, 3112210 caused CL1-5 cell death through ER stress and apoptosis. In addition to verifying its toxicity toward CL1-5, we performed migration and invasion assays using dosage at about IC20. The results indicated that 3112210 also inhibited cancer cell migration and invasion, and MMP-2, -9 were also inhibited. These anti-metastatic effects were endowed via integrin- related pathways and EMT transcriptional factors, as demonstrated by western blot experiments. To sum, 3112210 is a novel non-covalent inhibitor for β-tubulin:CCT-β complex in CL1-5 lung adenocarcinoma cells to induce cancer cell death and impeded cell metastasis.
陳美妤. „The role of integrin β3 and fibroblasts in OPN-a isoform mediated growth regulation in CL1-5 lung cancer cell line“. Thesis, 2011. http://ndltd.ncl.edu.tw/handle/86224130108290881934.
Der volle Inhalt der Quelle中山醫學大學
醫學分子毒理學研究所
99
Osteopontin (OPN) is a glyco-phosphoprotein which is overexpressed in many cancers. The expressin of OPN is significantly correlated with tumor metastasis. Three OPN splicing variants, OPN-a, OPN-b and OPN-c, were identified and the expression of OPN-a is the highest among them in patients with lung cancer tissue and cancer cell lines. Different splicing variants of OPN have distinct impact on the growth and invasion of lung cancer cell lines. It is surprising that the full-length OPN (OPN-a) inhibited CL1-5 cell growth and invasion, and also inhibited invasion of A549 cells but had no effect on cell growth. We further confirmed that the differences of the effect on cell growth by OPN-a between CL1-5 and A549 was due to the diferential expression level of integrin β3 (ITGβ3). Knock-down the expression of ITGβ3 in CL1-5, blocked the effect of OPN-a mediated growth inhibition. On the other hand, overexpression of ITGβ3 in A549, exhibited OPN-a induced growth inhibition. Interestingly, in the absence of ITGβ3, OPN-a not only lost growth inhibition ability but promoted cell growth through NFκB pathway. Although ITGβ3 is required for OPN-a mediated growth inhibition, knock-down expression of ITG 3 almost completely inhibited growth of CL1-5 in the absence of OPN-a. Our results suggested that ITGβ3 is essential for the growth of CL1-5; however, ITGβ3 is no longer required if cells express OPN-a. Thus, the growth rate of CL1-5 may be subjected to the balance between OPN-a and ITGβ3 levels. The growth and invasion inhibitory roles of OPN-a in lung cancer cells are contradictory to the well recognized oncogenic role of OPN. Therefore, we hypothesized that the expression of OPN may promote cross-talk between cancer cells and its microenvironment. Our results showed that conditioned medium collected from fibroblasts treated with tumor secreted OPN-a greatly enhanced growth of CL1-5 cells, but had no effect on the ability of invasion. Thus, although OPN-a secreted by lung cancer cells would inhibit CL1-5 cell growth through autocrine pathway, the secreted OPN-a can activate fibroblast cells through paracrine pathway to secrete growth factor or cytokines that in turn promotes cancer cell growth. Moreover, cancer cells may reverse OPN-a mediated growth inhibition to growth enhancement by down-regulation the expression of ITGβ3. This study reveals two aspects on OPN-a regulated cancer cell growth: one is OPN-a mediated cross-talk between tumor and microenvironment; the other is regualated by the expression levels of different OPN receptors. Therefore, simutaneouly targeting several different receptors may be required in order to inhibit growth of lung cancer cells with overexperssed OPN-a.
Sz-Yu und 劉思妤. „Characterize the effect of different domain of slit2 C terminal on cell growth and invasion in CL1-5 lung cancer cell line“. Thesis, 2010. http://ndltd.ncl.edu.tw/handle/05297408913015078762.
Der volle Inhalt der Quelle中山醫學大學
醫學分子毒理學研究所
98
Slit2 is a 200 kDa secreted glycoprotein. Its role in axon repellent and cell migration were extensively studied in different systems. Recent studies pointed that slit2 possesses tumor suppressor activity by inhibition of tumor growth and invasion. We discovered different exon15 splicing isoforms during slit2 cDNA cloning. With exon 15, Slit2-WT inhibited cell invasion of CL1-5 lung cancer cells, while without exon15, Slit2-△E15 not only inhibited cell invasion but also inhibited cell growth. Previous studies showed that Slit2 can be cleaved into two fragments in neuron cells: a 140 kDa slit2-N terminal fragment; and a 55-60 kDa slit2-C terminal fragment. Previously, we discovered that slit2-C terminal protein can inhibit cell growth and cell invasion. To identify which domain(s) is/are involved in Slit-△E15-mediated growth and/or invasion inhibition activity, we deleted individual domain on slit2-△E15 cDNA. Our studies showed that Slit2-△E15 lacking EGF6-LamG domains lost the ability to inhibit cell growth and cell invasion. To clarify whether the EGF6-LamG domains play a modulation role in Slit2-△E15-mediated growth and invasion inhibition indirectly or these domains possess direct role in growth and/or invasion inhibition? We constructed and expressed individual domain of slit2-C terminal. We found that the C-terminal region of LamG domain (LamG-C; a.a.(1228-1318)) by itself possessed ability to inhibit cell growth but not cell invasion. Our results also suggested that the N-terminal of LamG domain (LamG-N; a.a. (1182-1227)) has an effect on slit2-△E15-mediated cell invasion, but we were unable to resolve whether LamG-N inhibits cell invasion by itself. Thus, we are currently narrow-down the peptide domain in EGF6 and LamG regions, and identify the minimum peptide domain(s) that has/have ability to inhibit cell growth and invasion. Furthermore, we will investigate the receptor(s) involved in slit2-mediated growth and invasion inhibition.
Kuo, Yu-Ting, und 郭育廷. „Disrupting β-tubulin/CCT-β complexes induces apoptosis and suppresses migration and invasion of CL1-5 cells through MMP-2 and AKT/GSK-3β inhibition“. Thesis, 2017. http://ndltd.ncl.edu.tw/handle/4jgwn2.
Der volle Inhalt der Quelle國立臺灣大學
生化科學研究所
105
We have previously demonstrated that I-Trp with an iodomethyl ketone warhead to alkylate Cys354 of β-tubulin, thereby disrupting the protein-protein interaction (PPI) of -tubulin with chaperonin-containing TCP-1β (CCT-β), causes cancer cell apoptosis [1]. In this study, we found that in CL1-5 cells, I-Trp activates both ER stress related proteins and proteasome activity to eliminate the imbalance proteins loading in ER, thereby mitigating ER stress, at the onset of β-tubulin/CCT-β complexes disruption. In addition, ER stress-associated apoptotic signaling is usually accompanied with intracellular Ca2+ release and the activation of MAPKs. We also observed the elevated intracellular Ca2+ levels, activation of MAPKs and caspase over-activation. Since CL1-5 cells are a highly metastatic lung cancer cell line, we assayed for its migration/invasion in the presence of I-Trp, where there were 80% survived cells to ensure most of the cells were not killed. The experimental results demonstrate the dose-dependent inhibition of CL1-5 cell migration and invasion. Furthermore, the mechanistic studies revealed that I-Trp inhibited phosphorylation AKT, and GSK-3β of CL1-5 cells, thereby downregulating MMP-2 expression and activation. In conclusion, this study reveals a novel therapeutic strategy potential for evoking apoptotic signaling by targeting β-tubulin/CCT-β complexes, and its anti-migration/invasion activity against human lung adenocarcinoma.