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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

Pin1-£]-catenin-cyclin D1 as a potential chemotherapy target for esophageal squamous cell carcinoma

Li, Yu-Cheng 16 August 2006 (has links)
It has been demonstrated that overexpression of Pin1, a novel cell cycle regulator, in human breast cancer and might play an important role in tumorigenesis. However, the role of Pin1 and whether Pin1 is overexpressed in esophageal squamous cell carcinoma (ESCC) remained unclear. There are two specific aims in this study. The first specific aim is to study the correlation between Pin1 and human ESCC cancer. The second specific aim is to discover drugs that can intervent the Pin1 mediated signaling and provide a novel chemotherapy for human ESCC. In this dissertation, we have demonstrated that Pin1 was overexpressed in more than 65% of clinical esophageal cancer tissues and its level correlated with £]-catenin and Cyclin D1 expression by western blotting and immunohistochemistry analyses. The RT-PCR results suggested that Pin1 overexpression maybe due to the up-regulation of Pin1 transcription. By statistic analysis, we have demonstrated that ESCC patients with Pin1 overexpression had significantly poorer survival rate than those non-Pin1 overexpression patients (p< 0.001). Pin1 therefore can be used as a prognosis marker for ESCC. In addition, we have demonstrated that Pin1 suppression by shRNA could downregulate £]-catenin and Cyclin D1 expression and inhibit ESCC cell proliferation efficiently. Taken together, these results suggest that Pin1-£]-catenin and Cyclin D1 could be used as a potential chemotherapy target for ESCC. In order to discover novel drugs in the chemoprevention or therapy of human ESCC, we screened a chemical library using cell proliferation assay. Among them, compound VGHKS-040 not only effectively inhibited the cell proliferation rate in ESCC cell lines with IC50 value of 4.8¡Ó0.6£gM but also abated protein levels of Pin1, £]-catenin, and cyclin D1. By colony forming assay as well as the Xenograft SCID and nude mice model, we have demonstrated that VGHKS-040 can inhibit the tumor growth in vitro and in vivo. These results suggested that VGHKS-040 provide a new avenue for chemotherapy of esophageal squamous cell carcinoma.
2

Phosphorylation and Functional Regulation of Alzheimer's Tau by GSK3-beta and Prolyl Isomerase Pin1

Ko, Chiung-Yuan 17 June 2003 (has links)
Alzheimer¡¦s disease (AD), one of the most common dementia, is characterized by the formation two types of aggregation in the brain: senile plaques and neurofibrillary tangles (NFTs). NFTs are composed of hyperphosphorylated Tau. Tau protein mainly expressed in brain and was identified as one of the microtubule-associated proteins (MAPs). Hyperphophorylation on Tau affects its binding to tubulin and capacity to promote microtubule assembly. A number of proline-directed kinase capable of phosphorylating PHF-Tau have been identified, including Glycogen Synthase Kinase-3£] (GSK-3£]). Here we demonstrated that GSK3£] can co-purify with PHFs and can co-localize with Tau in vitro in N18 cells. To examine the phosphorylation mechanism of Tau by GSK-3£], N-terminal, C-terminal, T231A, T231E, 154~441, S396A, S400A, S404A, S413A and S396A S400A mutants of Tau were used, respectively. We were able to demonstrate that phosphorylation on Thr231 and Ser404 in Tau may play important roles for GSK3£] phosphorylation and its functional regulation. Most importantly, we have proved that T231P motif is necessary and critical for Tau phosphorylation by GSK3£]. Moreover, we used T231E, S396E and S400E mutants of Tau to understand the functional regulation of Tau by GSK3£] phosphorylation by tubulin assembly assay. Surprisingly, we observed all of these Tau mutants can promote tubulin assembly and form tubulin bundles in N18 cells. It has been proved that Pin1 WW domain can bind to Cdc2-phosphorylated Thr-231-Pro motif of Tau and restore the ability of Tau to promote tubulin assembly. In this study, we also studied whether Pin1 can regulate GSK3£]- phosphorylated Tau. The results show that Pin1 WW domain can bind to phosphorylated Thr-231 of Tau by GSK3£] and restore the ability of Tau to promote tubulin assembly.
3

Vliv strigolaktonu na větvení stonku rostlin a polární transport auxinu

Daňková, Nela January 2012 (has links)
No description available.
4

Understanding Binding-Induced Conformational Change in the Pin1 Prolyl Isomerase

Gyamfi, Hawa 14 December 2013 (has links)
Pin1 is a Prolyl Isomerase that catalyzes cis-trans isomerization of peptides with pSer/Thr-Pro motifs in many cell signaling proteins. This conformational switch is implicated in diseases. Pin1 activity is considered a target for therapeutic applications. Pin1 targets motifs by its N-terminal WW-binding domain. A C-terminal PPIase domain is responsible for catalysis. To understand how Pin1 coordinates its enzymatic activities, it is necessary to probe how the domains behave in the presence of substrates. Here, we used novel (Histone H1 and Sic1) and other existing peptides to characterize the dynamics of Pin1 and impact of substrate binding on inter-domain interactions. Pin1- peptide complexes have been used to show that peptide addition causes a conformational change in the two domains. 15N-relaxation data suggest that the flexibility of these domains depends on the substrate peptide We have constructed a hypothesis about which substrate residues may be important for conferring tight binding and inter-domain interactions.
5

Étude du rôle de PIN1 dans la régulation de la signalisation NOTCH et la croissance des cellules pancréatiques tumorales humaines

Paré, Émanuel January 2016 (has links)
Le manque d’outils diagnostiques et thérapeutiques efficaces font de l’adénocarcinome ductal pancréatique le cancer le plus létal pour les Canadiens, avec son taux de survie à 5 ans de 8 %. Il est caractérisé par une fréquence élevée de mutations de RAS (90 %) qui est requise pour l’initiation et le maintien de la carcinogenèse. De plus, il a été démontré qu’une activation aberrante de la voie de signalisation NOTCH coopère avec la signalisation RAS dans la promotion de la carcinogenèse pancréatique. La famille NOTCH comprend quatre récepteurs transmembranaires qui subissent une série de clivages protéolytiques suite à la liaison avec leurs ligands. Ces clivages permettent la libération du domaine intracellulaire de NOTCH (NIC) dans le cytosol. NIC transloque ensuite au noyau pour s’associer avec ses partenaires transcriptionnels CSL et MAML1 et favoriser l’expression de gènes cibles tels qu’HES1. Nous avons récemment démontré que l’activation des sérine/thréonine kinases ERK1/2, en aval de RAS, promeut l’expression d’HES1 de façon NOTCH-dépendante dans les cellules pancréatiques tumorales humaines. Bien que cela suggère une interaction entre les voies ERK et NOTCH, les mécanismes sous-jacents cette interaction restent à être identifiés. Il a été suggéré que PIN1, une prolyl-isomérase qui reconnait spécifiquement des résidus proline lorsque ceux-ci sont précédés d’une sérine ou d’une thréonine phosphorylée, interagit avec NIC1. Ainsi, nous avons émis l’hypothèse que la prolyl-isomérase PIN1 régule l’activité de la voie NOTCH et a un effet positif sur la croissance des cellules pancréatiques tumorales humaines. Pour y répondre, un modèle stable de cellules pancréatiques tumorales humaines MIAPaCa2 exprimant un shARN dirigé contre PIN1 a été généré. Nous avons démontré que PIN1 et la voie RAS/RAF/MEK/ERK régulent positivement les niveaux d’expression de NIC1. De plus, les niveaux d’expression de PIN1 régulent positivement les niveaux d’expression du récepteur NOTCH1 et du ligand DLL3 sans influencer les niveaux d’expression du récepteur NOTCH3 et des ligands JAGGED 1 et JAGGED 2. PIN1 a une influence positive sur les niveaux d’expression des gènes cibles de la voie NOTCH c-MYC et cycline D1 et une influence négative sur les niveaux d’expression d’HES1. Cette étude a également démontré que les niveaux d’expression de PIN1 influencent positivement la croissance en 2D ainsi que certains régulateurs du cycle cellulaire. Lorsque les cellules MIAPaCa2 sont ensemencées à faible densité, la taille des clones formés est influencée à la fois par les niveaux d’expression de PIN1 et par la voie RAS/RAF/MEK/ERK. Cependant, dans un contexte de croissance en indépendance d’ancrage, PIN1 influence négativement la croissance des cellules MIAPaCa2. Cette étude a démontré que PIN1 pouvait influencer le phénotype des cellules pancréatiques humaines. De plus, l’étude des mécanismes de régulation de la voie NOTCH a révélé une régulation complexe impliquant PIN1.
6

Pin1 Overexpression in Hepatocellular Carcinoma

Weng, Wei-Teng 05 July 2006 (has links)
By Western blotting and immunohistochemical analyses, we have demonstrated that Pin1 was overexpressed in 71.4% of hepatocellular carcinoma (HCC) and its levels correlated with the clinical survival rate. This conclusion was supported by the results from examining Pin1 protein in HCC cancer cell lines. RT-PCR was performed to examine the Pin1 transcription level in tumor part and was compared with that in non-tumor part. Our results indicated that pin1 overexpression was due to the upregulation of Pin1 transcription. Interestingly, most of the cases with upregulation of Pin1 have been shown to correlate with £]-catenin and Cyclin D1 accumulation in HCC specimens. These results were consistent with the previous studies that Pin1 caused £]-catenin and Cyclin D1 elevation in breast cancer. The concordance between hepatitis virus chronic infection and Pin1 overexpression of HCC patients was also analysis. Taken together, these data indicated that Pin1 overexpression leading to £]-catenin and Cyclin D1 accumulation might play a critical role in hepatocellular carcinogenesis and tumor progression. Pin1 levels therefore can be used as a prognostic marker for HCC, and our results suggested that Pin1 is a potential target for therapeutic intervention in hepatocellular carcinoma.
7

Interaction and Regulation of beta-Amyloid Precursor Protein by APPBP1 and Pin1

Guo, Jia-Wen 17 July 2002 (has links)
b-amyloid is derived from amyloid precursor protein (APP) and tightly associated with the pathogenesis of Alzheimer¡¦s disease (AD). Structurally, APP belongs to type I transmembrane protein family and is composed of a large glycosylated extracellular component, a single membrane-spanning region, and a short cytoplasmic domain. Although physiological function of APP remains unclear, the proteolytic processing of APP by b secretase and g secretase gives rise to the production and secretion of b-amyloid. The C-terminus of APP is believed to participate in the intracellular trafficking of APP and signal transduction via interacting with adaptors and signaling proteins, respectively. Three phosphorylation sites (Thr654, Ser655 and Thr668, numbering for APP695 isoform) and several functional motifs in the cytoplasmic domain of APP have been identified and demonstrated that the phosphorylation can indeed affect APP metabolism including: the rate of secretion, endocytosis and b-amyloid production. In this study, we focused on how APP binding protein1 and the phosphorylation affect on APP metabolism. The reasons are as following: (1) Among many APP associated proteins, APP binding protein 1 (APPBP1) is involved in S-M checkpoint regulation. (2) Recent evidence indicates that aberrantly activation of mitotic events may play an important role in development of AD. Since progression through mitosis is regulated by Cdc2 that has been demonstrated to phosphorylate APP on Thr668-Pro669, the phosphorylation of APP at Thr668 may play the important role in regulating APP metabolism and may also relate to AD development. (3) Moreover, protein phosphorylation induces the conformational change and affects the protein- protein interaction. Phosphorylation of Ser / Thr-Pro motif is a central mechanism controlling progression of the cell cycle, including mitosis. Proline residues provide a potential backbone switch in the polypeptide chain controlled by the cis / trans isomerization. Pin1 is an important mitotic regulator and a highly specific peptidyl-prolyl cis / trans isomerases (PPIase) that catalyzes the isomerization of phosphorylated Ser / Thr-Pro bonds. Our unpublished data have shown that Pin1 can bind to the phosphorylated Thr668-Pro669 APP peptide with high affinity (20 nM) that suggested that Pin1 may interact and regulate mitotic APP. Taken together, these data suggested that the interaction of APP and APPBP1 or Pin1 may affect the APP metabolism and its physiological function. This study investigated the hypothesis above and revealed includes the following results (i) the subcellular localization of the C-terminus of APP and APPBP1; (ii) the interaction between APPBP1 and the C-terminus of APP in vivo and in vitro; (iii) Thr668 of APP is the Cdc2 phosphorylation site; (iv) the binding of APPBP1 to the C-terminus of APP reduces the phosphorylation of APP by Cdc2; (v) the phosphorylation at Thr668 can abolish the interaction between APPBP1 and the C-terminus of APP; (vi) the C-terminus of APP is one of the caspase 3 targets; (vii) the phosphorylation of APP at Thr668 also reduces the caspase 3 activity forward to the C-terminus of APP cleavage; (viii) both APPBP1 and Pin1 can inhibit the C-terminus of APP cleavage by caspase 3 that suggested two novel mechanisms to regulate APP metabolism.
8

Pin1: WW domain ligands, catalytic inhibitors, and the mechanism

Mercedes-Camacho, Ana Yokayra 25 May 2011 (has links)
The peptidyl prolyl cis/trans isomerase, PPIase, has been the focus of numerous studies in the field of cell cycle regulation since proline-directed phosphorylation is an essential signaling mechanism that might arrest cancer proliferation. Pin1 is the first phosphorylation-dependent PPIase enzyme to be discovered. The Pin1 regulatory mechanism, acting on other mitotic proteins in vivo and in vitro, remains largely unknown. For the study of Pin1 function, two types of assays were used to identity ligands for Pin1: (1) The Enzyme-Linked Enzyme Binding Assay (ELEBA) for the identification of WW domain ligands, (2) a catalytic assay to identified inhibitors of Pin1 catalytic activity. The ELEBA offers a selective approach for detecting ligands that bind to the Pin1 WW domain from chemical libraries. By using the ELEBA, a pSer-Pro peptidomimetic library of 315 ligands was screened, identifying three promising ligands cis-D2, O2, and M18. Competitive Kd values for cis-D2, O2, and M18 were determined to be 263 ± 6.4, 206 ± 3.4, and 130 ± 3.0μM, respectively. Furthermore, we screened the pSer-Pro peptidomimetic library using a Pin1 discontinuous-catalytic assay to identify inhibitors of Pin1. Ligands D20 and K7 were identified to decrease more than 90% of the Pin1 catalytic activity. To investigate the nature of the Pin1 interaction with c-Myc, we synthesized and characterized four peptides corresponding to the c-Myc sequence. These peptides were used in NMR isomerization studies of Pin1 by our collaborator Dr. Jeffry Peng (University of Notre Dame). Preliminary work shows that Pin1 binds and isomerizes the Ac–LLPpTPPLSPS–NH₂ peptide at the cMyc pThr58 position. Finally, we measured a secondary kinetic isotope effect (2º KIE) to study the Pin1 catalytic mechanism of proline isomerization. The ratio of kH/kD for unlabeled and [d₃]Ser-labeled substrate gave a SKIE value of 1.34 ± 0.01. The normal 2º KIE value indicates that carbonyl-serine hybridization is not changing from sp² to sp³. This result supports substrate analogue inhibitor studies, and previous solvent and SKIE results on Pin1, that suggest a twisted amide mechanism assisted by a transient hydrogen bond in the transition state. / Ph. D.
9

Development of Bicyclic Peptidyl Inhibitors against Peptidyl-Prolyl Isomerase Pin1

Jiang, Bisheng 19 May 2015 (has links)
No description available.
10

Characterization of Novel Extracellular and Intracellular Modifiers of Apurinic/Apyrimidinic Endonuclease 1

Stevens, Rachel L. 08 September 2010 (has links)
No description available.

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