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1
Gundurao, Ramya Mavinkaihalli. "Systematic analysis of protein-protein interactions of oncogenic Human Papilloma Virus." Thesis, University of Edinburgh, 2013. http://hdl.handle.net/1842/8829.
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Human papilloma virus (HPV) is a ubiquitous virus implicated in a growing list of cancers, particularly cervical cancer‐ the second most common cancer among women worldwide. Although persistent infection with high‐risk oncogenic HPVs such as types ‐16 or ‐18 is necessary, additional factors like co‐infection with other viruses can play a role in cancer progression. Protein‐protein interactions play a central role in the infection, survival and proliferation of the virus in the host. Although some interactions of HPV proteins are well characterised, it is essential to discover other key viral interactions to further improve our understanding of the virus and to use this knowledge for the development of newer biomarkers and therapeutics. The aim of this study was to systematically analyse the interactions of HPV‐16 proteins using yeast two‐hybrid (Y2H). To achieve this, a clone collection of the viral proteome was generated by recombinatorial cloning and three independent Y2H screens were performed: (i) Intra‐viral screen to identify interactions among the HPV‐16 proteins; (ii) Inter‐viral screen to identify interactions with proteins of Herpes Simplex Virus (HSV) which is suggested to be a co‐factor; and (iii) Virus‐host screen to identify novel cellular binding partners. The intra‐viral Y2H screen confirmed some of the previously known interactions and also identified binding of the E1 and E7 proteins. Deletion mutagenesis was performed to map the interaction domains to the amino‐terminal 92 amino acids of E1 and carboxy‐terminal CxxC domain of E7. Replication assays suggest a possible repression of E1‐mediated episomal replication by direct binding of E7. The inter‐viral Y2H screen identified interactions of HPV proteins with seventeen HSV‐1 proteins including transcriptional regulator ICP4 and neurovirulance factor ICP34.5. The biological relevance of these interactions in the context of co‐infection is discussed. The virus‐host screen performed against a human cDNA library identified 54 interactions, a subset of which was validated by biochemical pull‐down assays. The functional relevance of an interaction between E7 and a proto‐oncogene spermatogenic leucine zipper protein (SPZ1) was further investigated suggesting a role of SPZ1 in E7‐mediated cell proliferation. The work presented in this thesis identifies several novel interactions of HPV proteins. Future work will involve the in‐depth elucidation of biological relevance of these interactions. In particular, the interactions of E7 with E1 and SPZ1 are of great interest to improve our understanding of the life cycle and pathogenesis of the virus which can be applied for improved strategies of prevention and treatment of malignancies caused by HPV.
2
Sumner, Evan T. "Characterizing the Oncogenic Properties of C-terminal Binding Protein." VCU Scholars Compass, 2016. http://scholarscompass.vcu.edu/etd/4153.
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The paralogous C-terminal binding proteins (CtBP) 1 and 2 are evolutionarily conserved transcriptional coregulators that target and disrupt the expression of several genes essential for multiple cellular processes critical to regulating tumor formation. CtBP’s ability to govern the transcription of genes necessary for apoptosis, tumor suppression, invasion/migration and EMT gives rise to its oncogenic activities. Both isoforms of CtBP are found to be overexpressed in cancers including colorectal, pancreatic, ovarian, and breast, with higher levels correlating to lower overall median survival. Although multiple lines of evidence suggest CtBP plays a role in tumorigenesis, it has never been formally characterized as an oncogene. For this reason, the goal of this dissertation was to design a set of experiments to determine the transforming ability of CtBP2 in vitro using both murine and human fibroblast and in vivo using the Apcmin/+ mouse model of cancer. Specifically, we demonstrate that overexpression of CtBP2 alone can drive transformation of NIH3T3 cells leading to loss of contact inhibition, increased x invasion/migration, and anchorage independent growth. In addition, CtBP2 was found to cooperate with the large T-antigen (LT) component of the simian virus 40 (SV40) to lead to transformation of murine embryonic fibroblasts (MEFs) and with both LT and small T-antigen (ST) to induce migration/invasion and anchorage-independent growth in BJ human foreskin fibroblasts. To confirm the role of Ctbp2 in a mouse tumor model with Ctbp overexpression, we bred Apcmin/+ mice to Ctbp2 heterozygous (Ctbp2+/-) mice, which otherwise live normal lifespans. CtBP is a known target of the APC tumor suppressor and is thus stabilized in APC mutated human colon cancers and is found in high levels in Apcmin/+ polyps. Remarkably, removing an allele of Ctbp2 doubled the median survival of Apcmin/+ mice (P <0.001) and reduced polyp formation to near undetectable levels. These data suggest the importance of CtBP2 in driving cellular transformation and identify it as a potential target for prevention or therapy in APC mutant backgrounds.
3
Dubé, Nadia Marie-Noël. "Protein tyrosine phosphatase 1B regulates metabolic, oncogenic, and hematopoietic function." Thesis, McGill University, 2004. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=85155.
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Protein tyrosine phosphatase 1B (PTP1B) is a ubiquitously expressed enzyme that is involved in multiple signaling pathways. Biochemical and substrate trapping studies have implicated PTP1B in the dephosphorylation of various tyrosine kinases, including the EGFR, PDGFR, IR, IGF-IR, JAK2, p210Bcr-Abl, and Src. Of particular interest, gene-targeting studies in mice have established PTP1B as a critical physiological regulator of metabolism by attenuating insulin and leptin signaling. Indeed, PTP1B null mice exhibit resistance to diet-induced diabetes and obesity. Although PTP1B is involved in signaling pathways that contribute to oncogenesis, PTP1B null mice do not develop spontaneous tumors. Therefore, my doctoral research focuses on identifying the physiological significance of PTP1B in these pathways. Our laboratory has previously demonstrated that PTP1B modulates leptin signaling via the tyrosine kinase JAK2. Accordingly, I have shown that PTP1B dephosphorylates JAK2 in a growth hormone (GH)-dependent manner, thus negatively regulating GH signaling and downstream effectors such as STAT3 and STAT5. Consequently, mice lacking PTP1B remain sensitive to GH action after starvation. In addition, I showed that the absence of PTP1B could improve glycemia during streptozotocin-induced type 1 diabetes. In the second part of my research, I have elucidated the mechanism for the previously reported decreased ERK activation in PTP1B null fibroblasts. I demonstrated that Ras activity is reduced in these cells, which is due to increased p120RasGAP expression and p62Dok hyperphosphorylation. Both of these molecules negatively regulate Ras activity by promoting the intrinsic GTPase activity of Ras, leading to decreased ERK activation. Finally, I developed a mouse model of cancer to study the role of PTP1B in tumorigenesis. Since the majority of cancers harbor mutations in p53, I generated p53/PTP1B double null mice. In the absence of p53, PTP1B heterozygous
4
Quill, Lee. "Fragment-based screening of the oncogenic protein tyrosine phosphatase SHP2." Thesis, University of Birmingham, 2017. http://etheses.bham.ac.uk//id/eprint/7425/.
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Protein tyrosine phosphatases represent a family of signalling enzymes with emerging therapeutic potential. The cytoplasmic protein tyrosine phosphatase SHP2, encoded by the PTPN11 gene, plays a central role in the activation of downstream signalling events at multiple growth factor and cytokine receptors, and was the first oncogenic protein tyrosine phosphatase to be discovered. Aberrant SHP2 signalling underlies the pathology of numerous developmental disorders such as Noonan and LEOPARD syndrome, and is a known driver of breast cancer and myeloproliferative disease. To gain a deeper insight into ligand interactions with the SHP2 catalytic domain in solution, NMR backbone resonance assignments of the 34 KDa SHP2 catalytic domain were determined and utilised in conjunction with 15N-1H HSQC NMR spectroscopy to map the structurally undisclosed binding site of the previously reported SHP2 inhibitor, NSC-87877. In addition, use of a fragment-based screening approach to accelerate the discovery of novel SHP2 inhibitors has enabled the identification of two novel and distinct chemical scaffolds, both of which now serve as validated chemical precursors for the development of more potent SHP2 lead inhibitors.
5
Tse, Wai Choi Eric. "Studies of oncogenic protein function and potential for cancer therapy." Thesis, University of Cambridge, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.620964.
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Cen, Ling. "Phosphorylation profiling and targeting of oncogenic signaling proteins in cancer cells." Columbus, Ohio : Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1186666790.
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7
徐智 and Zhi Xu. "Yes associated protein (YAP) in hepatocellular carcinoma: oncogenic functions and molecular targeting." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2009. http://hub.hku.hk/bib/B43278589.
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Xu, Zhi. "Yes associated protein (YAP) in hepatocellular carcinoma oncogenic functions and molecular targeting /." Click to view the E-thesis via HKUTO, 2009. http://sunzi.lib.hku.hk/hkuto/record/B43278589.
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9
Marchetti, Laura. "Dynamics and interactions of an oncogenic homeotic protein within human replicative complexes." Doctoral thesis, Scuola Normale Superiore, 2010. http://hdl.handle.net/11384/85944.
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The regulation of human DNA replication operates via the time-programmed activation
and deactivation of approximately 30,000 replication origins distributed along the
genome. A multi-protein replicative complex recognizes and assembles onto each
origin; this determines the local unwinding of the origin DNA and the start of two
oppositely moving replicative forks. The mechanism that governs the selection of a
specific DNA sequence as human (and, more generally, metazoan) origin, in the course of G1 phase of the cell-cycle, is still poorly understood. The lack of DNA-sequence consensus among well-characterized replication origins, together with the little bindingspecificity displayed by the Origin Recognition Complex, suggest that origin selection might rather be determined by local chromatin structures and/or accessory targeting proteins. With regard to the latter possibility, it was interesting to find out that three homeotic proteins, namely HOXC13, HOXC10, and HOXA13 display a specific affinity for a DNA fragment corresponding to the sequence covered by the Replicative Complex of the human Lamin B2 replication origin.
In the study conducted during this Ph.D. program, the possible role of homeotic
proteins in origin function was explored by investigating the involvement of a selected homeotic protein, namely HOXC13, within the replicative complexes in living human cells. To this purpose, recent advances in biophysical microscopy technologies were exploited to study in vivo the localization, dynamics, and interactions of HOXC13 protein in the context of DNA replication regulation. The data reported in this thesis demonstrate that HOXC13 indeed participates in origin function. The protein is a stable component of early replicating chromatin, as it displays stable chromatin binding in
correspondence to the nuclear areas where replication foci of early S phase are
collected. This peculiar behavior is driven by the homeodomain and relies mainly on the
conserved homeodomain arginine-5 anchoring to the DNA minor groove. Furthermore,
HOXC13 displays unambiguous affinity for origin sequences and for selected
replicative-complex proteins. The close proximity of HOXC13 to both Cdc6 and ORC2
proteins measured in living cells proves that the homeotic protein is involved in direct
protein-protein interactions within the replicative-complex; not unexpectedly, such
interactions are modulated in a cell-cycle dependent fashion that is consistent with
origin function. These observations are not restricted to a single origin, but rather appear to have a
general significance in the nuclear architecture of DNA replication; nor are they
restricted to a single homeotic protein, as the HOXC13 exerts its function via highly
conserved homeodomain residues. Hence, this dissertation argues that the
homeoproteins functionally contribute in a general manner, dependent on their
chromatin-binding properties, to the specification of origins, likely the early replicating
ones. In this view, HOX proteins, probably in the context of a multi-protein homeotic
effector, contribute to recruit and stabilize the replicative complexes onto early
replicating origins, in presence of specific chromatin and topological configurations.
Considering that HOXC13, involved in development and differentiation, is also an
oncoprotein, the data presented in this thesis, besides offering an indication for the basis
of origin selection, hint at the homeotic proteins as actors in the cross-talk between
development and DNA replication regulation.
10
Green, Melanie M. L. "A study of carcinogenesis involving expression of the Epstein-Barr virus onco-protein LMPI." Thesis, King's College London (University of London), 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.368906.
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Curran, John Andrew. "The oncogenic activity of the latent membrane protein of EBV in transgenic mice." Thesis, University of Glasgow, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.388552.
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Rosa, Jack. "Perturbation and Modulation of Microtubule Cytoskeletal Elements in Response to the Potentially Oncogenic Molecules, Survivin and P53, and Cytokinesis: A Dissertation." eScholarship@UMMS, 2006. https://escholarship.umassmed.edu/gsbs_diss/280.
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A complex network of protein filaments collectively known as the cytoskeleton carries out several crucial cellular processes. These functions include, but are not limited to, motility, cell shape, mitosis and organelle trafficking. The cytoskeleton is also highly responsive, allowing the cell to alter its shape in response to its immediate needs and environment. One of the major components of the cytoskeleton is the microtubule network. To refer to the array of micro tubules in the cell as a skeleton is a misnomer. Microtubules, by virtue of their structure and nature, are highly dynamic, continuously growing and shrinking. They also bind a variety of accessory molecules that aid in regulating and directing their dynamic activity. In this way they provide a structural basis for integral cell functions that require rapid assembly and disassembly. In some cases, perturbations of the microtubule network results in structural anomalies that lead to undesirable outcomes for the cell, namely chromosomal missegregation events and instability. The accumulation of these events may induce aneuploidy, which has been a fundamental component of tumorigenesis. This dissertation examines the role of the microtubule cytoskeleton within three distinct contexts. The first chapter investigates the association of the anti-apoptotic protein survivin with the microtubule network and its potential impact upon the cell from interphase to cytokinesis. The second chapter of this dissertation explores a little-studied, microtubule-dense organelle, referred to as the midbody, and the highly orchestrated events that take place within it during cytokinesis. The third and final chapter describes a unique experimental condition that may further our understanding of the interaction between the tumor suppressor p53 and the centrosome in cell cycle regulation and tumorigenesis.
13
Ratnayake, Wishrawana Sarathi Bandara. "Role of Oncogenic Protein Kinase C-iota in Melanoma Progression; A Study Based on Atypical Protein Kinase-C Inhibitors." Scholar Commons, 2019. https://scholarcommons.usf.edu/etd/7895.
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Irrespective of plentiful efforts to enhance primary prevention and early detection, the number of melanoma cases in the United States has increased steadily over the past 30 years, thus greatly affecting public health and the economy. We have investigated the effects of five novel aPKC inhibitors; 2-acetyl-1,3-cyclopentanedione (ACPD), 3,4-Diaminonaphthalene-2,7-disulfonic acid (DNDA), [4-(5-amino-4-carbamoylimidazol-1-yl)-2,3-dihydroxycyclopentyl] methyl dihydrogen phosphate (ICA-1T) along with its nucleoside analog 5-amino-1-((1R,2S,3S,4R)-2,3-dihydroxy-4-methylcyclopentyl)-1H-imidazole-4-carboxamide (ICA-1S) and 8-hydroxy-1,3,6-naphthalenetrisulfonic acid (ζ-Stat) on cell proliferation, apoptosis, migration and invasion of two malignant melanoma cell lines compared to normal melanocyte cell lines. Molecular docking data suggested that both ACPD and DNDA specifically bind to protein kinase C-zeta (PKC-ζ) and PKC-iota (PKC-ι) while both ICA-1 compounds specifically bind to PKC-ι, and ζ-Stat showed a high affinity towards PKC-ζ. Kinase activity assays were carried out to confirm these observations. Results suggest that PKC-ι is involved in melanoma malignancy than PKC-ζ. Both isoforms promote the activation of nuclear factor (NF)-κB and protein kinase B (AKT) thereby supporting survival and progression. In addition, we demonstrated that PKC-ι induced the metastasis of melanoma cells by activating Vimentin, and PKC-ι inhibition downregulated epithilial-mesencymal transition (EMT), while inducing apoptosis. Of note, PKC-ἱ specific inhibitors downregulated the expression of both PKC-ι and phosphorylated PKC-ι, suggesting that PKC-ι plays a role in regulating its own expression in melanoma. We also report the underlaying mechanisms of the transcriptional regulation of PKC-ι (PRKCI gene) expression in melanoma. c-Jun, interferon-stimulated gene factor 3 (ISGF3), paired box gene 3 (PAX3), early growth response protein 1 (EGR1) and forkhead box protein O1 (FOXO1), which bind on or near the promoter sequence of the PRKCI gene, were analyzed for their role in PKC-ι regulation in SK-MEL-2 and MeWo cell lines. We silenced selected transcription factors using siRNA, and the results revealed that the silencing of c-Jun and FOXO1 significantly altered the expression of PRKCI. The levels of both phosphorylated and total PKC-ι increased upon FOXO1 silencing and decreased upon c-Jun silencing, suggesting that c-Jun acts as an upregulator, while FOXO1 acts as a downregulator of PRKCI expression. We also used a multiplex ELISA to analyze multiple pathways other than NF-κB that were affected by treatment with PKC-ι inhibitor. The silencing of NF-κB p65 and PKC-ι by siRNA suggested that the regulation of PKC-ι expression was strongly associated with FOXO1. In addition, we observed a significant decrease in the mRNA levels of both interleukin (IL)-6 and IL-8, with a significant increase in the levels of IL-17E and intercellular adhesion molecule 1 (ICAM-1) upon the knockdown of expression of PKC-ι in both cell lines. This suggested that PKC-ι expression was affected by these cytokines in an autocrine manner. Overall, the findings of this study suggest that PKC-ι inhibition suppresses its own expression, diminishing oncogenic signaling, while upregulating anti-tumor signaling, thus rendering it an effective novel biomarker for use in the design of novel targeted therapeutics for melanoma.
14
Kauke, Monique Jacqueline. "Targeting immunosuppression in the tumor microenvironment and protein-based antagonism of oncogenic K-Ras." Thesis, Massachusetts Institute of Technology, 2017. http://hdl.handle.net/1721.1/114310.
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Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemical Engineering, 2017.Cataloged from PDF version of thesis.
Includes bibliographical references (pages 163-170).
Cancer is routinely treated with surgery, chemotherapy, and radiotherapy, but in recent decades, two new modes of treatment have emerged, targeted therapy and immunotherapy. Targeted therapies exploit differences between cancerous and healthy cells, targeting the proteins and pathways that exclusively drive cancer cell growth, while immunotherapies harness the body's immune system to destroy cancer cells. With these new treatment strategies, tumor regression and complete remission of disease have become attainable for a larger subset of patients. Nevertheless, the fight against cancer continues to be met with significant challenges, including development of resistance to targeted therapies and immunosuppressive factors that cripple anti-tumor immune responses. Broadly, the work presented in this thesis focuses on the development of novel therapeutic cancer agents using protein engineering. First, we explore combination immunotherapies designed to simultaneously activate an anti-tumor immune response, using a tumor-targeting antibody and a serum-persistent form of the immunostimulatory cytokine interleukin-2 (IL-2), and reduce immunosuppression in the tumor microenvironment, via blockade of either transforming growth factor-p (TGF-[beta]) or phosphatidylserine. We performed in vitro characterization and extensive preclinical evaluation of our constructs in syngeneic murine tumor models but failed to show therapeutic efficacy. Our studies nevertheless contribute to the field and demonstrate the complex and interdependent nature of the immune system, something that must be considered in future endeavors in combination immunotherapies. In the field of targeted therapy, mutant K-Ras continues to be the holy grail of oncogenic targets, but remains undruggable due to its high affinity for activating nucleotide GTP and a lack of welldefined drug-binding pockets. We engineered a protein binder RI 1.1.6 that binds mutant K-Ras with nanomolar affinity and exhibits specificity over the wildtype protein. The work in this thesis further characterizes RI 1.1.6 and shows inhibition of K-Ras-driven signaling in a model system. Translation to human cancer cell lines, however, failed to recapitulate this RI 1.1.6-mediated signaling disruption. Mathematical modeling of Raf-competitive Ras antagonism by R11.1.6 revealed that insufficient inhibition of Ras-Raf complexes is attained, offering an explanation of the lack of biological effects we observed.
by Monique Jacqueline Kauke.
Ph. D.
15
Matthews, Benjamin Phillip. "The oncogenic protein E2a-Pbx1 alters cellular proliferation or apoptosis in haematopoietic and fibroblast tissues." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape4/PQDD_0003/MQ45287.pdf.
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Paluncic, Jasmina. "Identification of Melanotransferrin (MTf), as a Novel Pro-Oncogenic Signalling Protein Involved in Melanoma Pathogenesis." Thesis, The University of Sydney, 2019. http://hdl.handle.net/2123/21152.
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It has been hypothesised that MTf may participate in melanoma progression due to the fact that the MTf plays a vital role in proliferation and tumorigenesis. This suggestion has been supported by the high levels of MTf expression in melanoma cells and the fact that previous studies demonstrated silencing MTf decreased melanoma tumour xenograft growth in vivo. In contrast, N-myc downstream regulated gene 1 (NDRG1), is a potent metastasis suppressor and acts to inhibit several oncogenic pathways, such as WNT, PI3K/AKT, etc. This thesis sought to elucidate the mechanism of MTf activity as a novel pro-oncogenic signalling protein involved in melanoma pathogenesis and whose molecular mechanism(s) of action remain unclear. Since metastasis accounts for most cancer deaths and is a major problem in melanoma, it was critical to further discover the molecular mechanisms that underlie NDRG1’s ability to inhibit progression and metastasis of melanoma. Furthermore, this thesis examined a promising anti-metastatic therapeutic strategy by assessing the novel, clinically trialled, anti-cancer agent, namely di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC), which potently up-regulates NDRG1 in a variety of tumour cells. This dissertation consists of 6 chapters: A comprehensive literature review in Chapter 1 and a general materials and methods chapter (Chapter 2). This is followed by 3 results chapters, namely: Chapter 3 examining the inter-relationship between NDRG1 and MTf in vitro and in human melanoma samples; Chapter 4: exploring the effect of MTf on the crucial upstream receptors of WNT- and PI3K signalling, including LRP6, c-Met, VEGFR2 and FGFR1; and Chapter 5 understanding how MTf drives proliferation and activates these oncogenic pathways when c-Myc is silenced. These chapters are then followed by Chapter 6, which is a general discussion of findings and future directions.
17
Darwish, Hanni. "Genomic and functional studies of SERTAD3, an oncogenic protein of the SERTAD family of transcription factors." Thesis, McGill University, 2006. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=100790.
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Gene amplification alters gene expression and can promote oncogenesis. In particular, the amplification of chromosome 19q13.1-13.2 has been found in several cancers and is known to contain the AKT2 oncogene. Two members of the SERTAD gene family of transcription factors, SERTAD1 and SERTAD3, are also located within this region. We report herein the genomic structure, regulation, and functions of SERTAD3. This gene has two transcript variants with short mRNA half-lives, and one of the variants is tightly regulated throughout G1 and S phases of the cell cycle. Overexpression of SERTAD3 induces cell transformation in vitro and tumor formation in mice, while inhibition of SERTAD3 by siRNA results in a 2-4 fold reduction in cell growth rate. Furthermore, luciferase assays based on E2F-1 binding indicate that SERTAD3 increases the activity of E2F, which can be strongly reduced by siRNA inhibition of SERTAD3. Together, our data support that SERTAD3 contributes to oncogenesis at least in part via an E2F-dependent mechanism.
18
曾可澄 and Ho-ching Felice Tsang. "Identification of ankyrin repeats and SOCS box protein 4 (ASB4) as oncogenic biomarker in liver cancer." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2008. http://hub.hku.hk/bib/B40738814.
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Tamaki, Sakura. "SS18-SSX, the Oncogenic Fusion Protein in Synovial Sarcoma, Is a Cellular Context-Dependent Epigenetic Modifier." Kyoto University, 2016. http://hdl.handle.net/2433/215458.
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Tsang, Ho-ching Felice. "Identification of ankyrin repeats and SOCS box protein 4 (ASB4) as oncogenic biomarker in liver cancer." Click to view the E-thesis via HKUTO, 2008. http://sunzi.lib.hku.hk/hkuto/record/B40738814.
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Comelli, Laura. "Localization and dynamics of homeotic oncogenic protein HOXC13 in pre-initiation complex of human DNA replication origins." Doctoral thesis, Scuola Normale Superiore, 2010. http://hdl.handle.net/11384/85938.
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In metazoan cells the DNA replication origins are not well defined. Differently
from what observed for bacteria cells and for budding yeast, in metazoan the origins
does not show a conserved sequence and they appear to be specified by many factors. In
order to better understand the mechanisms involved in the origin specification, many
studies have been done to identify the proteins involved in the recognition and
activation of the origins. From these kind of analysis is emerging that, beside the wellknown
proteins of the pre replicative complex, also other factors might be involved.
Between these, the HOX proteins seem to be able to play a role in the origin activity.
One of the first studies of this involvement was done by our group and leads to the
identification of three homeotic proteins able to specifically bind in vitro the human
lamin B2 origin. Thus, in the study conducted during this PhD program, was
investigated the involvement of one of these homeotic proteins, namely HOXC13, with
human DNA replication origins and with replicative complexes.
We found an interaction of HOXC13 with two crucial factors of the pre
Replication Complex (pre-RC), ORC1 and Cdc6 and that HOXC13 binds a good
fraction of the origins, in particular the early replicating ones, like the lamin B2 origin
and other known human origins. The HOXC13 protein is bound to origin chromatin, at
least for the lamin B2 origin, at a precise site within the pre-RC at specific moments of
the cell cycle. Interaction with the origin occurs within the area protected by the pre-RC
in G1, very close to the start sites of leading strand synthesis and to the binding sites of
ORC1, ORC2, Cdc6, topoisomerase (topo) I and topo II. The protein is absent from the
origin in M and appears on it at the beginning of G1, reach a peak at G1/S and as
synthesis starts, the interaction of HOXC13 with the origin fades, in parallel with the
transition from this large pre-RC to a smaller and differently organized post-RC.
Recently also other HOX proteins have been identify as proteins involved in
regulation processes of DNA replication, suggesting that the interaction of HOXC13
with the origins might occur in a multi-homeotic proteins complex. Depletion of one of
these proteins however is compatible with the continuation of the cell cycle and,
according with what observed for the other homeotic proteins, we found that also the
depletion of HOXC13 does not alter cell cycle progression or S phase entry. This is
probably due to the redundancy of homeotic proteins and indicates a relatively generic
function for the HOX proteins. Among the identified elements influencing the choice and the activity of a
sequence as DNA replication origin, much relevance is assumed by the chromatin
structure and topology of DNA. Therefore, we analysed the effects of chromatin
structure disruption using Tricostatin A, a histone deacetylase inhibitor. The alteration
of chromatin caused by this treatment not only sharply reduces origin function, but also
disturbs the binding of replication complex members like HOXC13 and the well known
Cdc6 to the DNA replication origins, while does not affect the binding of other
unrelated proteins like USF1. On the basis of this finding, we infer that an appropriate
chromatin organization and DNA topology strongly influence the binding between
factors of the pre Replication Complex and DNA replication origins. This influence
could be a key element in origin specification.
The described interactions are not restricted to a single origin nor to a single
homeotic protein, leading us to conclude that HOX proteins, probably in the context of a
multi-protein homeotic effectors, contribute to recruit and stabilize the replicative
complexes onto early replicating origins, in presence of specific chromatin and
topological configurations.
The relevance of HOXC13 in DNA replication is also underlined by its
involvement in oncogenesis, clearly demonstrated in acute myeloid leukaemia when
HOXC13 is fused with NUP98 protein.
22
Waldman, Lynne K. "Effects of oncogenic Ras and p38 mitogen-activated protein kinase on the adhesion of normal human cells." Thesis, Massachusetts Institute of Technology, 2010. http://hdl.handle.net/1721.1/57995.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2010.Vita. Cataloged from PDF version of thesis.
Includes bibliographical references.
Activating mutations in RAS oncogenes commonly arise in human cancers. However, in experimental settings, oncogenic RAS has most often been studied at supraphysiological levels of expression. Importantly, work by others showed that the response of murine cells to expression of oncogenic ras from the endogenous promoter is strikingly different from the response of both human and murine cells to high levels of ectopically expressed oncogenic RAS. Thus, to study the outcome of oncogenic Ras signaling in human cells at a more physiological level, I developed a system in which I could activate oncogenic Ras signaling to either low or high extents in normal human fibroblasts. A low level of oncogenic Ras signaling induced cellular hyperproliferation, whereas a high level of signaling induced cellular senescence. A growing body of literature links loss of p38 mitogen-activated protein kinase (MAPK) activity with the promotion of Ras-induced transformation in murine cells. Accordingly, I examined the effect of inhibiting p38 in normal human cells in which I also activated a low level of oncogenic Ras signaling. Interestingly, the inhibition of p38 cooperated with low activation of oncogenic Ras to alter the morphology and adhesive properties of cells. My results suggest that the inhibition of p38 could predispose human cells to partial transformation by oncogenic Ras through alterations in cellular adhesion.
by Lynne K. Waldman.
Ph.D.
23
Ercolani, Luisa. "Protein S-glutathionylation: new insights on pre-oncogenic cellular model and formulation of a new molecular mechanism." Doctoral thesis, Università Politecnica delle Marche, 2013. http://hdl.handle.net/11566/242733.
Full textAbstract:
La glutationilazione proteica è un importante modifica post-traduzionale che permette sia di proteggere i residui di cisteina delle proteine dall'ossidazione irreversibile che può verificarsi durante lo sbilanciamento redox cellulare, sia di influenzare cambiamenti nella struttura, nell'attività o nella localizzazione sub-cellulare delle proteine. Modificazioni della S-glutationilazione a carico delle proteine sono state associate con una serie di patologie umane, quali diabete, malattie cardiovascolari e polmonari, malattie neurodegenerative e cancro. Data l'importanza della glutationilazione, obiettivi di questo lavoro sono stati 1) indagare i possibili legami tra glutationilazione e senescenza oncogene-indotta in cellule che esprimono H-Ras e 2) scoprire un nuovo possibile catalizzatore della glutationilazione prendendo in considerazione un enzima con caratteristiche adeguate al ruolo.
L’ oncogene H-Ras richiede la deregolazione di altri oncogeni o l’inattivazione di proteine tumore-soppressore per aumentare la velocità di proliferazione cellulare e trasformare completamente le cellule. Infatti, l'espressione di H-RasV12 costitutivamente attivato induce arresto della crescita cellulare e senescenza prematura, che agiscono come barriere oncogeniche nelle lesioni pre-neoplastiche. Le cellule trasfettate con H-RasV12 hanno mostrato una drammatica modificazione della morfologia e senescenza prematura seguita da morte cellulare indotta da autofagia e apoptosi. Questo fenotipo è indotto principalmente dalle vie PI3K e MAPK. È stato dimostrato che la senescenza prematura è associata con uno squilibrio redox cellulare e con un’alterata S-glutationilazione. Infatti, è stato osservato un diverso pattern di proteine glutationilate tra le cellule controllo e quelle esprimenti H-RasV12. In particolare, sono state identificate mediante spettrometria di massa tre proteine: vimentina, ATP sintasi subunità-β ed α-enolasi. In conclusione, la riduzione della difesa antiossidante, la deplezione di glutatione e la successiva S-glutationilazione di proteine bersaglio possono contribuire ad arrestare la crescita cellulare, portando alla morte dei fibroblasti esprimenti l’oncogene H-Ras costitutivamente attivato ed agendo quindi come barriera oncogenica che ostacola la progressione della trasformazione cellulare.
I meccanismi di S-glutationilazione proteica sono lontani dall’essere completamente compresi in quanto diverse reazioni possono promuovere questa reazione, sia spontaneamente sia tramite catalizzatori. Ad oggi tre potenziali
catalizzatori di glutationilazione proteica sono stati proposti, tuttavia, altri enzimi
possono essere implicati in questo tipo di catalisi. In questo lavoro, è stata studiata la
gliossalasi II come nuovo candidato potenziale per promuovere la S-glutationilazione.
Per dimostrare la sua partecipazione attiva nella glutationilazione di proteine sono state
utilizzate proteine purificate notoriamente glutathionilate per effettuare esperimenti in
vitro. Per la prima volta è stato dimostrato il coinvolgimento della gliossalasi II nella Sglutationilazione
di proteine, suggerendo un nuovo meccanismo per la formazione di
addotti proteina-SSG. La gliossalasi II, infatti, permette una rapida e specifica
formazione di proteina-SSG, consentendo la regolazione enzimatica della Sglutationilazione
in proteine di diversa origine e compartimentalizzazione cellulare.Protein S-glutathionylation is an important post-translational modification which allows to protect cysteine residues against irreversible oxidation during redox imbalance and to affect proteins changes in structure, activity or sub-cellular localization. Modifications in S-glutathionylation are been associated with a number of human pathologies, such as diabetes, cardiovascular, lung and neurodegenerative diseases and cancer. Aims of this work were 1) to investigate possible links between this post-translational modification and oncogene-induced senescence in oncogenic H-Ras expressing cells, and 2) to discover a new possible catalyst of glutathionylation. H-Ras oncogene requires deregulation of additional oncogenes or inactivation of tumor suppressor proteins to increase cell proliferation rate and completely transform cells. Indeed, the expression of the constitutively activated H-RasV12 induces cell growth arrest and premature senescence, which act like barriers in pre-neoplastic lesions. H-RasV12 transfected cells showed a dramatic modification of morphology and premature senescence followed by cell death induced by autophagy and apoptosis. This phenotype is induced mainly by the PI3K and MAPK pathways. Moreover, it was provided evidence that the premature senescence is associated with cellular redox imbalance (due to a strong reduction of total antioxidant capacity and significant decrease of glutathione levels) as well as with altered S-glutathionylation. Different proteins S-glutathionylation patterns were observed in control and H-RasV12 expressing cells. Particularly, three proteins were identified by mass spectrometry: vimentin, ATP synthase β-subunit and α-enolase. So, antioxidant defense reduction, glutathione depletion and subsequent modification of S-glutathionylation of target proteins contribute to arrest cell growth, leading to death of fibroblasts expressing constitutively active H-Ras oncogene, thus acting as oncogenic barriers that obstacle the progression of cell transformation. Mechanisms of protein S-glutathionylation are far to be completely understood and several reactions can promote it, either spontaneously or catalyzed. To date, three potential catalysts of protein glutathionylation are been proposed, however, other enzymes may be implicated in this type of catalysis. In this work, it was studied glyoxalase II as a new potential candidate to promote S-glutathionylation. To demonstrate its active involvement in protein glutathionylation were used purified proteins known to be glutathionylated for in vitro experiments. For the first time this work shows active involvement of cytosolyc glyoxalase II for in vitro protein Sglutathionylation, suggesting a new mechanism of protein-SSG formation. Glyoxalase II, indeed, allows a rapid and specific protein-SSG formation, allowing enzymatic regulation of S-glutathionylation in proteins of different origin and cellular compartmentalization.
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Arcipowski, Kelly Marie. "Molecular mechanisms of TRAF6 function in signaling pathways of the oncogenic viral mimic of CD40, LMP1." Diss., University of Iowa, 2012. https://ir.uiowa.edu/etd/3560.
Full textAbstract:
Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) plays important roles in EBV-mediated B cell transformation, development of EBV-associated malignancies, and exacerbation of certain autoimmune conditions. LMP1 functionally mimics tumor necrosis factor receptor (TNFR) superfamily member CD40, but LMP1 signals are amplified and sustained compared to those induced by CD40. CD40 and LMP1 rely on TNFR-associated factors (TRAFs) to mediate signaling, but use TRAFs differently. TRAF6 is important for CD40 signaling, and was implicated in LMP1 signaling in non-B cells. Here, we addressed the hypothesis that TRAF6 is a critical regulator of a subset of LMP1 signals in B cells.
We found that TRAF6 was required for LMP1-mediated kinase activation and costimulatory molecule upregulation, and associated with the LMP1 TRAF1/2/3/5 binding site (TBS). Additionally, TRAF6 and the TBS contributed to LMP1-induced autoreactivity and antibody (Ab) production in vivo. Finally, in contrast to CD40, LMP1 required the TRAF6 receptor-binding domain to mediate TRAF6-dependent pathways. Thus, TRAF6 is critical for LMP1 signaling and requires LMP1 interaction to propagate signals. Importantly, TRAF6 associates with LMP1 in a manner distinct from CD40, raising the possibility of disrupting LMP1 functions while leaving normal CD40 signaling intact. We next investigated roles of the kinase TAK1 in TRAF6-dependent LMP1 functions. TAK1 was required for CD40- and LMP1-mediated JNK activation in B cells, leading to IL-6 and Ab production.
Understanding mechanisms of CD40 and LMP1 signaling provides important insights into normal regulatory control of CD40 functions and how LMP1-mediated pathogenesis escapes or subverts these regulatory mechanisms. LMP1 itself may be a difficult therapeutic target, because it lacks an extracellular domain and is continually processed from the cell surface. Thus, it is important to elucidate similarities and differences between CD40 and LMP1 signals to identify therapeutic targets to block LMP1-mediated pathogenesis. Comparing and contrasting CD40 and LMP1 also increases our understanding of the critical mechanisms used to regulate normal CD40 signaling.
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Tong, Michael. "Evaluation of protein kinases for solution NMR spectroscopy and the structural mechanism of inhibition and activation of an oncogenic calcium calmodulin dependent protein kinase." Thesis, University of Birmingham, 2012. http://etheses.bham.ac.uk//id/eprint/3877/.
Full textAbstract:
Protein kinases are important mediators of cell signalling that are often implicated in disease when deregulation occurs. The catalytic kinase domain is highly conserved with 518 identified members in the super family. Kinase structural studies are mainly based on relatively static crystal structures. However protein kinases are inherently dynamic entities in solution. Several Ser/Thr protein kinases were evaluated by NMR in order to obtain an amenable target for solution structure and functional characterisation. Subsequently a calcium calmodulin dependent protein kinase dubbed CaMK1D was identified as the optimal system. CaMK1D normally mediates intracellular signalling downstream of chemokines. It is amplified in breast cancer, and induces cell proliferation, migration and invasion. Here we report the backbone resonance assignments for the 38 kDa human autoinhibited CaMK1D in its free state, encompassing a canonical bi-lobed kinase fold and autoinhibitory and calmodulin binding domains. These assignments allowed us to probe the binding mode of CaMK1D with small molecule ligands and refine the crystal structure via dihedral angle restraints for a more complete structure. Furthermore we investigated the solution structure of the CaMK1D∙Ca\(^{2+}\)/CaM complex and propose a model of the activation mechanism and establish a key residue implicated in complex formation.
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Tichauer, Ruth Elena. "In silico screening of NRas protein oncogenic mutations : new structural and physico-chemical insights into the catalytic activity." Electronic Thesis or Diss., Toulouse 3, 2019. http://www.theses.fr/2019TOU30028.
Full textAbstract:
Les protéines Ras jouent un rôle majeur dans le développement cellulaire. Faisant partie de la catégorie de petites GTPases, elles sont dotées d'un mécanisme fonctionnant tel un interrupteur moléculaire qui, dans leur cas, contrôle la transmission de signaux de croissance cellulaire. Liées au GTP, ces protéines adoptent une conformation leur permettant d'interagir avec des effecteurs en aval et, ainsi, activer la réplication et différenciation cellulaires. La réaction d'hydrolyse du GTP qui se déroule en leur centre, est accompagnée d'un changement conformationnel qui met fin à ces interactions, conduisant ainsi à l'état inactif de Ras, lié au GDP. Des mutations spécifiques de résidus bien déterminés entraînent une baisse du taux d'hydrolyse, laissant ainsi Ras liée au GTP. Or, de fortes concentrations de cette forme active de Ras ont été associées à une prolifération cellulaire anormale, caractéristique de la dissémination de tissus cancéreux. Il apparaît alors que l'élucidation des mécanismes employés par Ras pour accélérer le clivage du GTP constitue une étape majeure dans le développement de thérapies ciblées contre le cancer. Elles consisteraient à rétablir, au sein des mutants oncogéniques, un taux d'hydrolyse proche à celui mesuré au sein du type sauvage. Dans le but de mieux comprendre au niveau atomique les propriétés catalytiques de Ras, nous avons mené des simulations de dynamique moléculaire (MD) en décrivant le domaine G à différents niveaux de théorie (Mécanique Moléculaire (MM), Semi-empirique et Théorie de la Fonctionnelle de la Densité (DFT)). Ces calculs ont été réalisés pour les formes sauvage et mutées au niveau du résidu 61 de NRas. Ils ont été couplées à des caractérisations biomécaniques des complexes protéine-ligand étudiés, en utilisant la méthode des modes statiques. Cette méthode permet d'identifier des points chauds, réactifs, de la biomolécule et qui, suivant le critère de contrainte choisi, ont une influence mécanique sur la fonction GTPase de la protéine. Par conséquent, ils pourraient servir en temps que sites appropriés pour héberger des molécules médicamenteuses contenant des groupes chimiques spécifiques qui faciliteraient l'hydrolyse du GTP. Tout d'abord, les résultats obtenus montrent que le positionnement des molécules d'eau dans le cite actif est crucial pour catalyser efficacement la réaction. En effet, la répartition précise du solvant, observée dans le type sauvage, est perdue au sein des mutants de NRas considérés ici. Cette distribution différente des molécules d'eau ainsi que les modifications structurales du site actif engendrées par les substitutions du résidu Gln 61, ont un impact direct sur la densité électronique du GTP. Cette dernière présente un profil de type GDP au sein de la protéine de type sauvage uniquement, comme déterminé expérimentalement dans des études précédentes. Il apparaît donc que les mutations oncogéniques de Gln 61 perturbent cet effet catalytique majeur de NRas. Parmi trois propositions faites au cours de cette thèse sur des modifications à apporter à la forme mutée Q61R de NRas, une est présentée pendant la soutenance tandis que toutes les trois sont décrites dans le manuscript. Les groupes chimiques insérés au niveau du site identifié permettent de rétablir une distribution de l'eau comme celle observée dans le type sauvage. Pour terminer, lors de la soutenance uniquement, un chemin réactionnel alternatif de l'hydrolyse enzymatique du GTP est proposéRas subfamily of small GTPase proteins holds a key position in cell proliferation pathways. Indeed, the transmission of cell growth signals is controlled by proteins belonging to it. In their GTP-bound conformation, these proteins interact and activate downstream effectors of cell replication and differentiation. The hydrolysis reaction that takes place in their center, terminates these interactions, thereby leading to the GDP-bound inactive state. Point mutations of key residues lead to a hydrolysis rate drop that keeps Ras in a GTP-bound active state. Now, high concentrations of active Ras have been associated to abnormal cell proliferation, emblematic of cancerous tissues dissemination. With this into consideration, the elucidation of Ras mechanisms for accelerating GTP cleavage appears as a major step in the development of cancer targeted therapies that would consist in restoring the hydrolysing capabilities within oncogenic Ras to a wild-type rate. In an attempt to gain insight into Ras catalysing properties at the atomic level, unconstrained Molecular Dynamics (MD) simulations describing the G domain at different levels of theory (Molecular Mechanics (MM), Semi-empirical and Density Functional Theory (DFT)) were carried out for NRas member in its wild-type and Gln 61 mutated forms. These simulations were coupled to biomechanic characterisations of the complexes under inspection employing the static modes approach. The latter method, allows the identification of hot spots {\it i.e.} responsive residues of the biomolecule, that have a mechanical influence on the GTPase function of the protein. Hence, they could serve as suitable sites to host drug-like molecules containing specific chemical groups that would facilitate GTP hydrolysis. The obtained results show that water molecules positioning is crucial for efficiently catalysing the reaction that takes place in NRas center. Indeed, the precise positioning observed within the wild-type is lost within the mutants studied here. Furthermore, the active site structural modifications undergone upon Gln 61 substitutions, together with solvent distribution in it, impact directly GTP electronic density. The latter is accommodated to a GDP-like state within the wild-type protein only, as experimentally determined in previous investigations. Thus, oncogenic Gln 61 mutations impair this major catalysing effect. Among three engineered NRas proteins of the Q61R mutated form, proposed during this thesis, one is presented during the defence while the three are described in the manuscript. The chemical groups inserted at the identified site enable the recovery of water distribution as within the wild-type. To end, during the defence only, an alternative reaction pathway of the enzymatic reaction is proposed
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Edelbrock, Michael Aaron. "Cell Cycle Regulation of DNA Mismatch Repair Protein Expression and Activity at the H-ras Oncogenic Hot Spot." University of Toledo Health Science Campus / OhioLINK, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=mco1192129938.
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Baxter, Daniel. "Combining library screening approaches, and modifying peptides with helix constraints, to generate novel antagonists of oncogenic Activator Protein-1." Thesis, University of Bath, 2017. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.715244.
Full textAbstract:
Activator Protein-1 (AP-1) is an oncogenic transcription factor that is dysregulated in numerous human cancers, making it an attractive therapeutic target. AP-1 forms via interaction of cJun and cFos proteins, which intertwine to generate a ‘coiled coil’ (CC) structure. Thus, the cJun/cFos α-helical CC domains responsible for dimerisation are appealing targets for inhibiting AP-1 formation and activity. Helical peptide antagonists that sequester cJun can be derived from the cFos CC domain by selection of more optimal amino acids for increased binding affinity. Peptides can then be downsized and modified to improve therapeutic potential. Two approaches aimed to identify novel short peptides against cJun. The first was to covalently cyclise amino acid side chains in existing cFos-derived peptide “FosW”, with the aim of constraining FosW into a stable helix to allow downsizing without significant loss of binding structure and affinity. Using circular dichroism spectroscopy and isothermal titration calorimetry, a series of helix constrained peptides were characterised, from which a peptide was identified that retained 88 % of FosW binding affinity whilst being 22 % shorter, and which entered breast cancer cells in vitro, with preliminary data suggesting potential ability to inhibit AP-1 in cellulo. The second approach was to combine two existing high-throughput peptide selection systems, with the aim of benefitting from overlap in their strengths and weaknesses. Combination of in vitro CIS display and in cellulo Protein-fragment Complementation Assay successfully isolated a high affinity peptide from a hugely diverse library, and future refinements to further exploit this approach, particularly for short peptide selection, were formulated. Thus, molecules and techniques derived here may expedite the future development of therapies for cancers featuring AP-1 dysregulation.
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Chan, Steven Man Cheong. "Protein microarray technology for profiling signaling patwhays [sic] : insights into pro-oncogenic notch signaling in T cell acute lymphoblastic leukemia /." May be available electronically:, 2006. http://proquest.umi.com/login?COPT=REJTPTU1MTUmSU5UPTAmVkVSPTI=&clientId=12498.
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Freudenberger, Nora [Verfasser], and Thomas [Akademischer Betreuer] Dobner. "Role of minor core protein V during productive infection with human adenovirus type 5 and the proteins relevance to oncogenic transformation processes / Nora Freudenberger ; Betreuer: Thomas Dobner." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2017. http://d-nb.info/1139492837/34.
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Gonterman, Ryan M. "Parathyroid hormone-related protein gene expression and function relationship with oncogenic pathways in the skin and squamous cell carcinomas of the lung /." [Bloomington, Ind.] : Indiana University, 2008. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3324517.
Full textAbstract:
Thesis (Ph.D.)--Indiana University, Dept. of Medical Sciences, 2008.Title from PDF t.p. (viewed on May 13, 2009). Source: Dissertation Abstracts International, Volume: 69-08, Section: B, page: 4693. Adviser: John G. Foley.
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Genera, Mariano. "Structural and functional study of the human phosphatase PTPN3 and its interaction with oncogenic viruses." Electronic Thesis or Diss., Sorbonne université, 2019. http://www.theses.fr/2019SORUS112.
Full textAbstract:
PTPN3 est une protéine humaine contenant un domaine PDZ avec un rôle soit de suppresseur de tumeur soit de promoteur de tumeur dans de nombreux cancers. Cependant, sa fonction dans la signalisation cellulaire reste encore floue. Fait intéressant, les papillomavirus humains (HPV) génitaux à haut risque de types 16 et 18 et le virus de l'hépatite B (HBV) ciblent le domaine PDZ de PTPN3 (PTPN3-PDZ) par le biais de motifs de reconnaissance au domaine PDZ (PBMs) dans l’oncoprotéine E6 et la protéine de capside HBc de HPV et HBV respectivement. Nous avons étudié les interactions entre le PTPN3-PDZ et ses ligands cellulaires et viraux. Nous avons étudié les propriétés structurales et fonctionnelles du PTPN3-PDZ et les principaux déterminants structuraux de la reconnaissance des PBMs en combinant des expériences de biophysique, de RMN et de diffraction aux rayons X. Nous nous sommes ensuite intéressés à la protéine de capside HBc de HBV. En criblant une bibliothèque contenant l’ensemble des domaines PDZ des protéines humaines, nous avons identifié 28 partenaires cellulaires potentiels interagissant avec le PBM de HBc. Nous avons confirmé que PTPN3 pouvait interagir avec le PBM de HBc au sein d’une capside virale et nous avons montré que les PBMs viraux interagissaient avec PTPN3-PDZ avec des affinités similaires aux ligands endogènes de PTPN3. En utilisant des hépatocytes infectés par HBV, nous avons observé que la surexpression de PTPN3 avait des effets multiples sur l’infection. Enfin, nous avons étudié l’interactome de PTPN3-PDZ afin de mieux comprendre le rôle de PTPN3 dans la signalisation cellulaire et les effets perturbateurs de HBV sur celle-ciThe human protein tyrosine phosphatase non-receptor type 3 (PTPN3) is a PDZ (PSD-95/Dlg/ZO-1) domain-containing phosphatase with a tumor-suppressive or a tumor-promoting role in many cancers, although its role in cell signalling is still unclear. Interestingly, the high-risk genital human papillomavirus (HPV) types 16 and 18 and the hepatitis B virus (HBV) target the PDZ domain of PTPN3 through PDZ-binding motifs (PBMs) in their E6 and HBc proteins. Here, I report a detailed study of the interactions between the PDZ domain of PTPN3 and its cellular and viral ligands. First, we combined biophysical, NMR and X-ray experiments to investigate the structural and functional properties of the PDZ domain of PTPN3 and its interaction with the E6 PBM. We then extended our structural study of PTPN3-PDZ to other cellular and viral partners, and gained insights into the main structural determinants of recognition of PBMs. We then focused on the HBV HBc protein. We screened a library of human PDZ-containing proteins for HBc binders and identified 28 cellular HBc-interacting partners, most of which are involved in cell polarity. We confirmed that PTPN3 can bind the HBc PBM in the context of the viral capsid, and we showed that viral PBMs interact with PTPN3-PDZ with similar affinities to endogenous PTPN3 ligands. Using HBV-infected hepatocytes we observed that overexpression of PTPN3 has multiple effects on HBV infection. Finally, we investigated the interactome of PTPN3-PDZ to gain insights into the role of this protein in cell signalling and the disruptive effects of HBV
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Xu, Shenyuan. "Nuclear Magnetic Resonance Spectroscopy Studies of At2g44920, a Pentapeptide Repeat Protein from Arabidopsis thaliana and X-ray Crystallography, Isothermal Titration Calorimetry Studies of K-Ras, a Human Oncogenic GTP-ase Signaling Protein." Miami University / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=miami1500896385881469.
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Lowe, Julie. "Identification of NF-kappa B and DNA-dependent protein kinase (DNA-PK) as new players in the regulation and signaling of the oncogenic phosphatase Wip1." Connect to Electronic Thesis (CONTENTdm), 2010. http://worldcat.org/oclc/642326246/viewonline.
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Maurizio, Elisa. "Post-translational modifications and conformational transitions of the intrinsically disordered oncoproteins High-Mobility Group A." Doctoral thesis, Università degli studi di Trieste, 2011. http://hdl.handle.net/10077/4591.
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2009/2010Intrinsically disordered proteins (IDPs) are flexible molecules, able to adapt to the surfaces of different molecular partners by means of specific, but easily reversible interactions. IDPs carry out pivotal biological functions participating in almost all cell signaling and regulatory pathways. Importantly, IDPs activities are finely modulated by the addition/removal of numerous post-translational modifications (PTMs) which are important conformational modulators. Prototypes of IDPs are High Mobility Group A (HMGA) proteins, which are expressed at high levels and play essential functions both in embryonic and cancer cells. HMGA protein family (HMGA1a, HMGA1b, and HMGA2) belong to the non-histone HMG chromatin protein super-family and are multifunctional architectural transcription factors. HMGA conformational adaptability and intricate pattern of dynamic and constitutive PTMs are thought to be responsible for this multifunctionality. We performed a liquid chromatography-mass spectrometry (LC-MS) screening in twenty different cell lines in order to evaluate HMGA proteins PTM pattern and we evidenced relevant intra-family differences. Moreover, we focused on the poorly characterized HMGA2 and we mapped HMGA2 phosphorylation sites by mass sequencing demonstrating that, similarly to HMGA1, it is phosphorylated on the acidic C-terminal tail by CK2. Importantly, this modification turned out to affect HMGA2 DNA binding. Since truncated HMGA proteins are more oncogenic than full-length ones and since HMGA are in vivo heavily modified on their C-terminal domain, we dissected the role of this domain and its phosphorylations from a structural point of view. We probed HMGA IDPs compactness and accessibility taking advantage of an innovative approach combining limited proteolysis and MS-based techniques. By limited proteolysis, ESI (electrospray ionization)-MS, and IMS (ion mobility separation)-MS we demonstrated that HMGA can assume a compact conformation and that their compactness degree is dependent upon the presence of the acidic C-terminal domain and its constitutive phosphorylations. Moreover, LC-MS analyses after enzymatic assays showed that HMGA forms with a deletion of acidic C-terminal tail are more susceptible to PTMs, thus supporting the idea that the acidic tail is involved in masking the accessibility of modifying enzymes to their own consensus sites. We evidenced macroscopic differences regarding PTMs affecting the three HMGA family members and provided the first data about in vivo HMGA2 PTMs and their effect on DNA binding. Our structural investigations revealed a structure/PTMs relationship dictated by the presence of the C-terminal domain. This evidence, together with the already known in vivo functional outcome of HMGA C-terminal truncation, suggests a structure/function link between HMGA tails, their PTMs, and their oncogenic properties, paving the way for the development of interfering therapeutic strategies based on targeting HMGA proteins.
Le proteine intrinsecamente disordinate (PID) sono molecole flessibili in grado di adattarsi alle superfici di differenti partner molecolari tramite interazioni specifiche, ma facilmente reversibili. Queste proteine compiono funzioni biologiche essenziali partecipando in quasi tutte le vie di segnalazione e regolazione cellulari. La modulazione delle loro attività avviene tramite l’aggiunta/rimozione di numerose modificazioni post-traduzionali (MPT), le quali possono comportare anche cambiamenti conformazionali. Le proteine High Mobility Group A (HMGA) sono considerate prototipo delle PID. Esse sono espresse ad alti livelli e giocano funzioni chiave sia durante lo sviluppo embrionale che durante il processo di trasformazione neoplastica. Le proteine della famiglia HMGA (HMGA1a, HMGA1b e HMGA2) appartengono alla super-famiglia delle proteine cromatiniche non istoniche HMG e sono fattori trascrizionali architetturali multifunzionali. L’adattabilità conformazionale e l’intricato pattern di MPT dinamiche e costitutive delle HMGA sono ritenute essere alla base della loro multifunzionalità. In questo lavoro di tesi è stato effettuato uno screening delle MPT a cui sono soggette le HMGA in venti linee cellulari diverse mediante analisi di cromatografia liquida accoppiata alla spettrometria di massa (LC-MS) e si sono evidenziate rilevanti differenze tra i tre diversi membri della famiglia HMGA. Inoltre, concentrandosi sulla poco caratterizzata proteina HMGA2, abbiamo dimostrato mediante mass sequencing che, al pari della proteina HMGA1a, essa è fosforilata sul C-terminale e che tale modificazione comporta un’alterazione delle sue proprietà di legame al DNA. Diversi tipi di tumore esprimono forme tronche delle proteine HMGA mancanti del dominio acidico C-terminale. Dal momento che queste forme sono state dimostrate essere maggiormente oncogeniche rispetto alle controparti a lunghezza completa abbiamo deciso di investigare il ruolo della coda acidica e delle sue fosforilazioni da un punto di vista strutturale. La compattezza e l’accessibilità delle HMGA è stata esplorata sfruttando un approccio innovativo che combina esperimenti di proteolisi limitata e tecniche di spettrometria di massa (MS). Tramite proteolisi limitata, ESI (electrospray ionization)-MS, and IMS (ion mobility separation)-MS abbiamo dimostrato che le HMGA possono assumere una conformazione compatta e che il loro grado di compattezza è dipendente dalla presenza del dominio acidico C-terminale e delle sue fosforilazioni costitutive. Inoltre, analisi LC-MS effettuate dopo saggi enzimatici hanno mostrato come le forme delle HMGA presentanti una delezione della coda acidica C-terminale sono più suscettibili alle MPT, supportando quindi l’idea che la coda acidica sia coinvolta nel mascherare l’accessibilità degli enzimi di modificazione sui siti consensus lungo la sequenza di HMGA. In questo lavoro abbiamo evidenziato differenze macroscopiche riguardanti le MPT che interessano i tre membri della famiglia HMGA e abbiamo fornito i primi dati circa le MPT di HMGA2 in vivo e il loro effetto sul legame al DNA. Le nostre investigazioni strutturali hanno rivelato una relazione struttura/MPT dettata dalla presenza del dominio C-terminale. Questa evidenza, insieme al già noto esito funzionale in vivo della delezione del C-terminale di HMGA, suggerisce un collegamento struttura/funzione tra la coda acidica delle HMGA, le loro MPT, e le loro proprietà oncogeniche.
XXIII Ciclo
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Liu, Xiaohu. "Functional and structural study of the AHI-1 SH3 domain, characterization of the BCR-ABL-AHI-1-Dynamin-2 protein complex and investigation of oncogenic roles of dynamin-2 in chronic myeloid leukemia." Thesis, University of British Columbia, 2016. http://hdl.handle.net/2429/60191.
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Tyrosine kinase inhibitor (TKI) therapies have been introduced into clinical practice with remarkable effects on chronic myeloid leukemia (CML). However, early relapse, acquired drug resistance and persistence of leukemic stem cells (LSCs) remain problematic. Improved treatments specifically targeting key molecular elements active in CML LSCs are needed. One candidate is the oncoprotein AHI-1 (Abelson helper integration site-1), which is highly deregulated in LSCs. It harbors two key domains, SH3 and WD40-repeat, which are known important mediators of protein-protein interactions. An AHI-1-mediated protein complex containing BCR-ABL and JAK2 has been shown to modulate transforming activity and TKI-response/resistance of CML LSCs. In this study, I investigated the functional roles of the AHI-1 SH3 domain in regulation of cellular resistance of primitive CML cells to TKIs. I showed that deletion of the SH3 domain of Ahi-1 significantly enhanced apoptotic response of BCR-ABL⁺ cells to TKIs compared to cells expressing full-length Ahi-1. I solved the crystal structure of the AHI-1 SH3 domain and identified several unique features, providing potential target sites for designing specific drugs. Using immunoprecipitation/mass spectrometry, I identified a novel protein interaction between AHI-1 and Dynamin-2 (DNM2), a GTPase, through the AHI-1 SH3 domain. I showed that DNM2 expression was significantly upregulated in CML stem/progenitor cells compared to normal bone marrow cells. I also determined that the AHI-1 SH3 domain and the proline rich domain of DNM2 were mainly responsible for their interaction. Most importantly, I identified a novel protein complex in CML cells, containing BCR-ABL, AHI-1 and DNM2. Furthermore, I demonstrated an oncogenic role of DNM2 in primitive CML cells by showing that knockdown of DNM2 greatly impaired the survival of CML stem/progenitor cells and sensitized them to TKI treatments. Lastly, I illustrated that DNM2 might be involved in deregulation of endocytosis, ROS production and autophagy in TKI-insensitive CML stem/progenitor cells. This study detailed the identification and characterization of the newly-identified BCR-ABL-AHI-1-DNM2 protein complex and described the oncogenic functions of DNM2 in primitive CML cells. It further suggested that targeting DNM2 may facilitate eradication of LSCs as a new treatment option in CML.Medicine, Faculty of
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Helt, Anna-Marija. "Multiple biological activities of the human papillomavirus type 16 E7 oncoprotein contribute to the abrogation of human epithelial cell cycle control /." Thesis, Connect to this title online; UW restricted, 2002. http://hdl.handle.net/1773/11514.
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Protopopova, Marina. "Modulation of activity of the tumour suppressor p53 by small molecules and damaged DNA /." Stockholm, 2004. http://diss.kib.ki.se/2004/91-7349-926-9/.
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Fladvad, Malin. "Structure and function in c-Myc and Grx4 : two key proteins involved in transcriptional activation and oxidative stress /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7357-007-9/.
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Hase, Manuela. "Molecular and ultrastructural analysis of Tpr, a nuclear pore complex-attached coiled-coil protein /." Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-525-5/.
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Yan, Weisi. "Functional proteomic study of Akt reveals novel substrates in translation /." Access full-text from WCMC, 2008. http://proquest.umi.com/pqdweb?did=1619246521&sid=9&Fmt=2&clientId=8424&RQT=309&VName=PQD.
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Lindström, Mikael. "Functional characterization of the alternative reading frame protein p14ARF /." Stockholm, 2004. http://diss.kib.ki.se/2004/91-7349-917-x.
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Pääjärvi, Gerd. "Xenobiotics-induced phosphorylations of MDM2 /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-951-3/.
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CLEMENTI, LETIZIA. "Potenziale ruolo oncogenico della proteina multifunzionale tau." Doctoral thesis, Università degli Studi dell'Aquila, 2022. http://hdl.handle.net/11697/192067.
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La proteina Tau è stata individuata in diversi tumori umani inclusi il carcinoma della prostata, della mammella, dello stomaco, del pancreas e del colon retto dove, mostra una struttura e funzione simili alla più studiata Tau neuronale. La Tau viene considerata una proteina multifunzionale ma, il suo ruolo principale sembra essere quello di assemblaggio e stabilizzazione dei microtubuli. La proteina Tau è codificata dal gene MAPT (Microtubule Associated Protein Tau) e a seguito di splicing alternativo degli esoni 2, 3 e 10 del trascritto primario, si ottengono sei isoforme. In aggiunta al differenziale processamento del trascritto primario, la proteina Tau è bersaglio di complesse modificazioni post-traduzionali che includono la fosforilazione. Quello che è noto dalla letteratura suggerisce che, il mantenimento dell’omeostasi tra l’attività delle chinasi e delle fosfatasi è fondamentale per regolare l’affinità di legame della proteina ai microtubuli. La perdita di questo equilibrio promuove una fosforilazione anomala della proteina, un evento che è stato associato alle sue funzioni patologiche. La Tau iper-fosforilata non è più in grado di legare la tubulina ma anzi, sembra svolgere un ruolo “infettivo” sequestrando altre forme della proteina e aggregando in strutture progressivamente più grandi e insolubili che compromettono l’integrità cellulare. A tal proposito è noto che l’Alzheimer (condizione patologica che rientra nelle taupatie) è associata a iper fosforilazione della proteina che, si stacca dai microtubuli con conseguente distruzione del citoscheletro insieme alla formazione e all'accumulo di oligomeri Tau solubili e di grovigli neurofibrillari Tau non solubili. In questa tesi di dottorato di ricerca abbiamo indagato le possibili implicazioni associate all’equilibrio monomeri/oligomeri e le modificazioni post-traduzionali aberranti che può subire la proteina Tau in un modello diverso da quello delle malattie neurodegenerative come i tumori. In particolare ci si è proposti di investigare come Tau, attraverso la sua associazione ai microtubuli del fuso mitotico e l’accumulo delle forme oligomeriche iper-fosforilate, possa interferire in un tratto distintivo del cancro quale la deregolamentazione del ciclo cellulare. I nostri studi in vitro hanno dimostrato che, in presenza degli inibitori dell’autofagia Clorochina o Bafilomicina, si assiste all’accumulo di oligomeri Tau e contemporaneamente alla formazione di fusi mitotici aberranti, con aumento delle rotture a doppio filamento del DNA. L’inibizione dell’autofagia in mitosi si è quindi rivelata sinergica rispetto all’azione citotossica dei taxani. Tale ipotesi è stata confermata tramite l’eliminazione degli oligomeri per inibizione chimica o per silenziamento della proteina. I nostri dati hanno inoltre evidenziato che la formazione di oligomeri in mitosi è strettamente legata alla fosforilazione di Tau in fase G2/M e che la modulazione delle chinasi e fosfatasi coinvolte è capace di interagire con l’azione degli agenti anti-mitotici. In particolare l’inibizione della CDK5 è risultata svolgere un ruolo chiave nella capacità delle cellule bloccate in fase G2/M di progredire in maniera forzata nelle fasi successive del ciclo. In conclusione, considerando il nostro studio come preliminare per la comprensione del ruolo di Tau nei tumori, possiamo ipotizzare che Tau, potrebbe rivelarsi importante per la possibilità di migliorare l’efficienza delle terapie antimitotiche, agendo in particolare nella stabilizzazione del fuso mitotico. Quello che sembra più rilevante a livello patologico è il rapporto delle varie forme post-traduzionali nelle diverse fasi del ciclo cellulare e come questo rapporto, condizioni la resistenza a farmaci antimitotici o la capacità delle cellule tumorali di avanzare durante i checkpoint del ciclo in condizioni aberranti.
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Leanna, Candice A. "Loss of IkB[alpha]-mediated regulation correlates with increased oncogenicity of mutant c-Rel proteins." free to MU campus, to others for purchase, 1998. http://wwwlib.umi.com/cr/mo/fullcit?p9901255.
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Tang, Norina Mei Ngon. "Regulation of protein synthesis and induction of oncogenesis by a cellular protein kinase inhibitor /." Thesis, Connect to this title online; UW restricted, 1998. http://hdl.handle.net/1773/11501.
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Collins-De, Peyer Laurence. "Screening of a rat thymus and a human hippocampus cDNA library for a novel fyn-related oncogene." Thesis, Hong Kong : University of Hong Kong, 1999. http://sunzi.lib.hku.hk/hkuto/record.jsp?B21253870.
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Sandberg, Eric M. "Jak2 tyrosine kinase new insights regarding structure, function, and pharmacology /." [Gainesville, Fla.] : University of Florida, 2004. http://purl.fcla.edu/fcla/etd/UFE0006882.
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Thesis (Ph.D.)--University of Florida, 2004.Typescript. Title from title page of source document. Document formatted into pages; contains 118 pages. Includes Vita. Includes bibliographical references.
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Chen, Mingzi. "Mos regulation in activating the MAP kinase pathway /." Thesis, Connect to this title online; UW restricted, 1997. http://hdl.handle.net/1773/9195.
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Liang, Hongjian [Verfasser]. "Characterization of the oncogenic properties of human papillomavirus E6 proteins / Hongjian Liang." Konstanz : KOPS Universität Konstanz, 2017. http://d-nb.info/1188202790/34.
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