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Chan, Ho Man. "Molecular basis of cell cycle control : p300 and pRb." Thesis, University of Glasgow, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.326430.
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Jayatunga, Madura Kelum Perera. "Modulation of the hypoxic response in cancer : inhibition of the HIF-1α/p300 protein-protein interaction." Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:a3ae9d39-f7cc-4ba5-b921-2a7855ee1512.
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Hypoxia inducible factor (HIF)-1α is a heterodimerically-activated transcription factor central to the cellular response to hypoxic environments and is often upregulated in cancer. Binding of HIF-1α to the co-activator p300 is necessary for the hypoxia-induced transcription of many oncogenic proteins. The aim of this project was to develop novel small molecule inhibitors of the HIF-1α/p300 protein-protein interaction (PPI). Initial work focused on designing, validating and optimising two high-throughput competition binding assays to screen for inhibitors of the PPI (Chapter 2). Alongside these, zinc ejector assays for both p300 and KDM4A proteins were developed to probe the mechanism of action and selectivity. Analysis of hits from a natural product high-throughput screen (HTS) revealed two compound classes; benzoquinones and 2-substituted indandiones, which modulate the PPI. The potency of these series correlated with the reactivity of the core functional groups, which act as electrophiles to covalently modify reactive cysteines, ejecting structural zinc and disrupting the p300/KDM4A protein fold (Chapter 3). Conjugating electrophilic groups to putative HIF-1α/p300 inhibitors did not replicate the activity of the zinc ejecting HTS hits (Chapter 4). Further work focused on non-covalent inhibitors of the HIF-1α/p300 interaction, first with peptide truncates, and then rationally designed α-helix peptidomimetics. An 11mer truncate showed encouraging activity (IC50 ≈ 70 μM), and corresponded to a key α-helix in the HIF-1α C-terminal transactivation domain. Three distinct double-sided scaffolds were used to imitate up to five hot-spot ampiphilic residues on this α-helix (Chapter 6 and 7). Of the 35 compounds screened, only modest inhibition was observed (IC50 ≈ 200-500 μM). Future work will look to conjugate electrophilic functionality onto the 11mer peptide in an attempt to gain potency from zinc ejection, while maintaining selectivity for p300.
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Kyle, Hannah Frances. "Biophysical and structural characterisation of protein-protein interactions, HIF-1α/p300 and eIF4E/eIF4G to inform inhibitor rational design." Thesis, University of Leeds, 2015. http://etheses.whiterose.ac.uk/10404/.
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Protein-protein interactions (PPIs) are an important class of therapeutic target, however due to their large interaction interface they are considered difficult to inhibit. The two PPIs of interest in this thesis are the HIF-1α (hypoxia inducible factor-1α)/p300 and eIF4E (eukaryotic initiation factor 4E)/eIF4G interactions, both of which have been shown to be involved in many different cancers and are hypothesised to be good targets for targeted therapy. A rational design approach is favoured for PPIs, however for this to be possible a detailed understanding of the binding interface is required. Biophysical assessment of the HIF-1α CTAD/p300 CH1 interface has revealed a key binding “hot-spot” of p300 where the helix three region of HIF-1α binds to p300, this area has subsequently been targeted using oligoamide α-helix mimetics to disrupt the interaction. This binding site was found by two approaches, used to probe the HIF-1α binding surface on p300, first, by analysis of the binding of shorter HIF-1α peptide fragments; and second, by phage display experiments. The HIF-1α fragment study demonstrated that HIF-1α helix 3 region binds to p300 with a higher affinity than any of the short (<20 amino acids) peptide regions of HIF-1α and a peptide containing helices 2 and 3 binds with a higher affinity than a peptide containing helices 1 and 2, this importance of the helix 3 binding site was validated using mutagenesis. The phage display experiment found 12mer peptides that bind to p300 with a higher affinity than any short peptide region of HIF-1α. Structural techniques and mutagenesis were the used to verify that this binding site was similar to that of HIF-1α helix 3. The rationally designed mimetics of HIF-1α helix 3 were able to disrupt the interaction with low micromolar affinity. A second phage display experiment found Adhirons which bound with low nanomolar affinity and were able to disrupt the interaction with low micromolar affinity, docking of the crystal structure of this Adhiron indicated that it may be acting at a different site to the HIF-1α helix 3 region. This is a proof of principle that a detailed understanding of an interaction, using both biophysical and structural techniques, can directly lead to the development of inhibitors of challenging and therapeutically relevant PPIs.
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Shi, Dingding. "Defining the Roles of p300/CBP (CREB Binding Protein) and S5a in p53 Polyubiquitination, Degradation and DNA Damage Responses: A Dissertation." eScholarship@UMMS, 2010. https://escholarship.umassmed.edu/gsbs_diss/452.
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p53, known as the “guardian of the genome”, is the most well-characterized tumor suppressor gene. The central role of p53 is to prevent genome instability. p53 is the central node in an incredibly elaborate genome defense network for receiving various input stress signals and controlling diverse cellular responses. The final output of this network is determined not only by the p53 protein itself, but also by other p53 cooperating proteins.
p300 and CBP (CREB-Binding Protein) act as multifunctional regulators of p53 via acetylase and ubiquitin ligase activities. Prior work in vitro has shown that the N-terminal 595 aa of p300 encode both generic ubiquitin ligase (E3) and p53-directed E4 functions. Analysis of p300 or CBP-deficient cells revealed that both coactivators were required for endogenous p53 polyubiquitination and the normally rapid turnover of p53 in unstressed cells. Unexpectedly, p300/CBP ubiquitin ligase activities were absent in nuclear extracts and exclusively cytoplasmic. In the nucleus, CBP and p300 exhibited differential regulation of p53 gene target expression, C-terminal acetylation, and biologic response after DNA damage. p300 activated, and CBP repressed, PUMA expression, correlating with activating acetylation of p53 C-terminal lysines by p300, and a repressive acetylation of p53 lysine-320 induced by CBP. Consistent with their gene expression effects, CBP deficiency augmented, and p300 deficiency blocked, apoptosis after doxorubicin treatment. Subcellular compartmentalization of p300/CBP’s ubiquitination and transcription activities reconciles seemingly opposed functions—cytoplasmic p300/CBP E4 activities ubiquitinate and destabilize p53, while nuclear p300/CBP direct p53 acetylation, target gene activation, and biological outcome after genotoxic stress.
p53 is a prominent tumor suppressor gene and it is mutated in more than 50% of human tumors. Reactivation of endogenous p53 is one therapeutic avenue to stop cancer cell growth. In this thesis, we have identified S5as a critical regulator of p53 degradation and activity. S5a is a non-ATPase subunit in the 19S regulatory particle of the 26S proteasome. Our preliminary data indicates that S5a is required for p53 instability and is a negative regulator of p53 tranactivation. As a negative regulator of p53, S5a may therefore also represent a new target for cancer drug development against tumors that specifically maintain wild type p53.
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Chou, Yu-Ting. "Cited2, an autoregulated transcriptional modulator, in TGF-beta signaling." Connect to text online, 2006. http://rave.ohiolink.edu/etdc/view?acc_num=case1147147222.
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Silk, Rhiannon Nicola. "Studies into host macrophage transcriptional control by the African Swine Fever Virus protein A238L." Thesis, University of Edinburgh, 2010. http://hdl.handle.net/1842/4808.
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African swine fever virus (ASFV) is a large double-stranded DNA virus which causes a lethal haemorrhagic fever in domestic pigs. This virus primarily infects cells from the monocyte/macrophage lineage and its ability to manipulate the function of these cells is key to the pathogenesis of this disease. ASFV encodes several proteins involved in immune evasion. One of these proteins, A238L, has been shown to inhibit host macrophage gene transcription. This protein has been shown to interact with several cellular proteins involved in signal transduction: a serine/threonine protein phosphatase, calcinerurin (CaN), the transcription factor NF-кB, and most recently the transcriptional co-activator CREB binding protein (CBP/P300). However its exact mechanism of action is not fully understood. Previous work has been limited to the investigation of individual signaling pathways and/or the expression of individual host genes. The aim of this study was to investigate the global effect of A238L on host macrophage gene transcription and also to carry out further investigation into the mechanism by which this protein functions. To determine the global effect of A238L on host macrophage gene transcription differential gene expression between porcine cells expressing A238L and control cells was examined using a porcine oligonucleotide microarray. These results demonstrated that A238L was a potent inhibitor of host macrophage gene expression. Functional characterisation of the annotated genes showed that a large proportion of A238L down-regulated genes are typically induced in response to cell stress. Significantly, genes regulated by the I kappa B kinase (IKK), mitogen-activated protein kinase (MAPK) and janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling pathways were all shown to be down regulated by A238L. Genes associated with the MAPK pathways were particularly enriched. The transcription of A238L-regulated genes is controlled by numerous different transcription factors, including NF-кB. All of the transcription factors identified interact with the transcription co-activator CBP/P300. This provides a common link between these factors, and indicates that A238L may target CBP/P300 to inhibit gene transcription. This observation supports recent work demonstrating that A238L interacts with and inhibits CBP/P300 function. To explore the potential mechanisms involved in the nuclear localisation of A238L, ASFV-infected Vero cells, expressing A238L under the control of its own promoter, were examined under a range of conditions using confocal microscopy. The results demonstrated that A238L was actively imported into the nucleus and exported by a CRM 1 mediated pathway, although a pool of A238L protein remained in the cytoplasm. Sequence analysis of A238L identified the presence of two putative nuclear localisation signals (NLS-1 and NLS-2). NLS-2 was located within A238L’s CaN docking motif. Mutation of these motifs indicated that both NLS-1 and NLS-2 are active and exhibit functional redundancy. Mutation of the CaN docking motif alone, in the presence of intact NLS-2, resulted in a dramatic increase in the nuclear localisation of A238L. These results are consistent with a model in which A238L functions within both the nucleus and the cytoplasm and suggest that binding of CaN to A238L masks NLS-2, contributing to the cytoplasmic retention of A238L.
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Kakita, Tsuyoshi. "p300 protein as a coactivator of GATA-5 in the transcription of cardiac-restricted atrial natriuretic factor gene." Kyoto University, 2001. http://hdl.handle.net/2433/150538.
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Michael, Bindhu. "Human T lymphotropic virus type 1 (HTLV-1) accessory protein p30(II) modulates cellular and viral gene expression." Connect to this title online, 2004. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1088784889.
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Thesis (Ph. D.)--Ohio State University, 2004.Title from first page of PDF file. Document formatted into pages; contains xvii, 250 p.; also includes graphics (some col.) Includes bibliographical references (p. 207-250). Available online via OhioLINK's ETD Center
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Love, Ian M. "Critical and Independent Roles of the P/CAF Acetyltransferase in ARF-p53 Signaling: A Dissertation." eScholarship@UMMS, 2011. https://escholarship.umassmed.edu/gsbs_diss/663.
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For 30 years, the tumor suppressor p53 has been a subject of intense research in nearly every discipline of scientific inquiry. While numerous surprising roles for p53 in health and disease are uncovered each year, the central role of its activation in preventing neoplastic transformation has been and will remain at the forefront of p53 research as investigators work to address an unexpectedly complex question—precisely how does p53 integrate upstream stress signals to coordinate activation of its target genes in response to stress?
One manner in which to address this question is at the level of transcription initiation—after upstream signals converge on p53 and produce a number of pools of post-transcriptionally modified p53, how exactly are specific target promoters activated in such a sensitive, context-specific manner? The work presented herein aims to address the role of histone acetylation at the p21 promoter—a critical mediator of G1/S arrest—by the P/CAF acetyltransferase in response to a variety of p53-activating stresses. We show that depletion of P/CAF strongly inhibits p21 expression in response to a variety of stresses, despite normal stabilization of p53 and recruitment to target promoters. This defect in p21 expression correlates closely with abrogation of stress-induced cell-cycle arrest. Strikingly, a p53 allele lacking putative P/CAF acetylation sites was still able to direct p21 expression, which was still dependent upon P/CAF. We show further that histone acetylation at H3K14 at the p21 promoter following stress is dependent upon P/CAF. Rescue of p21 expression with wild-type P/CAF or a ∆HAT point mutant indicates that P/CAF requires an intact HAT domain, suggesting that histone acetylation at H3K14 is catalyzed by P/CAF HAT activity, not the molecular bridging of a heterologous HAT by P/CAF. Furthermore, RNA polymerase II (RNAP II) was present at the p21 proximal promoter under all basal and stress conditions, but elongation of RNAP II after stress required the presence of P/CAF. These data indicate that H3K14 acetylation by P/CAF closely correlates with the activation status of the p21 promoter, and may be necessary for activation of a larger subset of p53-responsive promoters.
In addition to its critical role in p21 expression, we noted that p53 stabilization and cell-cycle arrest in response to p14ARF, but not other p53-stabilizing stresses, were also dependent on P/CAF. Cell-cycle arrest induced by p16INK4A was intact after P/CAF ablation, indicating a role for P/CAF in cell-cycle arrest specific to p14ARF-p53 signaling. Basal MDM2 levels were unaffected by P/CAF knockdown, as were p53- MDM2 and ARF-MDM2 complexes. A preliminary analysis of MDM2 localization was inconclusive, due to vastly different quantities of MDM2 in different conditions making analysis of subcellular localization difficult; however, the role of P/CAF in the relocalization of MDM2 to the nucleolus by p14ARF could potentially explain the defect in p53 stabilization, and should be explored further.
These observations, underscored by recent reports that P/CAF undergoes loss of heterozygosity in several tumor types, suggest that P/CAF plays a critical role in p53-mediated cell-cycle arrest through multiple, independent mechanisms. Further study should clarify whether P/CAF is lost in tumors maintaining wild-type p53, and whether its reintroduction into these tumors confers any potential therapeutic benefit.
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Delboni, Thomaz Pileggi. "Investigação genético-clínica em pacientes com síndrome de Rubinstein-Taybi." Universidade de São Paulo, 2009. http://www.teses.usp.br/teses/disponiveis/5/5141/tde-19022010-163029/.
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INTRODUÇÃO: A Síndrome de Rubinstein-Taybi (RTS) é uma doença genética rara, caracterizada por dismorfismos craniofaciais típicos, polegares e háluces alargados, deficiência mental e baixa estatura. A incidência estimada é de 1: 125 000 a 1: 330000 nativivos. A SRT geralmente ocorre esporadicamente, mas pode ser herdada com um padrão de herança autossômico dominante. O diagnóstico da SRT é essencialmente clínico. OBJETIVOS: Realizar o estudo genético-clínico e citogenético em 30 pacientes brasileiros com SRT, e descrever de forma sistematizada a freqüência de dismorfismos faciais e malformações múltiplas encontradas. MÉTODOS: Neste estudo observacional retrospectivo e prospectivo, os pacientes foram seguidos no período de agosto de 2005 a junho de 2009. O cariótipo com bandeamento G foi realizado em todos os pacientes. RESULTADOS: A maioria dos pacientes avaliados foi do sexo feminino (60%). As seguintes características foram observadas em todos os pacientes da nossa casuística: atraso de desenvolvimento neuropsicomotor, ponta nasal voltada para baixo, columela proeminente, sorriso característico, dificuldades alimentares na infância, persistência dos coxins fetais, falanges distais dos polegares alargadas e pés planos. A baixa estatura e a microcefalia foi observada em 80% e 76% dos casos, respectivamente. As principais características craniofaciais observadas foram: fronte proeminente (86%), ponte nasal larga (60%), hipertelorismo (70%), sobrancelhas espessas e arqueadas (96%) cílios longos em 93%, prega epicântica (76%), fissura palpebral infra vertidas (76%), abertura bucal estreita (93%), retrognatismo (76 %), sorriso característico em 100%, palato alto e estreito (93%), anomalias dentárias (83%). Outras anomalias identificadas foram: estrabismo, erros de refração, obstrução do canal lacrimal, háluces e polegares alargados, angulação de polegares, anomalias do pavilhão auricular (rotação/posição/tamanho/forma), angulação do hálux, clinodactilia, sobreposição dos pododáctilos, falanges distais alargadas de outros dedos, marcha rígida, hipotonia, sopro cardíaco, cardiopatia congênita, criptoquidia, hemangioma plano e hipertricose. Uma paciente apresentou translocação recíproca de novo 46, XX, t (2; 16)(q36.3; p13.3). CONCLUSÕES: A raridade da SRT e o amplo espectro das manifestações clínicas pode atrasar o diagnóstico clínico. A média da idade ao diagnóstico dos nossos pacientes com SRT foi de três anos e oito meses. Todas as crianças devem receber avaliação por geneticista pediátrico, cardiologista, oftalmologista, neuropediatra, e odontopediatraINTRODUCTION: Rubinstein-Taybi syndrome (RTS) is a rare genetic disorder characterized by distinctive craniofacial dysmorphisms, broad thumbs and toes and mental and statural deficiency. The prevalence of RTS has been estimated to be 1 in 125000 to 1: 330000 live births. RTS usually occurs sporadically although it can be inherited as an autosomal dominant disorder. The diagnosis of RTS is primarily based on clinical features. OBJECTIVES: We performed a clinical and cytogenetic assay in a group of 30 Brazilian RTS patients. We also decribed the frequencies of facial dysmorphisms and multiple malformations. METHODS: In this observational retrospective and prospective study, the patients were followed from August 2005 to June 2009. Chromosomal analysis was performed by G-banding karyotype. RESULTS: Most of the patients were female (60%).The following abnormalities were present in all of the patients: delayed psychomotor development, beaked nose, proeminent collumel, typical facies, broad thumbs and toes, flat feet, joint laxity, feeding problems during the childhood, and finger pads. Short stature was present in 80%, and microcephalia in 76% of the cases, respectively. Main craniofacial characteristics are frontal bossing (86%), wide nasal bridge (60%), ocular hyperthelorism (70%), high arched eyebrows (96%), long eyelashes (93%), epicathal folds (76%), downslanting palpebral fissures (76%), small opening of the mouth (93%), retrognathism (76%), grimacing smile (100%), high arched palate (93%), and dental anomalies (83%). Other findings were: strabism, refractive error, lacrimal obstruction, wide thumb and halux, angulated thumbs, external ears anomalies (rotation, implantation and morfology), angulated halux, clinodactyly, crowded toes, broad distal falanges of other fingers, stiff gait, hipotonia, cardiac murmur, congenital heart defect, undescendent testis, hypertrichosis, and hemangioma. One female patient has found to have a reciprocal de novo translocation t(2;16)(q36.3;p13.3) on G-banding karyotype CONCLUSIONS: The rarity of RTS and the wide spectrum of clinical manifestations, may delay the clinical diagnosis of RTS. The average age at the diagnosis of our patients was 3 years and 8 months. All children of RTS should receive an evaluation by a pediatric geneticist, cardiologist, ophthalmologist, pediatric neurologist, and pediatric dentist
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Bricambert, Julien. "Régulation de l'homéostasie énergétique par le facteur de transcription ChREBP et ses protéines associées : implication dans la physiopathologie de la NAFLD." Paris 7, 2014. http://www.theses.fr/2014PA077177.
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Le spectre de la NAFLD (Non Alcoholic Fatty Liver Disease) est caractérisé par des atteintes hépatiques allant de la simple stéatose à la cirrhose. Dans ce contexte, nous montrons que la sérine/thréonine kinase SIK2 (Salt inducible kinase 2) inhibe l'activité histone acétyltransférase (HAT) de p300 par phosphorylation sur sa sérine 89, ce qui abolit en contrepartie l'activité transcriptionnelle du facteur de transcription ChREBP (Carbohydrate Responsive Element Binding Protein), en diminuant son acétylation. ChREBP est le médiateur des effets transcriptionnels du glucose, en contrôlant l'expression des gènes de la glycolyse et de la lipogenèse, nos résultats montrent que cette boucle de régulation permet de limiter la synthèse des acides gras et le développement de la NAFLD dans le foie. Nous montrons également que l'activation de Phf2 (Plant Homeodomain Finger 2) favorise le captage, la synthèse, l'estérification et le stockage des acides gras dans les gouttelettes lipidiques. Phf2 agit comme un co-activateur de ChREBP qui, en déméthylant spécifiquement la lysine 9 diméthylée de l'histone H3 sur le promoteur des gènes cibles de ChREBP, favorise le recrutement de la machinerie transcriptionnelle et l'induction de la transcription en réponse au glucose. Ainsi Phf2 et ChREBP augmentent la synthèse d'acides gras mono-insaturés (MUFA) insulino-sensibilisateurs et les défenses anti-oxydantes du foie, en stimulant l'expression et l'activité du facteur de transcription Nrf2 (Nuclear Factor E2-related factor 2). Cette régulation épigénétique de ChREBP permet le développement d'une stéatose hépatique bénigne dissociée d'une résistance à l'action de l'insuline et de la fibroseThe spectrum of NAFLD (Non Alcoholic Fatty Liver Disease) is characterized by liver damage ranging from simple steatosis to cirrhosis. The understanding of the mechanisms responsible for this ectopic lipid storage is essential in the search for therapeutic approaches. In this context, we show that the serine / threonine kinase SIK2 (Salt inducible kinase 2) inhibits the histone acetyltransferase (HAT) p300 by a phosphorylation on its serine 89, which in turn, abolishes the activity of the transcription factor ChREBP (Carbohydrate Responsive Element Binding Protein), decreasing its acetylation. ChREBP mediates the transcriptional effects of glucose, controling the expression of glycolitics and Iipogenics genes. We show that this control loop limits the synthesis of fatty acids and the development of NAFLD in the liver. We also show that the histone demethylase PHF2 (Plant homeodomain Finger 2) activation promotes the uptake, the synthesis, the esterification and the storage of fatty acids into the lipid droplets. PHF2 acts as a co - activator for ChREBP which, specifically demethylates the dimethylated lysine 9 of the histone H3 in the promoter of its targets genes to induce the recruitment of the transcriptional machinery, to induce transcription in response to glucose. Thus PHF2 and ChREBP increase the synthesis of monounsaturated fatty acids insulin-sensitizing and anti- oxidant defenses of the liver by stimulating the expression and actiyity of the transcription factor Nrf2 (nuclear factor E2 -related factor 2). This epigenetic regulation of ChREBP allows the development of a benign hepatic steatosis dissociated from resistance to the action of insulin and fibrosis
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Nair, Amrithraj Muraleedharan. "Studies of retroviral vectors for in utero gene transfer and investigation of calcium-mediated gene regulation by Human T-lymphotropic virus type-1." The Ohio State University, 2004. http://rave.ohiolink.edu/etdc/view?acc_num=osu1088785797.
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Marotta, Nicole. "Mycoplasma pneumoniae protein P30 proline residues: Cytadherence, gliding motility, and P30 stability." Miami University / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=miami1412010755.
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Riggs, Hailey Erin. "Mycoplasma pneumoniae protein P30: Stability, interactions, and function." Miami University / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=miami1511952462541533.
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Qutbuddin, Habib Robar. "Expression and purification of p53-TAD and CBP/p300 taz-2 proteins : With binding interaction studies of the MDM2 and the p53-TAD proteins." Thesis, Uppsala universitet, Institutionen för kemi - BMC, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-256097.
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Millward, Laurie M. "Yeast Two-Hybrid Analysis of Cellular Proteins Interacting with HTLV-1 p30." The Ohio State University, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=osu1267727377.
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Kendirgi, Frederic. "P30 and BmOSP, two novel follicular cell specific proteins involved in silkmoth oogenesis." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape2/PQDD_0021/NQ54792.pdf.
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BOULANGER, FLORENCE. "Toxoplasma gondii : identification, localisation et quantification de quatre antigenes immunodominants : conformation moleculaire et relation structure-activite de l'antigene majeur p30." Reims, 1991. http://www.theses.fr/1991REIMM204.
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Datta, Antara. "Human T Lymphotropic Virus Type 1 (HTLV-1) Accessory Protein p30 Modulates Cell Cycle and DNA Damage Signaling." The Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=osu1184007936.
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Doueiri, Rami. "CHARACTERIZATION OF THE HUMAN T-CELL LEUKEMIA VIRUS TYPE-2 P28 ACCESSORY PROTEIN." The Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1343453789.
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Raselabe, Iyani Calvin. "Identification of cytokines induced by two strains of African swine fever virus recombinant proteins p30 p54 and p72." Diss., University of Pretoria, 2017. http://hdl.handle.net/2263/62579.
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African swine fever virus (ASFV) is a virus that infects pigs causing haemorrhagic fever called African swine fever (ASF) with 100% mortality in domestic pigs. No effective vaccine is available that protects across genotypes. Cellular immune responses were demonstrated in pigs that were protected against a virulent strain challenge subsequent to infection with a moderately virulent ASFV strain. However, pigs did not survive challenge with a non-related virulent strain resulting in the development of ASF symptoms and death. The cellular immune response toward ASFV is not fully understood and needs further investigation in order to produce a vaccine that can cross-protect different ASFV genotypes. Structural proteins P30, P54 and P72 are the most immunogenic proteins to which neutralization antibodies have been observed. These were expressed previously in baculovirus for diagnostic purposes targeting ASFV antibodies in sera. The major structural protein P72, encoded by the B646L gene, contains conformational neutralizing epitopes and elicits robust immune responses. The proteins have been found to stimulate a humoral immune response that was confirmed when neutralizing antibodies against proteins were detected. However, this humoral response is still not effective in protecting swine against ASF. On the other hand, a cellular immune response can be stimulated with whole virus and has proven that its stimulation can protect against infection from a closely related strain. It is unknown whether these proteins also induce a cellular immune response even though they have been shown to induce humoral immunity due to the presence of neutralizing antibodies against these structural proteins. Therefore, it is hypothesised that if the cellular immune profiles of structural proteins P30, P54 and P72 are determined it could help in identifying potential vaccine candidate epitopes or give a platform by which other ASFV proteins can be screened for vaccine development.Protection against ASFV has been proven between virus strains from the same genotype. As an example, pigs challenged with a non-virulent strain (OURT88/3) were protected against challenge with the related virulent (OURT88/1) strain. However, when the pigs were challenged with virulent strains from different genotypes the pigs developed disease symptoms and succumbed to the virus. There is no effective vaccine against ASFV that confers cross protection between heterologous strains. This is one of the major obstacles in development of an effective vaccine against ASF. Therefore, the aim was to identify the cytokines induced by ASFV recombinant proteins P30, P54 and P72 from two divergent strains, one from Malawi (MAL), MAL/11/02 genotype II and one from the South Africa (RSA), RSA/12/15 from genotype XIX. Proteins from these strains were expressed using a pET102/D-TOPO® bacterial expression system, cloning was performed using the Invitrogen TOP10 cloning cells and expressed in BL21 (DE3) cells using isopropyl β-D-1-thiogalactopyranoside (IPTG) induction. The proteins were purified by affinity chromatography using Nickel columns with affinity to the His tag incorporated.Dissertation (MSc)--University of Pretoria, 2017.
Veterinary Tropical Diseases
MSc
Unrestricted
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Awasthi, Soumya. "Role of the human T cell lymphotropic virus type-1 (HTLV-1) accessory protein p30(II) in adult T cell leukemogenesis." Ann Arbor, Mich. : ProQuest, 2007. 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:3274548.
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Thesis (Ph.D. in Molecular and Cellular Biology)--S.M.U., 2007.Title from PDF title page (viewed Mar. 18, 2008). Source: Dissertation Abstracts International, Volume: 68-07, Section: B, page: 4266. Adviser: Robert Harrod. Includes bibliographical references.
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Kramer, Daniela. "Cooperation of p300 and iASPP in apoptosis and tumour suppression." Doctoral thesis, 2013. http://hdl.handle.net/11858/00-1735-0000-0023-9927-6.
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Kirlin, Alyssa. "Elucidation of the interactions between the transcription factor E2A and the transcriptional co-activator CBP/p300." Thesis, 2013. http://hdl.handle.net/1974/8149.
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E2A is a transcription factor that plays a particularly critical role in lymphopoiesis. The chromosomal translocation 1;19, disrupts the E2A gene and results in the expression of the fusion oncoprotein E2A-PBX1, which is implicated in acute lymphoblastic leukemia. Both E2A and E2A-PBX1 contain two activation domains, AD1 and AD2, which comprise conserved ΦxxΦΦ motifs where Φ denotes a hydrophobic amino acid. These domains function to recruit transcriptional co-activators and repressors, including the histone acetyl transferase CREB binding protein (CBP) and its paralog p300. The PCET motif within E2A AD1 interacts with the KIX domain of CBP/p300, the disruption of which abrogates the transcriptional activation by E2A and the transformative properties of E2A-PBX1. The generation of a peptide-based inhibitor targeting the PCET:KIX interaction would serve useful in further assessing the role of E2A and E2A-PBX1 in lymphopoiesis and leukemogenesis. An interaction between E2A AD2 and the KIX domain has also been recently identified, and the TAZ domains of CBP/p300 have been shown to interact with several transcription factors that contain ΦxxΦΦ motifs. Thus the design of an inhibitor of the E2A:CBP/p300 interaction requires the full complement of interactions between E2A and the various domains of CBP/p300 to be elucidated. Here, we have used nuclear magnetic resonance (NMR) spectroscopy to determine that AD2 interacts with KIX at the same site as PCET, which indicates that the E2A:KIX interaction can be disrupted by targeting a single binding site. Using an iterative synthetic peptide microarray approach, a peptide with the sequence DKELQDLLDFSLQY was derived from PCET to interact with KIX with higher affinity than the wild type sequence. This peptide now serves as a lead molecule for further development as an inhibitor of the E2A:CBP/p300 interaction. Fluorescence anisotropy, peptide microarray technology, and isothermal titration calorimetry were employed to characterize interactions between both TAZ domains of CBP/p300 and the PCET motif and AD2 of E2A. Alanine substitution of residues within PCET demonstrated that the ΦxxΦΦ motif is a key mediator of these interactions, analogous to the PCET:KIX interaction. These findings now inform future work to establish possible physiological roles for the E2A:TAZ1 and E2A:TAZ2 interactions.Thesis (Master, Biochemistry) -- Queen's University, 2013-08-06 13:52:28.248
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Forster, Nicole [Verfasser]. "Die p300-Protein-Acetyltransferaseaktivität supprimiert eine dem humanen systemischen Lupus erythematosus ähnliche Autoimmunerkrankung in Mäusen / vorgelegt von Nicole Forster." 2008. http://d-nb.info/991561937/34.
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Salem, Mohamed M. A., Mohammad Shalbaf, Nick C. Gibbons, Bhavan Chavan, M. Julie Thornton, and Karin U. Schallreuter. "Enhanced DNA binding capacity on up-regulated epidermal wild-type p53 in vitiligo by H2O2-mediated oxidation: a possible repair mechanism for DNA damage." 2009. http://hdl.handle.net/10454/6168.
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Vitiligo is characterized by a patchy loss of inherited skin color affecting approximately 0.5% of individuals of all races. Despite the absence of the protecting pigment and the overwhelming evidence for hydrogen peroxide (H(2)O(2))-induced oxidative stress in the entire epidermis of these patients, there is neither increased photodamage/skin aging nor a higher incidence for sun-induced nonmelanoma skin cancer. Here we demonstrate for the first time increased DNA damage via 8-oxoguanine in the skin and plasma in association with epidermal up-regulated phosphorylated/acetylated p53 and high levels of the p53 antagonist p76(MDM2). Short-patch base-excision repair via hOgg1, APE1, and polymerasebeta DNA repair is up-regulated. Overexpression of Bcl-2 and low caspase 3 and cytochrome c levels argue against increased apoptosis in this disease. Moreover, we show the presence of high epidermal peroxynitrite (ONOO(-)) levels via nitrotyrosine together with high nitrated p53 levels. We demonstrate by EMSA that nitration of p53 by ONOO(-) (300 x 10(-6) M) abrogates DNA binding, while H(2)O(2)-oxidized p53 (10(-3) M) enhances DNA binding capacity and prevents ONOO(-)-induced abrogation of DNA binding. Taken together, we add a novel reactive oxygen species to the list of oxidative stress inducers in vitiligo. Moreover, we propose up-regulated wild-type p53 together with p76(MDM2) as major players in the control of DNA damage/repair and prevention of photodamage and nonmelanoma skin cancer in vitiligo.
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DE, OLIVEIRA LOPES CALCADA EDUARDO PAULO. "Intrinsically disordered proteins - from sample preparation to molecular basis of function." Doctoral thesis, 2014. http://hdl.handle.net/2158/836300.
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Yang, Sue fung, and 楊淑方. "Using a recombinant Toxoplasma surface antigen P30 as a marker protein for serodiagnosis." Thesis, 1998. http://ndltd.ncl.edu.tw/handle/82254377547561272262.
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碩士國立臺灣大學
獸醫學系研究所
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Toxoplasma gondii was an obligate intracellular parasite beloning to Apic omplexa and spread all of the world, could infect all warm-blooded animals. As human beings, it was easy to result in dealth for the immunosuppressive patie nts and abortion for the pregnant women. As having animals, the symptom that c aused by toxoplasma gondii was not only much similar to human but also could c ause very serious loss of econicoms. At present the diagnosis of toxoplasma go ndii antigen needs came from inoculation, cell celture. Because the highly dan gers of operation made contamination very easy, it was necessary to develop a safe, convenient antigen, as the development of rapid diagnosis reagent. This experiment tried to proceed toxoplasma gondii P30 gene expression as the antig en of serodiagnosis.P30 protein was a specific antigen, and its antibodies wer e detected in all the patients infected toxoplasmosis. To utilize anti-P30IgG, anti-P30IgM, anti-P30IgA as serodiagnosis could distinguish chronic infection from acute infection. This experiment used PCR to amplify P30 gene fragment f rom toxoplasma RH strain, and the product inserted into the pGEM-T easy vector to proceed nucleotide sequencing. After the nucleotide sequence confirmed, Th e P30 gene was subclomed into prokaryotic expression vector, pGEX-4T-1. The r esulted plasmid contains bacterial Glutathion-S-transferase/P30 fusion gene an d can be induced to express GST-P30 fusion protein by 3mM IPTG induction. The molecular weight of recombinant GST-P30 fusion protein was expected to be 63KD . After SDS-PAGE and Western bloting analysis, this protein can be identified specifically by polyclonal antiserum from toxoplasma infected cats. This resul t suggests that the GST-P30 fusion protein has antigenic epitopes with the spe cificity of Toxoplasma gondii. Detail analysis of defined antigenic determinan ts of this recombinant protein and their reaction to other infected domestic a nimals remained to be investigated, however, this protein exhibits potential t o develop as a sensitive and specific antigen for rapid diagnosis of toxoplasm a infection simply from blood examination.
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Reynoird, Nicolas. "Dérégulations épigénétiques induites par la protéine fusion BRD4-NUT et caractérisation de la proteine NUT au cours de la spermatogenèse et dans les cancers." Phd thesis, 2010. http://tel.archives-ouvertes.fr/tel-00534655.
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Il apparait de nos jours évident que les cancers ne peuvent se réduire uniquement à des aberrations génétiques, et qu'un nouveau paramètre est à prendre en considération, l'épigénétique. Au cours de ma thèse je me suis efforcé de caractériser la protéine fusion BRD4-NUT. Cette protéine résulte d'une translocation t(15;19) observée dans les carcinomes de la ligne médiane (NMC), extrêmement agressifs et létaux. La protéine BRD4 possède un double bromodomaine capable de s'associer à la chromatine acétylée, et recrute divers facteurs sur la chromatine. NUT est une protéine de fonction inconnue exprimée exclusivement au cours de la spermatogenèse. J'ai pu démontrer que la protéine fusion BRD4-NUT était suffisante pour induire la tumorigenèse, par un mécanisme de séquestration de la proteine histone acétyltransférase (HAT) CBP/p300. NUT interagit avec CBP/p300 et suractive son activité d'acétylation, créant des foci hyperacétylés de chromatine. BRD4-NUT empêche ainsi CBP/p300 d'aller co-activer la transcription de nombreux gènes, et bloque notamment la réponse apoptotique p53-dépendante. Une inhibition de BRD4-NUT – par siRNA, mutation des bromodomaines ou dérégulation de l'acétylation des foci par des inhibiteurs des histones déacétylases (HDAC) – réenclenche la voie d'apoptose et la mort de ces cellules tumorales. Cette étude est un exemple précis de l'impact qu'une dérégulation épigénétique peut avoir sur l'homéostasie cellulaire et son mécanisme d'induction de la tumorigenèse. Je me suis également interessé à caracteriser la protéine NUT lors de son contexte physiologique, la spermatogenèse, ou lors de son expression illégitime dans des lignées tumorales sans fusion avec BRD4. La protéine NUT est exprimée au niveau des stades de maturation des cellules germinales spermatides, et pourrait participer au remodelage du génome et à l'établissement de l'épigénome final du spermatozoïde. Nut semble également conférer un avantage prolifératif lors de son expression anormale dans au moins trois lignées cellulaires, U2OS, A549 et A7R5. Ainsi, la protéine NUT, seule ou fusionnée avec BRD4, est un facteur Cancer/Testiculaire capable d'influer négativement sur l'homéostasie des cellules somatiques dans lesquelles ses fonctions, normalement restreintes à la spermatogenèse, participent à la tumorigenèse.
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Schulte-Kreutz, Thomas [Verfasser]. "Organ- und Gewebelokalisation von P30, einem Protein aus der Gruppe der Strukturproteine / vorgelegt von Thomas Schulte-Kreutz (geb. Schulte)." 2008. http://d-nb.info/990222918/34.
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