subject:(I B Kinase )

University of Cambridge

1. Prescott, Jack. Interrogating novel functions of the I kappa B kinases via CRISPR-Cas9 gene editing and small molecule inhibition.

Degree: PhD, 2018, University of Cambridge

URL: https://doi.org/10.17863/CAM.24323 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.744930

► The NF-kB signalling pathway is a critical mediator of the cellular responses to inflammatory cytokines. The IκB kinase (IKK) complex, which is composed of two… (more)

▼ The NF-kB signalling pathway is a critical mediator of the cellular responses to inflammatory cytokines. The IκB kinase (IKK) complex, which is composed of two catalytic subunits (IKKα and IKKβ) and one regulatory subunit (IKKγ/NEMO) acts as the master regulator of NF-κB transcription factor activity. Seminal genetic studies in knockout (KO) mouse embryonic fibroblasts (MEFs) have defined two pathways of NF-κB activation; a canonical pathway, activated in response to cytokines such as TNFα/IL-1β, that requires NEMO and predominantly IKKβ catalytic activity; and a non-canonical pathway, activated in response to a subset of TNF-family cytokines, which requires IKKα and NIK kinase. We have generated and validated CRISPR-Cas9 IKKα, IKKβ and IKKα/β DKO HCT116 colorectal cancer cell lines to interrogate novel functions of the I kappa B kinases in colorectal cancer, including the relative contributions of these kinases to the activation of NF-κB signalling pathways downstream of TNFα induction. Contrary to the seminal studies in KO MEFs, IKKα appeared to make a more significant contribution to canonical NF-κB induction in these cells than IKKβ. Western blot studies demonstrated that both IKKs contributed to the phosphorylation and degradation of IκB and the phosphorylation of the NF-κB subunit, p65 at Serine 536. However, high-content immunofluorescence studies demonstrated that IKKα KO cells were defective in TNFα-induced nuclear translocation of p65 compared to WT and IKKβ KO cells. Additionally, NF-κB-driven luciferase reporter assays showed that IKKα, but not IKKβ, KO cells exhibited significantly reduced NF-κB-dependent gene expression following TNFα stimulation. We also have evidence to suggest that the phosphorylation site at Serine 468 on p65, previously defined as an IKKβ-dependent site, is in-fact an IKKα-dependent site in these cells. Furthermore, IKKα knockout revealed a potentially important role for IKKα activity in preventing the stabilisation of NIK protein following prolonged TNFα stimulation. RNA sequencing analysis of wild-type, IKKα KO, IKKβ KO and IKKα/β DKO cells stimulated with TNFα was performed to identify genes whose expression were differentially deregulated by IKK KO. These analyses confirmed the importance of IKKα for canonical NF-κB gene expression. Furthermore, IKKβ knockout had unexpected effects on the expression of a broad range of genes involved in chromatin organisation, cytoskeletal organisation, mitotic cell cycle control and the DNA damage response. During the characterisation of IKK KO cells it was discovered that the expression of NEMO was downregulated at the protein, but not mRNA level by approximately 50% in IKKα KO cells and 90% in IKKα/β DKO cells. IKKβ KO cells, meanwhile, exhibited wild-type NEMO expression. Emetine-chase and radioactive pulse chase labelling experiments demonstrated that the half-life of NEMO in IKKα and IKKα/β DKO cells was significantly shortened due to enhanced proteasomal turnover. Bioinformatics analyses predicted significant regions of intrinsic…

Subjects/Keywords: 616.99; NF-kappa B; I kappa B kinase; NEMO

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Prescott, J. (2018). Interrogating novel functions of the I kappa B kinases via CRISPR-Cas9 gene editing and small molecule inhibition. (Doctoral Dissertation). University of Cambridge. Retrieved from https://doi.org/10.17863/CAM.24323 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.744930

Chicago Manual of Style (16^th Edition):

Prescott, Jack. “Interrogating novel functions of the I kappa B kinases via CRISPR-Cas9 gene editing and small molecule inhibition.” 2018. Doctoral Dissertation, University of Cambridge. Accessed January 18, 2021. https://doi.org/10.17863/CAM.24323 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.744930.

MLA Handbook (7^th Edition):

Prescott, Jack. “Interrogating novel functions of the I kappa B kinases via CRISPR-Cas9 gene editing and small molecule inhibition.” 2018. Web. 18 Jan 2021.

Vancouver:

Prescott J. Interrogating novel functions of the I kappa B kinases via CRISPR-Cas9 gene editing and small molecule inhibition. [Internet] [Doctoral dissertation]. University of Cambridge; 2018. [cited 2021 Jan 18]. Available from: https://doi.org/10.17863/CAM.24323 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.744930.

Council of Science Editors:

Prescott J. Interrogating novel functions of the I kappa B kinases via CRISPR-Cas9 gene editing and small molecule inhibition. [Doctoral Dissertation]. University of Cambridge; 2018. Available from: https://doi.org/10.17863/CAM.24323 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.744930

University of Texas Southwestern Medical Center

2. Skaug, Brian. Mechanisms Governing NF-κB Regulation by the Anti-Inflammatory Protein A20.

Degree: 2013, University of Texas Southwestern Medical Center

URL: http://hdl.handle.net/2152.5/1706

► A20 is a potent anti-inflammatory protein that inhibits NF-ΚB, and A20 dysfunction is associated with autoimmunity and B-cell lymphoma. A20 harbors a deubiquitination enzyme domain… (more)

Subjects/Keywords: I-kappa B Kinase; Inflammation; Intracellular Signaling Peptides and Proteins; NF-kappa B

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APA (6^th Edition):

Skaug, B. (2013). Mechanisms Governing NF-κB Regulation by the Anti-Inflammatory Protein A20. (Thesis). University of Texas Southwestern Medical Center. Retrieved from http://hdl.handle.net/2152.5/1706

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Skaug, Brian. “Mechanisms Governing NF-κB Regulation by the Anti-Inflammatory Protein A20.” 2013. Thesis, University of Texas Southwestern Medical Center. Accessed January 18, 2021. http://hdl.handle.net/2152.5/1706.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Skaug, Brian. “Mechanisms Governing NF-κB Regulation by the Anti-Inflammatory Protein A20.” 2013. Web. 18 Jan 2021.

Vancouver:

Skaug B. Mechanisms Governing NF-κB Regulation by the Anti-Inflammatory Protein A20. [Internet] [Thesis]. University of Texas Southwestern Medical Center; 2013. [cited 2021 Jan 18]. Available from: http://hdl.handle.net/2152.5/1706.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Skaug B. Mechanisms Governing NF-κB Regulation by the Anti-Inflammatory Protein A20. [Thesis]. University of Texas Southwestern Medical Center; 2013. Available from: http://hdl.handle.net/2152.5/1706

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Universidade Estadual de Campinas

3. Weissmann, Laís, 1989-. A exposição ao material particulado MP 2,5 induz a resistência à leptina no hipotálamo e estimula a hiperfagia e a obesidade em camundongos : PM 2,5 exposure induces leptin resistance in the hypothalamus and drives hyperphagia and obesity in mice: PM 2,5 exposure induces leptin resistance in the hypothalamus and drives hyperphagia and obesity in mice.

Degree: 2018, Universidade Estadual de Campinas

URL: http://repositorio.unicamp.br/jspui/handle/REPOSIP/335778

► Abstract: Background: The exposure to environmental pollution is increasing overall affecting human health and global climate. The particulate matter with less than 2.5 diameters (PM2.5)… (more)

▼ Abstract: Background: The exposure to environmental pollution is increasing overall affecting human health and global climate. The particulate matter with less than 2.5 diameters (PM2.5) is the well-known air pollutant that cause cardiometabolic diseases. Objectives: The present study aimed to investigate whether an acute or chronic PM2.5 exposures may induce obesity and insulin resistance in mice and also to address the pathophysiological mechanism that underlined these outcomes, and to evaluate the role of IKK 'epsilon' in the hypothalamus. Methods: Male C57BL/6J mice were 6-8 weeks¿ old receiving a standard rodent chow were exposed to PM2.5 or filtrated air (FA) using the Harvard Ambient Fine Particles Concentrator for 1 or 5 days or 3 months. Metabolic parameters and gene expression were measured. The specifically knocking down of IKK? was done in the hypothalamus of mice exposed to PM2.5. Results: PM2.5 exposure increased fat mass and food intake (FI) as early as five days. After three months of PM2.5 exposures there was a robustly increased in weight gain and fat mass along with insulin resistance even in mice on chow diet. Chronic PM2.5 exposures also increased FI, decreased O2 consumption, CO2, heat and Ucp1 gene expression in the brown adipose tissue. The anorexigenic effect of leptin was marked disrupted in mice exposed to PM2.5 accompanied by a reduction on Pomc gene expression and a slight decrease in STAT3 phosphorylation in the hypothalamus. Pro-inflammatory genes expression as Ikbke, Tnf and Tlr4 were enhanced in the hypothalamus of PM2.5-exposed mice. Knocking down Ikbke in the hypothalamus of these mice was sufficient to improve leptin action/signaling and robustly decreased FI along with increased energy expenditure protecting them from weight gain and insulin resistance. Discussion: This study emphasizes the deleterious effects of air pollution on the progressively weight gain and hyperphagia and draws attention to the urgent need to control global pollution. The inflammatory protein IKK? plays a key role in the development of these pathologies. Inhibition of this protein reduces adiposity, food intake and increases energy expenditure, in addition to improving the resistance to leptin from animals that have been exposed to pollution Advisors/Committee Members: UNIVERSIDADE ESTADUAL DE CAMPINAS (CRUESP), Prada, Patrícia de Oliveira, 1971- (advisor), Universidade Estadual de Campinas. Faculdade de Ciências Médicas (institution), Programa de Pós-Graduação em Ciências Médicas (nameofprogram), Oliveira, Camila Andrea de (committee member), Moura, Leandro Pereira de (committee member), Ropelle, Eduardo Rochete (committee member), Oliveira, Alexandre Gabarra de (committee member).

Subjects/Keywords: Ar - Poluição; Material particulado; Quinase I-kappa B epsilon; Obesidade; Hipotálamo; Air pollution; Particulate matter; I-kappa B Kinase epsilon; Obesity; Hypothalamus

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Weissmann, Laís, 1. (2018). A exposição ao material particulado MP 2,5 induz a resistência à leptina no hipotálamo e estimula a hiperfagia e a obesidade em camundongos : PM 2,5 exposure induces leptin resistance in the hypothalamus and drives hyperphagia and obesity in mice: PM 2,5 exposure induces leptin resistance in the hypothalamus and drives hyperphagia and obesity in mice. (Thesis). Universidade Estadual de Campinas. Retrieved from http://repositorio.unicamp.br/jspui/handle/REPOSIP/335778

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Weissmann, Laís, 1989-. “A exposição ao material particulado MP 2,5 induz a resistência à leptina no hipotálamo e estimula a hiperfagia e a obesidade em camundongos : PM 2,5 exposure induces leptin resistance in the hypothalamus and drives hyperphagia and obesity in mice: PM 2,5 exposure induces leptin resistance in the hypothalamus and drives hyperphagia and obesity in mice.” 2018. Thesis, Universidade Estadual de Campinas. Accessed January 18, 2021. http://repositorio.unicamp.br/jspui/handle/REPOSIP/335778.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Weissmann, Laís, 1989-. “A exposição ao material particulado MP 2,5 induz a resistência à leptina no hipotálamo e estimula a hiperfagia e a obesidade em camundongos : PM 2,5 exposure induces leptin resistance in the hypothalamus and drives hyperphagia and obesity in mice: PM 2,5 exposure induces leptin resistance in the hypothalamus and drives hyperphagia and obesity in mice.” 2018. Web. 18 Jan 2021.

Vancouver:

Weissmann, Laís 1. A exposição ao material particulado MP 2,5 induz a resistência à leptina no hipotálamo e estimula a hiperfagia e a obesidade em camundongos : PM 2,5 exposure induces leptin resistance in the hypothalamus and drives hyperphagia and obesity in mice: PM 2,5 exposure induces leptin resistance in the hypothalamus and drives hyperphagia and obesity in mice. [Internet] [Thesis]. Universidade Estadual de Campinas; 2018. [cited 2021 Jan 18]. Available from: http://repositorio.unicamp.br/jspui/handle/REPOSIP/335778.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Weissmann, Laís 1. A exposição ao material particulado MP 2,5 induz a resistência à leptina no hipotálamo e estimula a hiperfagia e a obesidade em camundongos : PM 2,5 exposure induces leptin resistance in the hypothalamus and drives hyperphagia and obesity in mice: PM 2,5 exposure induces leptin resistance in the hypothalamus and drives hyperphagia and obesity in mice. [Thesis]. Universidade Estadual de Campinas; 2018. Available from: http://repositorio.unicamp.br/jspui/handle/REPOSIP/335778

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

4. Rajurkar, Mihir S. GLI-IKBKE Requirement In KRAS-Induced Pancreatic Tumorigenesis: A Dissertation.

Degree: Cancer Biology, Molecular, Cell and Cancer Biology Department, 2014, U of Massachusetts : Med

URL: http://escholarship.umassmed.edu/gsbs_diss/753

► Pancreatic ductal adenocarcinoma (PDAC), one of the most aggressive human malignancies, is thought to be initiated by KRAS activation. Here, we find that transcriptional… (more)

▼ Pancreatic ductal adenocarcinoma (PDAC), one of the most aggressive human malignancies, is thought to be initiated by KRAS activation. Here, we find that transcriptional activation mediated by the GLI family of transcription factors, although dispensable for pancreatic development, is required for KRAS induced pancreatic transformation. Inhibition of GLI using a dominant-negative repressor (Gli3T) inhibits formation of precursor Pancreatic Intraepithelial Neoplasia (PanIN) lesions in mice, and significantly extends survival in a mouse model of PDAC. Further, ectopic activation of the GLI1/2 transcription factors in mouse pancreas accelerates KRAS driven tumor formation and reduces survival, underscoring the importance of GLI transcription factors in pancreatic tumorigenesis. Interestingly, we find that although canonical GLI activity is regulated by the Hedgehog ligands, in the context of PDAC, GLI transcription factors initiate a unique ligand-independent transcriptional program downstream of KRAS, that involves regulation of the RAS, PI3K/AKT, and NF-кB pathways. We identify I-kappa-B kinase epsilon (IKBKE) as a PDAC specific target of GLI, that can also regulate GLI transcriptional activity via positive feedback mechanism involving regulation of GLI subcellular localization. Using human PDAC cells, and an in vivo model of pancreatic neoplasia, we establish IKBKE as a novel regulator pf pancreatic tumorigenesis that acts as an effector of KRAS/GLI, and mediates pancreatic transformation. We show that genetic knockout of Ikbke leads to a dramatic inhibition of initiation and progression of pancreatic intraepithelial viii neoplasia (PanIN) lesions in mice carrying pancreas specific activation of oncogenic Kras. Furthermore, we find that although IKBKE is a known NF-кB activator, it only modestly regulates NF-кB activity in PDAC. Instead, we find that IKBKE strongly promotes AKT phosphorylation in PDAC in vitro and in vivo, and that IKBKE mediates reactivation of AKT post-inhibition of mTOR. We also show that while mTOR inhibition alone does not significantly affect pancreatic tumorigenesis, combined inhibition of IKBKE and mTOR has a synergistic effect leading to significant decrease tumorigenicity of PDAC cells. Together, our findings identify GLI/IKBKE signaling as an important oncogenic effector pathway of KRAS in PDAC that regulates tumorigenicity, cell proliferation, and apoptosis via regulation of AKT and NF-кB signaling. We provide proof of concept for therapeutic targeting of GLI/IKBKE in PDAC, and support the evaluation of IKBKE as a therapeutic target in treatment of pancreatic cancer, and IKBKE inhibition as a strategy to improve efficacy of mTOR inhibitors in the clinic. Advisors/Committee Members: Junhao Mao, Ph.D..

Subjects/Keywords: Pancreatic Ductal Carcinoma; I-kappa B Kinase; Pancreatic Neoplasms; Phosphatidylinositol 3-Kinases; Transcription Factors; Carcinogenesis; Transcriptional Activation; Cancer Biology; Neoplasms

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Rajurkar, M. S. (2014). GLI-IKBKE Requirement In KRAS-Induced Pancreatic Tumorigenesis: A Dissertation. (Doctoral Dissertation). U of Massachusetts : Med. Retrieved from http://escholarship.umassmed.edu/gsbs_diss/753

Chicago Manual of Style (16^th Edition):

Rajurkar, Mihir S. “GLI-IKBKE Requirement In KRAS-Induced Pancreatic Tumorigenesis: A Dissertation.” 2014. Doctoral Dissertation, U of Massachusetts : Med. Accessed January 18, 2021. http://escholarship.umassmed.edu/gsbs_diss/753.

MLA Handbook (7^th Edition):

Rajurkar, Mihir S. “GLI-IKBKE Requirement In KRAS-Induced Pancreatic Tumorigenesis: A Dissertation.” 2014. Web. 18 Jan 2021.

Vancouver:

Rajurkar MS. GLI-IKBKE Requirement In KRAS-Induced Pancreatic Tumorigenesis: A Dissertation. [Internet] [Doctoral dissertation]. U of Massachusetts : Med; 2014. [cited 2021 Jan 18]. Available from: http://escholarship.umassmed.edu/gsbs_diss/753.

Council of Science Editors:

Rajurkar MS. GLI-IKBKE Requirement In KRAS-Induced Pancreatic Tumorigenesis: A Dissertation. [Doctoral Dissertation]. U of Massachusetts : Med; 2014. Available from: http://escholarship.umassmed.edu/gsbs_diss/753

Queen Mary, University of London

5. Johnson, Florence Lilian. The late inhibition of IκB kinase attenuates acute kidney injury and the subsequent development of renal fibrosis in animal models of ischaemia-reperfusion injury and unilateral ureteral obstruction.

Degree: PhD, 2016, Queen Mary, University of London

URL: http://qmro.qmul.ac.uk/xmlui/handle/123456789/36706 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.765842

► Acute kidney injury (AKI) is a major risk factor for chronic kidney disease (CKD). For patients who recover from AKI, there is a 25% increase… (more)

▼ Acute kidney injury (AKI) is a major risk factor for chronic kidney disease (CKD). For patients who recover from AKI, there is a 25% increase in the risk of CKD, and a mortality rate of up to 50% after 10 years. Nuclear factor kappa-B (NF-κB) is a family of transcription factors that regulates the transcription of many proteins that play a key role in inflammation. Inhibitor of IκB kinase (IKK) is directly upstream of NF-κB. My aim was to investigate a) the role of IKK in the progression of AKI to CKD, and b) whether its inhibition attenuates renal fibrosis. In this thesis I used a model of unilateral renal ischaemia-reperfusion injury with contralateral nephrectomy, to firstly map the acute time course of AKI. From the data generated from the time course, I decided to treat the animals at 24 h post reperfusion with the IKK inhibitor, IKK16, as i) this was at the peak of renal dysfunction (24 h post reperfusion), and ii) prior to the activation of NF-κB (48 h post reperfusion). The inhibition of IKK at 24 hours post reperfusion, as a delayed treatment, successfully attenuated renal dysfunction, NF-κB activation and renal structural damage. I subsequently increased the recovery time after ischaemia-reperfusion in my rat model to 28 days to study the development of fibrosis post AKI. The inhibition of IKK at 24 hours post reperfusion successfully attenuated the development of fibrosis, formation of myofibroblasts, macrophage infiltration, the expression of pro-fibrotic markers and the deposition of extracellular matrix components at 28 days post reperfusion. In addition, the delayed inhibition of IKK at days 7-13 post unilateral ureteral obstruction in a rat model, successfully attenuated the development of fibrosis, formation of myofibroblasts, macrophage infiltration, the expression of pro-fibrotic markers and the deposition of extracellular matrix components. These data indicate that the activation of the IKK complex drives tubulointerstitial fibrosis, and suggests that the inhibition of IKK could be a useful pharmacological tool for the creation of therapies to combat AKI and the subsequent development of fibrosis, via the reduction of both inflammation and the prevention of the expression of pro-fibrotic markers.

Subjects/Keywords: Translational Medicine and Therapeutics; Acute kidney injury; chronic kidney disease; Inhibitor of I?B kinase; renal fibrosis

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APA (6^th Edition):

Johnson, F. L. (2016). The late inhibition of IκB kinase attenuates acute kidney injury and the subsequent development of renal fibrosis in animal models of ischaemia-reperfusion injury and unilateral ureteral obstruction. (Doctoral Dissertation). Queen Mary, University of London. Retrieved from http://qmro.qmul.ac.uk/xmlui/handle/123456789/36706 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.765842

Chicago Manual of Style (16^th Edition):

Johnson, Florence Lilian. “The late inhibition of IκB kinase attenuates acute kidney injury and the subsequent development of renal fibrosis in animal models of ischaemia-reperfusion injury and unilateral ureteral obstruction.” 2016. Doctoral Dissertation, Queen Mary, University of London. Accessed January 18, 2021. http://qmro.qmul.ac.uk/xmlui/handle/123456789/36706 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.765842.

MLA Handbook (7^th Edition):

Johnson, Florence Lilian. “The late inhibition of IκB kinase attenuates acute kidney injury and the subsequent development of renal fibrosis in animal models of ischaemia-reperfusion injury and unilateral ureteral obstruction.” 2016. Web. 18 Jan 2021.

Vancouver:

Johnson FL. The late inhibition of IκB kinase attenuates acute kidney injury and the subsequent development of renal fibrosis in animal models of ischaemia-reperfusion injury and unilateral ureteral obstruction. [Internet] [Doctoral dissertation]. Queen Mary, University of London; 2016. [cited 2021 Jan 18]. Available from: http://qmro.qmul.ac.uk/xmlui/handle/123456789/36706 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.765842.

Council of Science Editors:

Johnson FL. The late inhibition of IκB kinase attenuates acute kidney injury and the subsequent development of renal fibrosis in animal models of ischaemia-reperfusion injury and unilateral ureteral obstruction. [Doctoral Dissertation]. Queen Mary, University of London; 2016. Available from: http://qmro.qmul.ac.uk/xmlui/handle/123456789/36706 ; https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.765842

IUPUI

6. Fears, Sharry L. Effect of Inhibition of S-Nitrosoglutathione Reductase on the NF-κB Pathway.

Degree: 2009, IUPUI

URL: http://hdl.handle.net/1805/1949

►

Indiana University-Purdue University Indianapolis (IUPUI)

S-nitrosoglutathione reductase (GSNOR) also known as glutathione- dependent formaldehyde dehydrogenase (FDH), is a zinc-dependent dehydrogenase. GSNOR oxidizes long chain alcohols… (more)

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Indiana University-Purdue University Indianapolis (IUPUI)

S-nitrosoglutathione reductase (GSNOR) also known as glutathione- dependent formaldehyde dehydrogenase (FDH), is a zinc-dependent dehydrogenase. GSNOR oxidizes long chain alcohols to an aldehyde with the help of a molecule of NAD+. GSNOR was initially identified as FDH because of its role in the formaldehyde detoxification pathway. The only S-nitrosothiol (SNO) substrate recognized by GSNOR is GSNO. A transnitrosation reaction transfers NO from nitrosylated proteins or S-nitrosothiols (RSNO) to glutathione to form S-nitrosoglutathione. This GSNO is finally converted to glutathione disulfide (GSSG) by a two step mechanism. Cellular GSNO is a nitric oxide reservoir that can either transfer to or remove from the proteins a NO group. Reduction of GSNO by GSNOR depletes this reservoir and therefore indirectly regulates protein nitrosylation. GSNOR inhibitors which can increase the basal GSNO levels will be another potential therapy. Several GSNOR inhibitors were identified in our laboratory and the aim of this study was to understand their cellular effects. One of the experiments studied the effect of the compound on protein-SNO. The role of nitric oxide in regulation of NF-κB pathway is reviewed by Bove and van der Vliet. We focused on identification of nitrosylated proteins using protein specific antibodies. We identified nitrosylation of IKKβ. So the question raised was whether nitrosylation of IKKβ affects its activity. IKKβ is responsible for phosphorylation of IκBα and phosphorylation of IκBα results in its degradation and activation of NF-κB pathway. Therefore, we studied the phosphorylation of IκBα in the presence of inhibitor C3. Results showed a dose-dependent decrease of pIκB. So the next question was whether the phosphorylation of IKKβ was affected by nitrosylation. We did not detect any change in pIKKβ with different concentrations of C3. The decreased degradation of IκBα caused by C3 translated into decreased NF-κB activity as seen by a dose-dependent decrease in amounts of ICAM-1 with increasing C3 concentration. This data supports the premise that the activity of transcription factor NF-κB is suppressed by inhibiting GSNOR with compound C3

Advisors/Committee Members: Sanghani, Sonal P., Sanghani, Paresh C., Bosron, William F..

Subjects/Keywords: I kappa B; I kappa B kinase beta; NF-kappa B; Nitric Oxide; S-Nitrosoglutathione reductase; Nitric oxide; Dehyrdogenases; Phosphorylation

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Fears, S. L. (2009). Effect of Inhibition of S-Nitrosoglutathione Reductase on the NF-κB Pathway. (Thesis). IUPUI. Retrieved from http://hdl.handle.net/1805/1949

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Fears, Sharry L. “Effect of Inhibition of S-Nitrosoglutathione Reductase on the NF-κB Pathway.” 2009. Thesis, IUPUI. Accessed January 18, 2021. http://hdl.handle.net/1805/1949.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Fears, Sharry L. “Effect of Inhibition of S-Nitrosoglutathione Reductase on the NF-κB Pathway.” 2009. Web. 18 Jan 2021.

Vancouver:

Fears SL. Effect of Inhibition of S-Nitrosoglutathione Reductase on the NF-κB Pathway. [Internet] [Thesis]. IUPUI; 2009. [cited 2021 Jan 18]. Available from: http://hdl.handle.net/1805/1949.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Fears SL. Effect of Inhibition of S-Nitrosoglutathione Reductase on the NF-κB Pathway. [Thesis]. IUPUI; 2009. Available from: http://hdl.handle.net/1805/1949

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

7. Ea, Chee-Kwee. Ubiquitination-Dependent Activation of IKK.

Degree: 2005, University of Texas Southwestern Medical Center

URL: http://hdl.handle.net/2152.5/382

► Ubiquitination plays two different roles in the nuclear factor κΒ (NF-κΒ ) pathway, the traditional K48-linked polyubiquitination-mediated IκΒ degradation and the non-traditional K63-linked polyubiquitination-mediated IKK… (more)

▼ Ubiquitination plays two different roles in the nuclear factor κΒ (NF-κΒ ) pathway, the traditional K48-linked polyubiquitination-mediated IκΒ degradation and the non-traditional K63-linked polyubiquitination-mediated IKK activation. TRAF6 is a RING domain ubiquitin ligase that mediates the activation of protein kinases such as TAK1 and IKK by promoting the formation of a unique polyubiquitin chain linked through lysine-63 of ubiquitin. Previous studies have suggested that the ubiquitin ligase and signaling activity of TRAF6 may be regulated by its oligomerization. However, it is not known whether there is an endogenous "oligomerizer" that regulates TRAF6 activity. TRAF-interacting protein with a forkhead-associated (FHA) domain (TIFA, also known as T2BP) is one of such TRAF6 "oligomerizers". Recombinant TIFA protein, but not TRAF6-binding defective mutant protein, can activate IKK in crude cytosolic extracts. Furthermore, TIFA activates IKK in an in vitro reconstitution system consisting of purified proteins including TRAF6, the TAK1 kinase complex and the ubiquitin conjugating enzyme complex Ubc13/Uev1A. Interestingly, a fraction of recombinant TIFA protein exists as high molecular weight oligomers, and only these oligomeric forms of TIFA can activate IKK. Importantly, TIFA induces the oligomerization and polyubiquitination of TRAF6, which leads to the activation of TAK1 and IKK through a proteasome-independent mechanism. The receptor interacting protein kinase 1 (RIP1) is essential for the activation of NF-κΒ in response to tumor necrosis factor a (TNFa) stimulation. RIP1 undergoes TNF-induced polyubiquitination at Lysine 377 in the intermediate domain and the polyubiquitination of RIP1 is required for proper signal transduction. Furthermore, when introducing RIPK377R mutant into RIP-/- Jurkat cells, it fails to restore TNF-dependent IKK activation, and these RIPK377R cells are sensitive to TNFa-induced cell death. In addition, TAK1 and IKK kinase complexes are not recruited to TNFR1 followed TNFa stimulation in the absence of RIP1 polyubiquitination. Moreover, TAB2 and NEMO bind to K63-linked polyubiquitin chains and function as receptors that bind polyubiquitinated RIP1. These results indicate a unique interaction between a polyubiquitinated protein and a polyubiquitin binding protein can trigger the activation of TAK1 and IKK. Advisors/Committee Members: Chen, Zhijian J..

Subjects/Keywords: TNF Receptor-Associated Factor 6; Ubiquitination; I-kappa B Kinase

…TABLE OF CONTENTS TITLE �� i DEDICATION… …xiv CHAPTER I: GENERAL INTRODUCTION… …21 I.B.3.b Ubiquitination and processing of p100 and p105… …66 III.B.7 IKK kinase assay… …77 III.C.4 Polyubiquitination of RIP1 is Required for Recruitment of TAK1 and IKK Kinase…

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Ea, C. (2005). Ubiquitination-Dependent Activation of IKK. (Thesis). University of Texas Southwestern Medical Center. Retrieved from http://hdl.handle.net/2152.5/382

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Ea, Chee-Kwee. “Ubiquitination-Dependent Activation of IKK.” 2005. Thesis, University of Texas Southwestern Medical Center. Accessed January 18, 2021. http://hdl.handle.net/2152.5/382.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Ea, Chee-Kwee. “Ubiquitination-Dependent Activation of IKK.” 2005. Web. 18 Jan 2021.

Vancouver:

Ea C. Ubiquitination-Dependent Activation of IKK. [Internet] [Thesis]. University of Texas Southwestern Medical Center; 2005. [cited 2021 Jan 18]. Available from: http://hdl.handle.net/2152.5/382.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Ea C. Ubiquitination-Dependent Activation of IKK. [Thesis]. University of Texas Southwestern Medical Center; 2005. Available from: http://hdl.handle.net/2152.5/382

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

8. Paquette, Nicholas Paul. Caspase Mediated Cleavage, IAP Binding, Ubiquitination and Kinase Activation : Defining the Molecular Mechanisms Required for Drosophila NF-кB Signaling: A Dissertation.

Degree: Interdisciplinary Graduate Program, Medicine, 2009, U of Massachusetts : Med

URL: https://escholarship.umassmed.edu/gsbs_diss/444

► Innate immunity is the first line of defense against invading pathogens. Vertebrate innate immunity provides both initial protection, and activates adaptive immune responses, including… (more)

▼ Innate immunity is the first line of defense against invading pathogens. Vertebrate innate immunity provides both initial protection, and activates adaptive immune responses, including memory. As a result, the study of innate immune signaling is crucial for understanding the interactions between host and pathogen. Unlike mammals, the insect Drosophila melanogasterlack classical adaptive immunity, relying on innate immune signaling via the Toll and IMD pathways to detect and respond to invading pathogens. Once activated these pathways lead to the rapid and robust production of a variety of antimicrobial peptides. These peptides are secreted directly into the hemolymph and assist in clearance of the infection. The genetic and molecular tools available in the Drosophila system make it an excellent model system for studying immunity. Furthermore, the innate immune signaling pathways used by Drosophilashow strong homology to those of vertebrates making them ideal for the study of activation, regulation and mechanism. Currently a number of questions remain regarding the activation and regulation of both vertebrate and insect innate immune signaling. Over the past years many proteins have been implicated in mammalian and insect innate immune signaling pathways, however the mechanisms by which these proteins function remain largely undetermined. My work has focused on understanding the molecular mechanisms of innate immune activation in Drosophila. In these studies I have identified a number of novel protein/protein interactions which are vital for the activation and regulation of innate immune induction. This work shows that upon stimulation the Drosophila protein IMD is cleaved by the caspase-8 homologue DREDD. Cleaved IMD then binds the E3 ligase DIAP2 and promotes the K63-polyubiquitination of IMD and activation of downstream signaling. Furthermore the Yersinia pestis effector protein YopJ is able to inhibit the critical IMD pathway MAP3 kinase TAK1 by serine/threonine-acetylation of its activation loop. Lastly TAK1 signaling to the downstream Relish/NF-κB and JNK signaling pathways can be regulated by two isoforms of the TAB2 protein. This work elucidates the molecular mechanism of the IMD signaling pathway and suggests possible mechanisms of homologous mammalian systems, of which the molecular details remain unclear. Advisors/Committee Members: Neal Silverman, Ph.D..

Subjects/Keywords: Immunity; Innate; I-kappa B Kinase; Drosophila Proteins; Bacterial Proteins; Yersinia pestis; Amino Acids, Peptides, and Proteins; Animal Experimentation and Research; Bacteria; Enzymes and Coenzymes; Hemic and Immune Systems

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Paquette, N. P. (2009). Caspase Mediated Cleavage, IAP Binding, Ubiquitination and Kinase Activation : Defining the Molecular Mechanisms Required for Drosophila NF-кB Signaling: A Dissertation. (Doctoral Dissertation). U of Massachusetts : Med. Retrieved from https://escholarship.umassmed.edu/gsbs_diss/444

Chicago Manual of Style (16^th Edition):

Paquette, Nicholas Paul. “Caspase Mediated Cleavage, IAP Binding, Ubiquitination and Kinase Activation : Defining the Molecular Mechanisms Required for Drosophila NF-кB Signaling: A Dissertation.” 2009. Doctoral Dissertation, U of Massachusetts : Med. Accessed January 18, 2021. https://escholarship.umassmed.edu/gsbs_diss/444.

MLA Handbook (7^th Edition):

Paquette, Nicholas Paul. “Caspase Mediated Cleavage, IAP Binding, Ubiquitination and Kinase Activation : Defining the Molecular Mechanisms Required for Drosophila NF-кB Signaling: A Dissertation.” 2009. Web. 18 Jan 2021.

Vancouver:

Paquette NP. Caspase Mediated Cleavage, IAP Binding, Ubiquitination and Kinase Activation : Defining the Molecular Mechanisms Required for Drosophila NF-кB Signaling: A Dissertation. [Internet] [Doctoral dissertation]. U of Massachusetts : Med; 2009. [cited 2021 Jan 18]. Available from: https://escholarship.umassmed.edu/gsbs_diss/444.

Council of Science Editors:

Paquette NP. Caspase Mediated Cleavage, IAP Binding, Ubiquitination and Kinase Activation : Defining the Molecular Mechanisms Required for Drosophila NF-кB Signaling: A Dissertation. [Doctoral Dissertation]. U of Massachusetts : Med; 2009. Available from: https://escholarship.umassmed.edu/gsbs_diss/444

Colorado State University

9. Caldas, Gina V. Kinetochore protein KNL1 links kinetochore-microtubule attachment and checkpoint signaling during mitosis, The.

Degree: PhD, Biochemistry and Molecular Biology, 2014, Colorado State University

URL: http://hdl.handle.net/10217/85026

► Mitosis is the phase of the cell cycle in which replicated chromosomes physically separate, resulting in the formation of two genetically identical daughter cells. This… (more)

▼ Mitosis is the phase of the cell cycle in which replicated chromosomes physically separate, resulting in the formation of two genetically identical daughter cells. This process is not only essential for the development of a single fertilized cell into a multicellular organism, but also for replacement of damaged and dying cells during the span life of an organism. The distribution of chromosomes during mitotic cell division requires accurate yet dynamic attachment between the plus-ends of spindle microtubules (MTs) and kinetochores, which are protein structures assembled at the centromeric region of replicated chromatids. The tightly regulated connection between kinetochores and MTs allows for chromosome congression to the metaphase plate and subsequent separation of the replicated chromosomes during anaphase. Not surprisingly, the inability of cells to resolve erroneous kinetochore-MT attachments results in missegregation of chromosomes, which is linked to uncontrolled cell proliferation and cancer. Thus, proper kinetochore-MT attachment during cell division is essential for the maintenance of genetic integrity. Despite a growing understanding of the identity of proteins that compose the kinetochore and the processes for which they are required, the precise functions of many kinetochore proteins are still unknown. KNL1, a large kinetochore scaffolding protein, contributes to several signaling pathways coordinated by the kinetochore. Yet, how KNL1 recruits its various binding partners to the kinetochore, and whether KNL1 directly or indirectly modulates protein function during mitosis are unresolved questions. In this dissertation, I examine the function of KNL1 in the regulation of kinetochore-MT attachment and determine the regions of KNL1 required for the accumulation of an array of kinetochore proteins. By loss of function analyses using a set of KNL1 mutants, combined with functional assays in cells, I demonstrate that the KNL1 N-terminus is essential for Aurora B kinase activity at kinetochores and for correct kinetochore-MT dynamics. Aurora B kinase phosphorylates kinetochore proteins during early mitosis, increasing kinetochore-microtubule (MT) turnover and preventing premature stabilization of kinetochore-MT attachments. Therefore, KNL1 is required for correct Aurora B-mediated kinetochore-MT attachment regulation during mitosis. I provide evidence that the KNL1 N-terminus influences Aurora B activity by mediating the activity of Bub1 kinase, a kinetochore protein required for the spindle assembly checkpoint (SAC). The SAC mediates amplification of an inhibitory signal to prevent mitotic exit until all chromosomes are correctly attached to MTs. Although the SAC is known to be tightly coupled to kinetochore-MT attachment, how such coupling occurs at the kinetochore is a major unanswered question. The finding that KNL1 mediates Aurora B activity through Bub1 establishes KNL1 as a key integrator of multiple signaling pathways at the kinetochore. Finally, I determine the regions of KNL1 required for the… Advisors/Committee Members: DeLuca, Jennifer (advisor), Allen, Christopher (committee member), Di Pietro, Santiago (committee member), Peersen, Olve (committee member), Prenni, Jessica (committee member).

Subjects/Keywords: Hec1; Aurora B kinase; kinetochore; KNL1; mitosis

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Caldas, G. V. (2014). Kinetochore protein KNL1 links kinetochore-microtubule attachment and checkpoint signaling during mitosis, The. (Doctoral Dissertation). Colorado State University. Retrieved from http://hdl.handle.net/10217/85026

Chicago Manual of Style (16^th Edition):

Caldas, Gina V. “Kinetochore protein KNL1 links kinetochore-microtubule attachment and checkpoint signaling during mitosis, The.” 2014. Doctoral Dissertation, Colorado State University. Accessed January 18, 2021. http://hdl.handle.net/10217/85026.

MLA Handbook (7^th Edition):

Caldas, Gina V. “Kinetochore protein KNL1 links kinetochore-microtubule attachment and checkpoint signaling during mitosis, The.” 2014. Web. 18 Jan 2021.

Vancouver:

Caldas GV. Kinetochore protein KNL1 links kinetochore-microtubule attachment and checkpoint signaling during mitosis, The. [Internet] [Doctoral dissertation]. Colorado State University; 2014. [cited 2021 Jan 18]. Available from: http://hdl.handle.net/10217/85026.

Council of Science Editors:

Caldas GV. Kinetochore protein KNL1 links kinetochore-microtubule attachment and checkpoint signaling during mitosis, The. [Doctoral Dissertation]. Colorado State University; 2014. Available from: http://hdl.handle.net/10217/85026

University of Sydney

10. Yeo, Reichelle. Redox Regulation of Protein Kinase B/Akt Function by an Allosteric Disulphide Bond .

Degree: 2019, University of Sydney

URL: http://hdl.handle.net/2123/20816

► Most proteins in nature are chemically modified after they are made to control how, when and where they function. One type of chemical modification is… (more)

▼ Most proteins in nature are chemically modified after they are made to control how, when and where they function. One type of chemical modification is the cleavage of disulphide bonds that link pairs of cysteine residues in the polypeptide chain. These cleavable bonds are known as allosteric disulphides. From an analysis of labile disulphide bonds in all protein structures from the Protein Data Bank (PDB), my colleagues and I identified a potential allosteric disulphide in the serine/threonine protein kinase B/Akt; linking cysteine residues 60 and 77 in the N-terminus pleckstrin homology (PH) domain. Akt plays a central role in glucose metabolism, cell survival and angiogenesis and is often hyper-activated in cancer cells. Akt is activated at the plasma membrane via binding to phosphatidylinositol-3,4,5-trisphosphate (PIP3) through its PH domain. Dissociation of Akt from the plasma membrane leads to PH domain-mediated autoinhibition of the kinase by a mechanism that is currently unknown. I hypothesised that the PH domain Cys60–Cys77 disulphide is an allosteric bond that regulates autoinhibition and inactivation of the kinase. To elucidate the role of the Cys60–Cys77 disulphide bond in Akt function, wild-type and reduced (Cys60 and/or Cys77 substituted with Ser) PH domain or full-length Akt mutants were analysed for PIP3 plasma membrane binding, Akt phosphorylation and Akt downstream substrate activation, transformation of fibroblasts, and angiogenesis, survival and development of zebrafish. Ablation of the Cys60–Cys77 disulphide bond did not appreciably affect binding of recombinant PH domain to PIP3, but markedly impaired insulin-stimulated binding of full-length Akt to the plasma membrane of adipocytes. Ablation of the Cys60–Cys77 disulphide bond had mixed effects on insulin-stimulated phosphorylation of Akt in fibroblasts. The Cys60Ser mutant was phosphorylated to the same extent as the wild-type, while the Cys77Ser mutant was poorly phosphorylated. Wild-type but not disulphide mutant Akt induced transformation of fibroblasts, indicating an oncogenic role for oxidised but not reduced Akt. Expression of disulphide mutant Akt in zebrafish increased the induction of angiogenesis and development of embryos but did not affect zebrafish survival. My findings imply that the Cys60–Cys77 disulphide bond in the PH domain of Akt is an allosteric disulphide involved in autoinhibition and functioning of the kinase.

Subjects/Keywords: protein kinase B/Akt; metabolism; cancer; mechanism

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Yeo, R. (2019). Redox Regulation of Protein Kinase B/Akt Function by an Allosteric Disulphide Bond . (Thesis). University of Sydney. Retrieved from http://hdl.handle.net/2123/20816

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Yeo, Reichelle. “Redox Regulation of Protein Kinase B/Akt Function by an Allosteric Disulphide Bond .” 2019. Thesis, University of Sydney. Accessed January 18, 2021. http://hdl.handle.net/2123/20816.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Yeo, Reichelle. “Redox Regulation of Protein Kinase B/Akt Function by an Allosteric Disulphide Bond .” 2019. Web. 18 Jan 2021.

Vancouver:

Yeo R. Redox Regulation of Protein Kinase B/Akt Function by an Allosteric Disulphide Bond . [Internet] [Thesis]. University of Sydney; 2019. [cited 2021 Jan 18]. Available from: http://hdl.handle.net/2123/20816.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Yeo R. Redox Regulation of Protein Kinase B/Akt Function by an Allosteric Disulphide Bond . [Thesis]. University of Sydney; 2019. Available from: http://hdl.handle.net/2123/20816

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of New South Wales

11. Huff, Belinda. The development of pyrrolopyrimidines as kinase inhibitors.

Degree: Chemistry, 2011, University of New South Wales

URL: http://handle.unsw.edu.au/1959.4/51897 ; https://unsworks.unsw.edu.au/fapi/datastream/unsworks:10566/SOURCE02?view=true

► This thesis is focussed on the synthesis of various pyrrolopyrimidines, which will be examined for their kinase inhibitory potential. In Chapter 2, the synthesis of… (more)

▼ This thesis is focussed on the synthesis of various pyrrolopyrimidines, which will be examined for their kinase inhibitory potential. In Chapter 2, the synthesis of analogs of marine alkaloid variolin B, a promising lead in the development of new kinase inhibitors, is discussed. Previously established methodologies to prepare differentially substituted analogs of variolin B were extended and a new, more efficient synthesis for C2’-substituted analogs was developed. Differential substitution altered the kinase inhibitory activity of analogs, with some being more potent and more selective than the lead. The affinity chromatography of three analogs was undertaken to elucidate the intracellular targets of variolin B – this information would aid in the design of new inhibitors. However, despite the functionalized analogs displaying excellent activity against various kinases, none of them were detected in the affinity chromatography experiments, suggesting that further work is needed to optimise the analogs for this protocol.In Chapter 3, a synthesis was developed for a truncated analog of variolin B. Metal-catalysed cycloisomerisation and ionic hydrogenation routes were investigated, with the latter affording the desired compound. Methodologies for the selective substitution of the truncated core were established and were used to prepare differentially substituted analogs, some of which were found to display better selectivity than variolin B against DYRK1A and CLK1. In Chapter 4, the synthesis of another family of truncated analogs, with a saturated heterocycle attached at C5, is discussed. A gold-catalysed, three-component coupling reaction provided access to the new scaffold in just one step from three simple precursors. However, this family of analogs proved to be poor inhibitors of the kinases that were examined, highlighting that the pendant ring plays an important role in the biological activity of this class of compounds. A summary of the work described in this thesis and the future directions for the project is given in Chapter 5. Full experimental procedures have been provided in Chapter 6. Advisors/Committee Members: Morris, Jonathan, Chemistry, Faculty of Science, UNSW.

Subjects/Keywords: Pyrrolopyrimidine; Kinase Inhibitors; Variolin B; Pyrrolopyrimidines

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Huff, B. (2011). The development of pyrrolopyrimidines as kinase inhibitors. (Doctoral Dissertation). University of New South Wales. Retrieved from http://handle.unsw.edu.au/1959.4/51897 ; https://unsworks.unsw.edu.au/fapi/datastream/unsworks:10566/SOURCE02?view=true

Chicago Manual of Style (16^th Edition):

Huff, Belinda. “The development of pyrrolopyrimidines as kinase inhibitors.” 2011. Doctoral Dissertation, University of New South Wales. Accessed January 18, 2021. http://handle.unsw.edu.au/1959.4/51897 ; https://unsworks.unsw.edu.au/fapi/datastream/unsworks:10566/SOURCE02?view=true.

MLA Handbook (7^th Edition):

Huff, Belinda. “The development of pyrrolopyrimidines as kinase inhibitors.” 2011. Web. 18 Jan 2021.

Vancouver:

Huff B. The development of pyrrolopyrimidines as kinase inhibitors. [Internet] [Doctoral dissertation]. University of New South Wales; 2011. [cited 2021 Jan 18]. Available from: http://handle.unsw.edu.au/1959.4/51897 ; https://unsworks.unsw.edu.au/fapi/datastream/unsworks:10566/SOURCE02?view=true.

Council of Science Editors:

Huff B. The development of pyrrolopyrimidines as kinase inhibitors. [Doctoral Dissertation]. University of New South Wales; 2011. Available from: http://handle.unsw.edu.au/1959.4/51897 ; https://unsworks.unsw.edu.au/fapi/datastream/unsworks:10566/SOURCE02?view=true

Université de Sherbrooke

12. Ear, Thornin. Signalisation en amont de la voie NF-[kappa]B et son impact sur la production de cytokines chez les neutrophiles humains.

Degree: 2008, Université de Sherbrooke

URL: http://savoirs.usherbrooke.ca/handle/11143/4274

► En premier lieu, en utilisant des inhibiteurs pharmacologiques du NF-[kappa]B, nous avons constaté que l'inhibition du facteur de transcription NF-[kappa]B chez ces cellules diminue de… (more)

▼ En premier lieu, en utilisant des inhibiteurs pharmacologiques du NF-[kappa]B, nous avons constaté que l'inhibition du facteur de transcription NF-[kappa]B chez ces cellules diminue de beaucoup l'expression génique et la sécrétion de diverses cytokines et chimiokines (TNF-[alpha], IL-8 ou CXCL8, Mip-1[alpha]/[bêta] induites par des stimuli tels que TNF-[alpha] ou LPS. Nous montrons ensuite que le complexe IKK (IKK[alpha], IKK[bêta], et IKK[gamma]) est aussi partiellement localisé dans le noyau, alors que les kinases reliées à IKK (IKK[epsilon] et TBK-1) sont cytoplasmiques; la kinase NIK, quant à elle, est strictement nucléaire. Suite à une activation des neutrophiles, IKK[bêta] et IKK[gamma] deviennent transitoirement phosphorylées dans le cytoplasme et le noyau, alors qu'IKK[alpha] disparaît temporairement de ces deux compartiments cellulaires d'une manière qui semble dépendante de IKK[bêta]. Ces réponses s'accompagnent, dans les deux compartiments, de la dégradation d'I[kappa]B[alpha] et de la phosphorylation du RelA sur la sérine 536. Bien que les deux protéines puissent être des substrats de IKK, l'inhibition de ce dernier empêche la dégradation d'I[kappa]B[alpha], tandis que le niveau de phosphorylation du RelA est essentiellement inchangé. Nous apportons enfin une preuve que des isoformes de IKK nucléaires s'associent à la chromatine suivant l'activation des neutrophiles, ce qui suggère un rôle potentiel dans la régulation de gènes. Deuxièmement, nous rapportons que les neutrophiles expriment la MAP3K, TAK1, ainsi que ses partenaires associés, TAB1/2, dans le cytoplasme et le noyau. La kinase TAK1 est associée de façon constitutive aux protéines TAB1 et TAB2, ainsi qu'au complexe IKK[alpha]/[bêta] dans les neutrophiles au repos. Le niveau d'interaction de ces complexes demeure inchangé suite au traitement des neutrophiles avec le TNF-[alpha] ou le LPS. La kinase TAK1 devient rapidement et transitoirement activée suite à une stimulation des cellules avec le TNF-[alpha] ou le LPS. L'inhibition de l'activité kinase de TAK1 avec un inhibiteur hautement sélectif (5z-7-oxozeaenol) a empêché la phosphorylation d'IKK[alpha]/[bêta], de RelA, et la dégradation de I[kappa]B[alpha] dans les fractions cytoplasmiques et nucléaires, ainsi que la liaison à l'ADN du NF-[kappa]B dans des neutrophiles activés.En conséquence, l'expression et la sécrétion de cytokines inflammatoires induites par le TNF-[alpha] ou le LPS ont été profondément altérées suivant une inhibition de TAK1.En revanche, la phosphorylation de IKK[gamma] induite par le LPS n'a pas été affectée par l'inhibition de TAK1. Finalement, nos résultats indiquent que l'activation du NF-[kappa]B et les réponses cellulaires dépendantes du NF-[kappa]B sont indépendantes des ROS endogènes dans les neutrophiles humains primaires ou dans la lignée promyélocytaire PLB-985, qui peut être différenciée en granulocytes et se comporte comme les neutrophiles. Parallèlement, nous avons optimisé les conditions de transfection des PLB-985 différenciées, ce qui nous a permis de montrer… Advisors/Committee Members: McDonald, Patrick (advisor).

Subjects/Keywords: Génération de cytokines et chimiokines; Facteurs de transcription NF-[kappa]B; Cascade de signalisation IKK/I[kappa]B/NF-[kappa]B nucléaire; Protéine kinase TAK1; Neutrophiles humains

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Ear, T. (2008). Signalisation en amont de la voie NF-[kappa]B et son impact sur la production de cytokines chez les neutrophiles humains. (Doctoral Dissertation). Université de Sherbrooke. Retrieved from http://savoirs.usherbrooke.ca/handle/11143/4274

Chicago Manual of Style (16^th Edition):

Ear, Thornin. “Signalisation en amont de la voie NF-[kappa]B et son impact sur la production de cytokines chez les neutrophiles humains.” 2008. Doctoral Dissertation, Université de Sherbrooke. Accessed January 18, 2021. http://savoirs.usherbrooke.ca/handle/11143/4274.

MLA Handbook (7^th Edition):

Ear, Thornin. “Signalisation en amont de la voie NF-[kappa]B et son impact sur la production de cytokines chez les neutrophiles humains.” 2008. Web. 18 Jan 2021.

Vancouver:

Ear T. Signalisation en amont de la voie NF-[kappa]B et son impact sur la production de cytokines chez les neutrophiles humains. [Internet] [Doctoral dissertation]. Université de Sherbrooke; 2008. [cited 2021 Jan 18]. Available from: http://savoirs.usherbrooke.ca/handle/11143/4274.

Council of Science Editors:

Ear T. Signalisation en amont de la voie NF-[kappa]B et son impact sur la production de cytokines chez les neutrophiles humains. [Doctoral Dissertation]. Université de Sherbrooke; 2008. Available from: http://savoirs.usherbrooke.ca/handle/11143/4274

13. Al Mohamad, Hazar. Etude de la balance réactivation/apoptose des cellules B infectées par l' EBV suite au traitement par un HDACi, le vorinostat : Study of the balance reactivation / apoptosis of B cells infected with EBV following treatment with a HDACi, vorinostat.

Degree: Docteur es, Immunologie, oncologie et infectiologie, 2016, Limoges

URL: http://www.theses.fr/2016LIMO0014

►

Les inhibiteurs des histones désacétylase (HDACi) constituent une classe prometteuse de médicaments anticancéreux. Ils peuvent déclencher la voie apoptotique et sont proposés pour le traitement… (more)

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Les inhibiteurs des histones désacétylase (HDACi) constituent une classe prometteuse de médicaments anticancéreux. Ils peuvent déclencher la voie apoptotique et sont proposés pour le traitement des désordres hématologiques. Cependant, les HDACi qui ciblent les HDAC de classe II, tel que le vorinostat, sont également des agents réactivateurs potentiels de l’EBV, un virus qui infecte de manière latente plus de 90% de la population adulte dans le monde et est associée à de nombreux lymphomes de type B. L’étude de la commutation entre le cycle latent et le cycle lytique de l’EBV est essentielle pour appréhender l’impact des HDACi lors du!traitement des lymphomes B associés à l’EBV (risque du relargage de virions en grande quantité lors des traitements chimio thérapeutiques).Notre étude a porté sur l'effet de vorinostat (25 μM pendant 48h) sur des cellules tumorales B infectées par l’EBV : trois lignées de lymphomes de burkitt (BL2B95.8, BL41B95.8 et P3HR1), trois lignées lymphoblastoides (1602, PRI et RUD) et la lignée B95.8 de marmouset en cycle lytique de l’EBV (contrôle positif). Nous avons mis en évidence que le vorinostat peut induire la réactivation de l’EBV (P3HR1 et B95.8) ou à l’apoptose (BL41B95.8, BL2B95.8, 1602, PRI et RUD) avec une inhibition mutuelle de ces deux processus. Au niveau moléculaire, nous avons pu montrer que le vorinostat active constitutivement et simultanément le facteur de transcription initiateur de la réactivation MEF2D (par déphosphorylation) et la MAP kinase pro-apototique p38 (par phosphorylation) suite à la diminution de l’expression de la MAP kinase phosphatase (MPK1) dont p38 est un substrat. Le pré-traitement avec un inhibiteur de p38 (SB203580) a mis en évidence que cette MAP kinase est à la fois impliquée dans les processus de réactivation de l’EBV et d’’apoptose. Cependant, les lignées cellulaires pour lesquelles l'activation de p38 augmente fortement lors du traitement par le vorinostat, entrent directement en apoptose, sans qu’il puisse y avoir réactivation de l’EBV.Nos résultats suggèrent que le niveau d’activation de la MAP kinase p38 permet de réguler la balance réactivation/apoptose des cellules B infectées par l’EBV lorsqu’elles sont soumises à un agent inducteur de la réactivation, en particulier dans le cas de cellules de lymphomes B traitées par le vorinostat. Ils posent la question de l’utilisation des HDACi lors du traitement des lymphomes associés à l'EBV, avec le risque d’une réactivation virale selon le niveau d’activation intracellulaire de p38 et la nécessité d’utiliser simultanément un anti-viral tel que le ganciclovir.

Histone deacetylase inhibitors (HDAC) are a promising class of anticancer drugs. They can trigger the apoptotic pathway and are available for treatment of blood disorders. However, the HDACi that target HDAC class II, as vorinostat, also are potential reactivators agents of EBV, a virus that infects latently over 90% of the adult population worldwide and is associated with many type B lymphomas the study of switching between the latent cycle…

Advisors/Committee Members: Feuillard, Jean (thesis director), Jayat-Vignoles, Chantal (thesis director).

Subjects/Keywords: EBV; Réactivation; Apoptose; Vorinostat; MAP kinase p38; Lymphocytes B; EBV; Reactivation; Apoptosis; Vorinostat; P38 MAP Kinase; B lymphocytes; 615.37

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Al Mohamad, H. (2016). Etude de la balance réactivation/apoptose des cellules B infectées par l' EBV suite au traitement par un HDACi, le vorinostat : Study of the balance reactivation / apoptosis of B cells infected with EBV following treatment with a HDACi, vorinostat. (Doctoral Dissertation). Limoges. Retrieved from http://www.theses.fr/2016LIMO0014

Chicago Manual of Style (16^th Edition):

Al Mohamad, Hazar. “Etude de la balance réactivation/apoptose des cellules B infectées par l' EBV suite au traitement par un HDACi, le vorinostat : Study of the balance reactivation / apoptosis of B cells infected with EBV following treatment with a HDACi, vorinostat.” 2016. Doctoral Dissertation, Limoges. Accessed January 18, 2021. http://www.theses.fr/2016LIMO0014.

MLA Handbook (7^th Edition):

Al Mohamad, Hazar. “Etude de la balance réactivation/apoptose des cellules B infectées par l' EBV suite au traitement par un HDACi, le vorinostat : Study of the balance reactivation / apoptosis of B cells infected with EBV following treatment with a HDACi, vorinostat.” 2016. Web. 18 Jan 2021.

Vancouver:

Al Mohamad H. Etude de la balance réactivation/apoptose des cellules B infectées par l' EBV suite au traitement par un HDACi, le vorinostat : Study of the balance reactivation / apoptosis of B cells infected with EBV following treatment with a HDACi, vorinostat. [Internet] [Doctoral dissertation]. Limoges; 2016. [cited 2021 Jan 18]. Available from: http://www.theses.fr/2016LIMO0014.

Council of Science Editors:

Al Mohamad H. Etude de la balance réactivation/apoptose des cellules B infectées par l' EBV suite au traitement par un HDACi, le vorinostat : Study of the balance reactivation / apoptosis of B cells infected with EBV following treatment with a HDACi, vorinostat. [Doctoral Dissertation]. Limoges; 2016. Available from: http://www.theses.fr/2016LIMO0014

14. Bendjeddou, Lyamin. Synthèse et évaluation biologique de nouveaux inhibiteurs de kinases : identification d‘inhibiteurs de kinases parasitaires : Synthesis and biological evaluation of new kinase inhibitors : identification of inhibitors of several parasite protein kinases.

Degree: Docteur es, Chimie thérapeutique, 2014, Université Paris Descartes – Paris V

URL: http://www.theses.fr/2014PA05P615

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La phosphorylation des protéines par les kinases est l’une plus importantes modification post-traductionnelle dans les processus cellulaires tels que la division, la différenciation, la prolifération… (more)

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La phosphorylation des protéines par les kinases est l’une plus importantes modification post-traductionnelle dans les processus cellulaires tels que la division, la différenciation, la prolifération et l’apoptose. Due à leur rôle clef, un dérèglement des protéines kinases peut entrainer de nombreuses pathologies proliférative telles que le cancer et non prolifératives telles que les maladies neurodégénératives. Le travail de thèse s’est construit autour de 2 séries d’inhibiteurs de protéine kinases comportant les noyaux imidazo[1,2-b]pyridazine et imidazo[4,5-b]pyridine. L’objectif est d’inhiber sélectivement les protéines kinases choisies, pour leurs implications dans les pathologies visées au laboratoire. Les imidazo[1,2-b]pyridazines ont été préparées pour identifier des inhibiteurs de CLK1 et DYRK1A, cibles potentielles dans la maladie d’Alzheimer. Parmi les imidazo[1,2-b]pyridazines synthétisées, plusieurs molécules se sont révélées particulièrement sélectives de DYRKs et CLKs, avec des IC50 < 100 nM. Une relation structure-activité basée sur la synthèse de 70 molécules, a permis de dégager des éléments structuraux de la sélectivité des molécules. L’évaluation des produits a également été portée sur les kinases de parasites. Il a ainsi été possible d’identifier quelques inhibiteurs actifs sur PfCLK1. La seconde partie de cette thèse avait pour objectif l’optimisation du protocole de synthèse imidazo[4,5-b]pyridines, analogue de la roscovitine. Des dérivés s’étaient révélés capables d’inhiber la formation de kystes, dans un modèle cellulaire de polykystose rénale. Une synthèse en sept étapes a conduit à plusieurs grammes d’imidazo[4,5-b]pyridine 3,5,7 trisubstitués, qui sont ainsi disponibles pour l’évaluation in vivo.

Phosphorylation by protein kinases is one of the most important post-translational modification in cellular processes such as division, differentiation, proliferation and apoptosis. Kinase deregulation is associated with numerous diseases such as cancer or neurodegenerative diseases. Imidazo[1,2-b]pyridazine and imidazo[4,5-b]pyridine were prepared to inhibit protein kinases involved in diseases targeted in the laboratory. The imidazo[1,2-b]pyridazines were synthesized to identify inhibitors of CLK1 and DYRK1A, potential targets in Alzheimer's disease. Among the imidazo[1,2-b]pyridazines synthesized, several molecules were found selective of DYRKs and CLKs, with IC50 < 100 nM. A structure-activity relationship based on the synthesis of 70 molecules, led to the identification of the structural bases of the selectivity. Products were also evaluated against parasite kinases. It was possible to identify some highly potent inhibitors on PfCLK1. The aim of second part of this thesis was to optimize the synthetic process to obtain imidazo[4,5-b]pyridines, which are close analogues of roscovitine. Derivatives had proved capable of inhibiting the formation of cysts in a cellular model of polycystic kidney disease. A seven-step synthesis has led to several grams of 3,5,7-trisubstituted…

Advisors/Committee Members: Galons, Hervé (thesis director).

Subjects/Keywords: Inhibiteur de protéine kinase; Imidazo[1,2-b]pyridazine; Imidazo[4,5-b]pyridine; Kinase cycline-dépendante (CDKs); CDC-like kinase (CLKs); Dual specificity tyrosine-phosphorylation-regulated kinase (DYRKs); Parasite unicellulaire; Maladie d’Alzheimer; Trisomie 21; Kinase inhibitor; Imidazo[1,2-b]pyridazine; Imidazo[4,5-b]pyridine; Dual specificity tyrosine-phosphorylation-regulated kinase (DYRKs); Cyclin-dependent kinase (CDKs); Unicellular parasite; Alzheimer’s disease; Down syndrome; 615.19

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Bendjeddou, L. (2014). Synthèse et évaluation biologique de nouveaux inhibiteurs de kinases : identification d‘inhibiteurs de kinases parasitaires : Synthesis and biological evaluation of new kinase inhibitors : identification of inhibitors of several parasite protein kinases. (Doctoral Dissertation). Université Paris Descartes – Paris V. Retrieved from http://www.theses.fr/2014PA05P615

Chicago Manual of Style (16^th Edition):

Bendjeddou, Lyamin. “Synthèse et évaluation biologique de nouveaux inhibiteurs de kinases : identification d‘inhibiteurs de kinases parasitaires : Synthesis and biological evaluation of new kinase inhibitors : identification of inhibitors of several parasite protein kinases.” 2014. Doctoral Dissertation, Université Paris Descartes – Paris V. Accessed January 18, 2021. http://www.theses.fr/2014PA05P615.

MLA Handbook (7^th Edition):

Bendjeddou, Lyamin. “Synthèse et évaluation biologique de nouveaux inhibiteurs de kinases : identification d‘inhibiteurs de kinases parasitaires : Synthesis and biological evaluation of new kinase inhibitors : identification of inhibitors of several parasite protein kinases.” 2014. Web. 18 Jan 2021.

Vancouver:

Bendjeddou L. Synthèse et évaluation biologique de nouveaux inhibiteurs de kinases : identification d‘inhibiteurs de kinases parasitaires : Synthesis and biological evaluation of new kinase inhibitors : identification of inhibitors of several parasite protein kinases. [Internet] [Doctoral dissertation]. Université Paris Descartes – Paris V; 2014. [cited 2021 Jan 18]. Available from: http://www.theses.fr/2014PA05P615.

Council of Science Editors:

Bendjeddou L. Synthèse et évaluation biologique de nouveaux inhibiteurs de kinases : identification d‘inhibiteurs de kinases parasitaires : Synthesis and biological evaluation of new kinase inhibitors : identification of inhibitors of several parasite protein kinases. [Doctoral Dissertation]. Université Paris Descartes – Paris V; 2014. Available from: http://www.theses.fr/2014PA05P615

15. Jiang, Shaoning. Molecular mechanisms of hepatic insulin resistance following injury.

Degree: PhD, 2010, University of Alabama – Birmingham

URL: http://contentdm.mhsl.uab.edu/u?/etd,1374

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Insulin resistance commonly occurs following injuries or critical illness independent of previous diabetic status. The development of insulin resistance and hyperglycemia is associated with increased… (more)

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Insulin resistance commonly occurs following injuries or critical illness independent of previous diabetic status. The development of insulin resistance and hyperglycemia is associated with increased mortality and morbidity in critically ill patients. However, the molecular mechanisms underlying the acute insulin resistance following injuries remain poorly understood. With an animal model of trauma and hemorrhage, we have previously demonstrated the rapid development of insulin resistance in liver, and a critical role of TNF? in hemorrhage-induced defects in insulin signaling following resuscitation. However, hepatic insulin signaling is impaired prior to a significant increase in plasma TNF?, suggesting the initial development of hemorrhage-induced hepatic insulin resistance may be TNF? independent. By inhibiting the activity of TNF? or reactive oxygen species (ROS), our current studies further demonstrated that elevated ROS is responsible for the initial development of hepatic insulin resistance following hemorrhage, while TNF? has a dominant role later, following resuscitation. The mechanisms by which ROS induces the rapid development of hepatic insulin resistance were next investigated. Both Inhibitory-?B kinases (IKK) and c-Jun Nterminal kinase (JNK) can be activated by ROS and inhibit insulin signaling, potentially by increasing serine phosphorylation of insulin receptor (IR) or insulin receptor substrates (IRSs). Activation of hepatic IKK and JNK was observed as early as 15 minutes after trauma and hemorrhage, which was concomitant with the rapid impairment of hepatic insulin signaling. The important roles of IKK and JNK in the early development of hemorrhage-induced insulin resistance were further demonstrated by direct inhibition of the IKKs (IKK? and ?) and JNK1 with adenovirus-mediated expression of dominant negative mutants of IKKs and JNK1 in liver. Using two approaches of Kupffer celldepletion, we further demonstrated that the early development of hemorrhage-induced hepatic insulin resistance and activation of IKK and JNK are Kupffer cell independent. Thus, acute activation of IKK and JNK likely occurs within hepatocytes where they directly interact with IR or IRS proteins and inhibit insulin signaling. In conclusion, our studies provide mechanistic insights into the acute onset of hepatic insulin resistance following injury. IKK and JNK are potential therapeutic targets for treating hyperglycemia in the Intensive Care Unit.

1 online resource (xii, 199 p.) :ill., digital, PDF file.

Joint Health Sciences

Acute insulin resistance, Injury, Liver, TNF?, Serine kinase, Kupffer cell

UNRESTRICTED

Advisors/Committee Members: Joseph L. Messina, Additional advisors: Jeonga Kim, John D. Mountz, Alexander Pereboev, Selvarangan Ponnazhagan..

Subjects/Keywords: Adenoviridae – metabolism<; br>; Adenoviridae Infections – metabolism<; br>; Diabetes Mellitus, Type 2 – physiopathology<; br>; Glucose – metabolism<; br>; I-kappa B Kinase – physiology <; br>; Insulin – metabolism<; br>; JNK Mitogen-Activated Protein Kinases – physiology <; br>; Liver

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Jiang, S. (2010). Molecular mechanisms of hepatic insulin resistance following injury. (Doctoral Dissertation). University of Alabama – Birmingham. Retrieved from http://contentdm.mhsl.uab.edu/u?/etd,1374

Chicago Manual of Style (16^th Edition):

Jiang, Shaoning. “Molecular mechanisms of hepatic insulin resistance following injury.” 2010. Doctoral Dissertation, University of Alabama – Birmingham. Accessed January 18, 2021. http://contentdm.mhsl.uab.edu/u?/etd,1374.

MLA Handbook (7^th Edition):

Jiang, Shaoning. “Molecular mechanisms of hepatic insulin resistance following injury.” 2010. Web. 18 Jan 2021.

Vancouver:

Jiang S. Molecular mechanisms of hepatic insulin resistance following injury. [Internet] [Doctoral dissertation]. University of Alabama – Birmingham; 2010. [cited 2021 Jan 18]. Available from: http://contentdm.mhsl.uab.edu/u?/etd,1374.

Council of Science Editors:

Jiang S. Molecular mechanisms of hepatic insulin resistance following injury. [Doctoral Dissertation]. University of Alabama – Birmingham; 2010. Available from: http://contentdm.mhsl.uab.edu/u?/etd,1374

16. Reyftmann, Romina. Studies of the Ubiquitin-NFκβ pathway in women and baboons with endometriosis .

Degree: 2012, University of Sydney

URL: http://hdl.handle.net/2123/8688

► Background: Our aim was to determine if changes in ubiquitin are correlated with proteins known to be affected directly or indirectly by the ubiquitin-proteasome pathway.… (more)

▼ Background: Our aim was to determine if changes in ubiquitin are correlated with proteins known to be affected directly or indirectly by the ubiquitin-proteasome pathway. For example, the intermediary kinase of the NFκβ pathway IKK is tagged directly by ubiquitin, aiding its degradation within the large, self-compartmentalised protease called the 26S proteasome. IKK degradation allows the release of NFκβ (an indirect consequence of ubiquitination) that then translocates into the nucleus to initiate the transcription of survival factors such as cIAP2, BCL-XL, BFL1, FLIP, IL-8, and TNF-α. Methods: Lyophilised baboon endometrial tissues from the University of Illinois at Chicago (UIC) and from women undergoing laparoscopy from the Sydney South West Area of Health Service (SSWAHS) were processed for RNA extraction and analysis. Immunohistochemical studies were also conducted on formalin fixed baboon and human endometrial tissues from UIC and from the Sydney West Area Health Service (SWAHS). Results: IKKα immunostaining were elevated in the cytoplasm of glands during late follicular phase and stromal cells during menses in the baboon, whilst proteasome was elevated in the nucleus of glands and stroma at menses, as well as within the glandular cytoplasm of endometriotic tissues. Comparable levels of Iκβα exists throughout the menstrual cycle of the eutopic endometrium, whilst a reduced glandular nuclear Iκβα was seen in endometriotic tissues of the animal model. TNF-α was increased within stromal cells at menses but was equivalent between the eutopic and ectopic endometrium. Ubiquitin was similar between LF and mid luteal phase of eutopic glands and stroma, as well as between eutopic and ectopic endometrium at mid luteal. IKKβ and NFκβ levels were alike within eutopic and ectopic tissues throughout the menstrual cycle. In women however, IKKα, IKKβ, Iκβα and NFκβ had comparable levels within all cell types and cycle phases, whilst a greater proteasome immunostaining was seen in the nucleus of eutopic stromal cells at secretory phase, as well as in the nucleus of ectopic stromal cells at proliferative phase. However, the nucleus of stromal cells and glandular cytoplasm of endometriotic tissues both had lower proteasome levels during the secretory phase. Conclusions: In this study, IKKα had a greater potential to activate the p65 subunit of NFκβ in ectopic stromal cells than IKKβ and TNF-α did not seem to be correlated with greater free ubiquitin expression in endometriosis in the baboon. This suggests that IKKα is a likely candidate for ectopic stromal cell survival in endometriosis in the animal model but this is unlikely to be mediated by the ubiquitin NFκβ pathway. Similarly, in women with endometriosis a different pathway to NFκβ is potentially responsible for a greater ectopic cell survival potential, however an increased patient cohort is required to definitively ascertain the involvement of IKKα in the future.

Subjects/Keywords: Endometriosis; Baboon; Ubiquitin; Nuclear factor-kappa beta; I kappa B kinase

…IKK Inhibitor of kappa beta kinase IKK1 I-kappa-B kinase 1 IKK2 I-kappa-B kinase 2… …IKKα I-kappa-B-kinase-alpha IKKβ I-kappa-B-kinase-beta IKKγ I-kappa-B-kinase-gamma IL… …kappa B xiv Iκβ Inhibitor of kappa beta Iκβα I-kappa-B-alpha IκBβ I-kappa-B-beta IκBγ… …I-kappa-B-gamma IκBKα Inhibitor of kappa light polypeptide gene enhancer in B cells… …kinase of alpha IKBKB Inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase…

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Reyftmann, R. (2012). Studies of the Ubiquitin-NFκβ pathway in women and baboons with endometriosis . (Thesis). University of Sydney. Retrieved from http://hdl.handle.net/2123/8688

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Reyftmann, Romina. “Studies of the Ubiquitin-NFκβ pathway in women and baboons with endometriosis .” 2012. Thesis, University of Sydney. Accessed January 18, 2021. http://hdl.handle.net/2123/8688.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Reyftmann, Romina. “Studies of the Ubiquitin-NFκβ pathway in women and baboons with endometriosis .” 2012. Web. 18 Jan 2021.

Vancouver:

Reyftmann R. Studies of the Ubiquitin-NFκβ pathway in women and baboons with endometriosis . [Internet] [Thesis]. University of Sydney; 2012. [cited 2021 Jan 18]. Available from: http://hdl.handle.net/2123/8688.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Reyftmann R. Studies of the Ubiquitin-NFκβ pathway in women and baboons with endometriosis . [Thesis]. University of Sydney; 2012. Available from: http://hdl.handle.net/2123/8688

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Mississippi State University

17. Leach, Charles Andrew. Efficacy of novel pyridinium oximes in preventing neural damage.

Degree: MS, Veterinary Medicine, College of, 2017, Mississippi State University

URL: http://sun.library.msstate.edu/ETD-db/theses/available/etd-10232017-093523/ ;

► Organophosphates are neurotoxic compounds that inhibit acetylcholinesterase producing excess cholinergic stimulation. This produces various toxic signs including excitotoxic neuronal damage. Oximes can be used… (more)

Subjects/Keywords: MAP Kinase; histopathology; Fluoro-Jade B; gene expression; pyridinium oxime; organophosphate

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Leach, C. A. (2017). Efficacy of novel pyridinium oximes in preventing neural damage. (Masters Thesis). Mississippi State University. Retrieved from http://sun.library.msstate.edu/ETD-db/theses/available/etd-10232017-093523/ ;

Chicago Manual of Style (16^th Edition):

Leach, Charles Andrew. “Efficacy of novel pyridinium oximes in preventing neural damage.” 2017. Masters Thesis, Mississippi State University. Accessed January 18, 2021. http://sun.library.msstate.edu/ETD-db/theses/available/etd-10232017-093523/ ;.

MLA Handbook (7^th Edition):

Leach, Charles Andrew. “Efficacy of novel pyridinium oximes in preventing neural damage.” 2017. Web. 18 Jan 2021.

Vancouver:

Leach CA. Efficacy of novel pyridinium oximes in preventing neural damage. [Internet] [Masters thesis]. Mississippi State University; 2017. [cited 2021 Jan 18]. Available from: http://sun.library.msstate.edu/ETD-db/theses/available/etd-10232017-093523/ ;.

Council of Science Editors:

Leach CA. Efficacy of novel pyridinium oximes in preventing neural damage. [Masters Thesis]. Mississippi State University; 2017. Available from: http://sun.library.msstate.edu/ETD-db/theses/available/etd-10232017-093523/ ;

University of Tasmania

18. Ng, JMJ. Elucidating the roles of aurora B kinase in neurons.

Degree: 2012, University of Tasmania

URL: https://eprints.utas.edu.au/15014/3/whole-ng-thesis-incl-pub-mat.pdf

► To reveal molecular determinates that underlie the intrinsic molecular pathways within neurons that support regeneration after injury, a DNA microarray study was performed on axotomized… (more)

▼ To reveal molecular determinates that underlie the intrinsic molecular pathways within neurons that support regeneration after injury, a DNA microarray study was performed on axotomized neuronal clusters that were maintained in culture and free from glial and astrocytes contamination. The microarray data indicated that post-injury regenerative sprouting requires two distinct pathways; a cell survival response to protect against pernicious secondary processes and a regenerative response driven by modulation of the neuronal cytoskeleton. From the transcriptomic data, cell cycle associated aurora B kinase (Aurkb), which was significantly up-regulated but never investigated in the context of neurons, was identified for further work. Immunohistochemical studies revealed that Aurkb is expressed extensively and cell-specifically in neurons of certain brain structures such as the cortex, hippocampus and amygdala. Its elevated expression in the embryonic brain cortex as compared to that of an adult implies that it may be involved in the process of brain maturation. Interestingly, the changing localization of Aurkb within developing cultured neurons and particularly its localisation outside of the nucleus at various stages of neuronal maturation further suggests that it may have direct roles neurite outgrowth. Indeed, impairing Aurkb activity in cultured neurons via different experimental approaches resulted in several key neuronal deficits. Generally, neurons with inactive Aurkb were found to have either shorter or no elaborated axons. They also possessed abnormally swollen cell bodies. Enlargement of the cell body, independent of nucleus size, was related to a substantial increase in microtubule mass within the area between the nucleus and axon hillock region. Furthermore, their expanded cell bodies are bordered by several aberrant, thin, frayed and highly disorganised neuritic processes. Next, yeast 2 hybrid identified INCENP as a binding partner of Aurkb in neurons. Subsequent phosphoproteomics studies coupled with functional analysis of protein associations have further revealed that inhibition of neuronal Aurkb affected a cluster of proteins and kinases that are major players of neuronal cytoskeleton regulation and organisation. In conclusion, this is the first comprehensive study of Aurkb in the brain and neurons. Specifically, the phosphoproteomic, pharmacological and molecular knockin and knockout studies provided considerable evidence that Aurkb has key roles in neurite cytoskeleton modulation. Taken together, the work in this thesis has clearly identified a novel and alternate cell cycle independent function of Aurkb in post-mitotic neurons.

Subjects/Keywords: neurite regeneration; microarray; Aurora B kinase; neurite outgrowth; neurons; brain; proteomics

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Ng, J. (2012). Elucidating the roles of aurora B kinase in neurons. (Thesis). University of Tasmania. Retrieved from https://eprints.utas.edu.au/15014/3/whole-ng-thesis-incl-pub-mat.pdf

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Ng, JMJ. “Elucidating the roles of aurora B kinase in neurons.” 2012. Thesis, University of Tasmania. Accessed January 18, 2021. https://eprints.utas.edu.au/15014/3/whole-ng-thesis-incl-pub-mat.pdf.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Ng, JMJ. “Elucidating the roles of aurora B kinase in neurons.” 2012. Web. 18 Jan 2021.

Vancouver:

Ng J. Elucidating the roles of aurora B kinase in neurons. [Internet] [Thesis]. University of Tasmania; 2012. [cited 2021 Jan 18]. Available from: https://eprints.utas.edu.au/15014/3/whole-ng-thesis-incl-pub-mat.pdf.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Ng J. Elucidating the roles of aurora B kinase in neurons. [Thesis]. University of Tasmania; 2012. Available from: https://eprints.utas.edu.au/15014/3/whole-ng-thesis-incl-pub-mat.pdf

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

University of Melbourne

19. Tsantikos, Evelyn. Dissecting autoimmune disease susceptibility in Lyn-deficient mice.

Degree: 2011, University of Melbourne

URL: http://hdl.handle.net/11343/36280

► This thesis dissects the nature of autoimmune disease development in mice deficient in the tyrosine kinase Lyn. In particular, the role of cellular defects, genetics,… (more)

▼ This thesis dissects the nature of autoimmune disease development in mice deficient in the tyrosine kinase Lyn. In particular, the role of cellular defects, genetics, inflammation and its consequences that influence the pathogenesis of autoimmune disease are studied. Lyn-deficient mice develop antibody-mediated autoimmune disease resembling systemic lupus erythematosus (SLE). In this disease hyperactive B cells are major contributors to pathology. It is believed that the primary defects in B cell development, including an expansion of antibody-producing plasma cells, are responsible for disease, as interference with molecules essential for B cell function and development renders the mice disease-free. This thesis dissects the role of other immune cell types and molecules that as well as B cells make important contributions to disease. In addition to B cell developmental defects, several immune cell populations are perturbed in diseased Lyn-/- mice, including the expansion of immunosuppressive regulatory T cells, activated pathogenic T cells, dendritic cells, myeloid cells and erythroid cells. Despite expansion of functional Tregs, Lyn-/- mice remain autoimmune-disease prone, suggesting that the inflammatory environment in these mice may alter the suppressive capacity of these cells. In Lyn-/- mice, B cells produce interleukin-6 (IL-6), which facilitates activation of B and T cells, enhanced myelopoiesis, splenomegaly, and ultimately, generation of pathogenic autoreactive antibodies. These pathogenic autoantibodies deposit in the kidneys causing kidney pathology. Genetic deletion of IL-6 on a Lyn-/- background ablates disease in these mice without altering B cell development or plasma cell accumulation, partitioning cellular changes that are intrinsic to loss of Lyn from induction of autoimmunity. Lyn is an important regulator of autoimmune susceptibility as genetic deletion of Lyn on multiple genetic backgrounds results in autoimmune disease. Lyn is also a haploinsufficient gene for autoimmune disease as Lyn+/- mice develop autoimmune disease of varying severity, albeit milder and delayed. Genetic interaction between heterozygote mutations of Lyn and the inhibitory phosphatase SHP-1 result in amplification of cellular activation and autoantibody levels, ultimately resulting in exacerbated kidney pathology. This synergistic interaction between loss of key inhibitory molecules is highly relevant to human autoimmune disease, which is extensively polygenic and relies on multiple genetic anomalies. This thesis also examines the role of lymphangiogenesis in the development and exacerbation of autoimmune disease. Lymphangiogenesis occurs during development and de novo, where lymphatic vessels form in response to a stimulus. The lymphatic vasculature in Lyn-/- and Mev mutants are severely perturbed. These perturbations occur in a setting of autoimmune disease, characterized by expansion and activation of several immune cell subsets.…

Subjects/Keywords: autoimmune disease; B cells; inflammation; genetic interaction; Lyn kinase

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APA (6^th Edition):

Tsantikos, E. (2011). Dissecting autoimmune disease susceptibility in Lyn-deficient mice. (Doctoral Dissertation). University of Melbourne. Retrieved from http://hdl.handle.net/11343/36280

Chicago Manual of Style (16^th Edition):

Tsantikos, Evelyn. “Dissecting autoimmune disease susceptibility in Lyn-deficient mice.” 2011. Doctoral Dissertation, University of Melbourne. Accessed January 18, 2021. http://hdl.handle.net/11343/36280.

MLA Handbook (7^th Edition):

Tsantikos, Evelyn. “Dissecting autoimmune disease susceptibility in Lyn-deficient mice.” 2011. Web. 18 Jan 2021.

Vancouver:

Tsantikos E. Dissecting autoimmune disease susceptibility in Lyn-deficient mice. [Internet] [Doctoral dissertation]. University of Melbourne; 2011. [cited 2021 Jan 18]. Available from: http://hdl.handle.net/11343/36280.

Council of Science Editors:

Tsantikos E. Dissecting autoimmune disease susceptibility in Lyn-deficient mice. [Doctoral Dissertation]. University of Melbourne; 2011. Available from: http://hdl.handle.net/11343/36280

University of Arizona

20. Dietrich, Justin David. The Design, Synthesis, and Evaluation of Novel DFG-out Allosteric Kinase Inhibitors .

Degree: 2008, University of Arizona

URL: http://hdl.handle.net/10150/195661

► Today, current drug discovery and lead generation efforts focus on high throughput screening of large chemical libraries as the primary source of lead candidates. A… (more)

▼ Today, current drug discovery and lead generation efforts focus on high throughput screening of large chemical libraries as the primary source of lead candidates. A lack of investment in novel chemotype development by pharmaceutical companies over the last 15 years coupled with the concurrent merger of screening collections and the availability of generic compound libraries commercially have resulted in many discovery efforts that lack uniqueness and do not offer a strong patent position to operate. The need for better, more diverse, and more drug-like libraries is essential in order to feed high throughput screening efforts with molecules that probe new dimensions of chemical space and allow for the discovery of untapped intellectual property.This dissertation details a complete structure based study to design novel inhibitors of B-Raf and p38a MAP Kinase. A structural evaluation of the important and similar interactions necessary for DFG-out allosteric inhibitors to bind their respective targets was accomplished through the synthesis and evaluation of three known allosteric kinase inhibitors, GleevecÂ®, NexavarÂ®, and BIRB-796, and 8 additional DFG-out allosteric inhibitors that were developed directly from fragments of these successful scaffolds. The structural insight that was gained from the evaluation of known DFG-out allosteric inhibitors was then utilized to design novel inhibitors that incorporated two unique scaffolds based on two new [3+2] cycloaddition reactions.A pyrrolo-3,4-dicarboximide scaffold has been developed through the utilization of a novel tandem [3+2] cycloaddition then elimination reaction scheme. This scaffold, which contains three sites for variation, was then rationally incorporated into lead molecules using structure-based methods and in silico feedback for the production of dual DFG-out allosteric kinase inhibitors of p38a and B-Raf kinase. These inhibitors display micromolar to submicromolar enzymatic IC50's for both p38a and B-Raf kinase and low micromolar inhibition of cell growth in 4 separate cancer cell lines.We also explored new chemistry that utilizes a key one pot, [3+2] cycloaddition reaction to obtain highly substituted imidazoles and their application in the design of specific allosteric B-Raf inhibitors. Inhibitors based on this scaffold display subnanomolar potency and a favorable kinase profile. Advisors/Committee Members: Polt, Robin (committeemember), Vaillancourt, Richard (committeemember), Hulme, Christopher (committeemember), Maggiora, Gerald (committeemember).

Subjects/Keywords: Allosteric; B-Raf; Kinase; p38

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Dietrich, J. D. (2008). The Design, Synthesis, and Evaluation of Novel DFG-out Allosteric Kinase Inhibitors . (Doctoral Dissertation). University of Arizona. Retrieved from http://hdl.handle.net/10150/195661

Chicago Manual of Style (16^th Edition):

Dietrich, Justin David. “The Design, Synthesis, and Evaluation of Novel DFG-out Allosteric Kinase Inhibitors .” 2008. Doctoral Dissertation, University of Arizona. Accessed January 18, 2021. http://hdl.handle.net/10150/195661.

MLA Handbook (7^th Edition):

Dietrich, Justin David. “The Design, Synthesis, and Evaluation of Novel DFG-out Allosteric Kinase Inhibitors .” 2008. Web. 18 Jan 2021.

Vancouver:

Dietrich JD. The Design, Synthesis, and Evaluation of Novel DFG-out Allosteric Kinase Inhibitors . [Internet] [Doctoral dissertation]. University of Arizona; 2008. [cited 2021 Jan 18]. Available from: http://hdl.handle.net/10150/195661.

Council of Science Editors:

Dietrich JD. The Design, Synthesis, and Evaluation of Novel DFG-out Allosteric Kinase Inhibitors . [Doctoral Dissertation]. University of Arizona; 2008. Available from: http://hdl.handle.net/10150/195661

University of Tennessee – Knoxville

21. Bai, Xiaofei. Investigating the Roles of Master Cell Cycle Regulators during Cytokinesis and Embryonic Development in Caenorhabditis elegans.

Degree: 2018, University of Tennessee – Knoxville

URL: https://trace.tennessee.edu/utk_graddiss/4919

► Faithful cell division is required to maintain ploidy and generate daughter cells with necessary genetic components for life. During mitosis, dividing cells face the challenge… (more)

▼ Faithful cell division is required to maintain ploidy and generate daughter cells with necessary genetic components for life. During mitosis, dividing cells face the challenge of coordinating multiple processes to ensure that nascent daughter cells inherit an exact copy of the parent cell’s genetic identity to maintain viability. To ensure the proper execution of cell division, multiple core cell cycle proteins, such as Aurora B kinase and separase, are involved in regulating chromosome segregation, cytokinesis and abscission. Interestingly, fundamental roles for these core cell cycle proteins are being characterized in this coordination. Separase regulates chromosome segregation and vesicle trafficking during meiotic and mitotic divisions. Aurora B kinase is well characterized to eliminate incorrect attachments of kinetochore with centromere through its phosphorylation. These faultless attachments initiate a series of signaling pathways to activate separase and promote chromosome segregation. Additionally, Aurora B kinase also phosphorylates centralspindlin to complete cytokinesis and midbody formation. The collection of work presented here addresses the role of these two master cell cycle regulators in cytokinesis, abscission, and cellular events during later morphogenesis. Chapter I outlines the contribution of separase to cytokinesis, highlight how the protease activity of separase regulates exocytosis in anaphase, and suggesting that an unknown substrate is involved in separase’s regulation of exocytosis. Chapter II elucidates how programmed cytokinesis in different tissues contributes to later cellular events during morphogenesis and uncovers the novel migration pattern of midbody to apical surface. Finally, in Chapter III, we present several live imaging methods for observing C. elegans embryogenesis which were applied for this study. Collectively, the work presented here addresses the roles of these master cell cycle regulators in exocytosis, cytokinesis, abscission, and later developmental events, which is critical to understand how failure of cell division promote tumorigenesis and aneuploidy. Finally, our study may provide insightful ideas to generate clinical technologies to cure human infertility, cancer and other genetic diseases.

Subjects/Keywords: Caenorhabditis elegans; Cell Division; Cytokinesis; RAB-11; Separase; Aurora B kinase

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Bai, X. (2018). Investigating the Roles of Master Cell Cycle Regulators during Cytokinesis and Embryonic Development in Caenorhabditis elegans. (Doctoral Dissertation). University of Tennessee – Knoxville. Retrieved from https://trace.tennessee.edu/utk_graddiss/4919

Chicago Manual of Style (16^th Edition):

Bai, Xiaofei. “Investigating the Roles of Master Cell Cycle Regulators during Cytokinesis and Embryonic Development in Caenorhabditis elegans.” 2018. Doctoral Dissertation, University of Tennessee – Knoxville. Accessed January 18, 2021. https://trace.tennessee.edu/utk_graddiss/4919.

MLA Handbook (7^th Edition):

Bai, Xiaofei. “Investigating the Roles of Master Cell Cycle Regulators during Cytokinesis and Embryonic Development in Caenorhabditis elegans.” 2018. Web. 18 Jan 2021.

Vancouver:

Bai X. Investigating the Roles of Master Cell Cycle Regulators during Cytokinesis and Embryonic Development in Caenorhabditis elegans. [Internet] [Doctoral dissertation]. University of Tennessee – Knoxville; 2018. [cited 2021 Jan 18]. Available from: https://trace.tennessee.edu/utk_graddiss/4919.

Council of Science Editors:

Bai X. Investigating the Roles of Master Cell Cycle Regulators during Cytokinesis and Embryonic Development in Caenorhabditis elegans. [Doctoral Dissertation]. University of Tennessee – Knoxville; 2018. Available from: https://trace.tennessee.edu/utk_graddiss/4919

University of Georgia

22. McNeill, Brian Wayne. Adenosine receptor mediated inhibition of tumor necrosis factor alpha in human monocytic cells.

Degree: 2014, University of Georgia

URL: http://hdl.handle.net/10724/21588

► Sepsis and septic shock is a continuing problem in the United States with an estimated 200,000 deaths annually. Septic shock occurs when conserved pathogen-derived mediators… (more)

▼ Sepsis and septic shock is a continuing problem in the United States with an estimated 200,000 deaths annually. Septic shock occurs when conserved pathogen-derived mediators are released and initiate a systemic activation of the innate immune system. Widespread activation of innate immune system cells results in the release of several proinflammatory mediators including: IL-1, IL-6, IL-12, nitric oxide, leukotrienes, and TNF?. Systemic release of these proinflammatory molecules can cause disseminated intravascular coagulation, hypotension, tachycardia, fever, multi-organ failure, and eventual cardiovascular collapse. While a number of strategies have been developed for the treatment of septic shock, few have proven efficacious in clinical trials. Recent evidence suggests that adenosine receptor agonists might be useful in the treatment of septic shock. Adenosine interacts with a family of four seven transmembrane spanning G-protein coupled receptors designated A1, A2A, A2B, and A3. These receptors exhibit differential tissue expression and couple to different G-proteins. Activation of the A2A and A3 receptor subtypes has been linked to a diminished inflammatory response to lipopolysaccharide, a cell wall component of Gram-negative bacteria. The goal of this study was to pharmacologically characterize the A2A and A3 receptor subtypes in the human monocytic cell line Mono Mac 6. Radioligand binding assays were used to demonstrate expression of each of these receptors on Mono Mac 6 cells. In addition, activation of the A2A receptor was shown to inhibit TNF? secretion induced by lipopolysaccharide and peptidoglycan a major component of the Gram-positive cell wall. A3 receptor agonists were found to inhibit LPS-induced TNF? production, however this effect was not mediated by the A3 receptor. The effect of adenosine receptor activation on signaling pathways activated by LPS was also examined. LPS-induced activation of the MAP kinases was unaffected by an A2A receptor agonist, however ERK activation was substantially inhibited by an A3 receptor agonist. Neither A2A nor A3 agonists modulated NF?B DNA binding. NF?Bdependent activation of a luciferase reporter construct was inhibited by the A2A receptor agonist.

Subjects/Keywords: LPS; sepsis; adenosine; TNFα; monocyte; NFκ; B; MAP kinase

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APA (6^th Edition):

McNeill, B. W. (2014). Adenosine receptor mediated inhibition of tumor necrosis factor alpha in human monocytic cells. (Thesis). University of Georgia. Retrieved from http://hdl.handle.net/10724/21588

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

McNeill, Brian Wayne. “Adenosine receptor mediated inhibition of tumor necrosis factor alpha in human monocytic cells.” 2014. Thesis, University of Georgia. Accessed January 18, 2021. http://hdl.handle.net/10724/21588.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

McNeill, Brian Wayne. “Adenosine receptor mediated inhibition of tumor necrosis factor alpha in human monocytic cells.” 2014. Web. 18 Jan 2021.

Vancouver:

McNeill BW. Adenosine receptor mediated inhibition of tumor necrosis factor alpha in human monocytic cells. [Internet] [Thesis]. University of Georgia; 2014. [cited 2021 Jan 18]. Available from: http://hdl.handle.net/10724/21588.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

McNeill BW. Adenosine receptor mediated inhibition of tumor necrosis factor alpha in human monocytic cells. [Thesis]. University of Georgia; 2014. Available from: http://hdl.handle.net/10724/21588

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

23. PIMENTA FILHO, Adenor Almeida. Impacto da esquistossomose mansônica no perfil lipídico e nas concentrações plasmáticas das apolipoproteínas A-I e B .

Degree: 2009, Universidade Federal de Pernambuco

URL: http://repositorio.ufpe.br/handle/123456789/1419

► A esquistossomose é uma doença parasitária intravascular presente em regiões de climas tropical e subtropical que acomete, aproximadamente, 200 milhões de pessoas no mundo. Estudos… (more)

Subjects/Keywords: Apolipoproteína B; Apolipoproteína A-I; lipídios; esquistossomose

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APA (6^th Edition):

PIMENTA FILHO, A. A. (2009). Impacto da esquistossomose mansônica no perfil lipídico e nas concentrações plasmáticas das apolipoproteínas A-I e B . (Thesis). Universidade Federal de Pernambuco. Retrieved from http://repositorio.ufpe.br/handle/123456789/1419

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

PIMENTA FILHO, Adenor Almeida. “Impacto da esquistossomose mansônica no perfil lipídico e nas concentrações plasmáticas das apolipoproteínas A-I e B .” 2009. Thesis, Universidade Federal de Pernambuco. Accessed January 18, 2021. http://repositorio.ufpe.br/handle/123456789/1419.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

PIMENTA FILHO, Adenor Almeida. “Impacto da esquistossomose mansônica no perfil lipídico e nas concentrações plasmáticas das apolipoproteínas A-I e B .” 2009. Web. 18 Jan 2021.

Vancouver:

PIMENTA FILHO AA. Impacto da esquistossomose mansônica no perfil lipídico e nas concentrações plasmáticas das apolipoproteínas A-I e B . [Internet] [Thesis]. Universidade Federal de Pernambuco; 2009. [cited 2021 Jan 18]. Available from: http://repositorio.ufpe.br/handle/123456789/1419.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

PIMENTA FILHO AA. Impacto da esquistossomose mansônica no perfil lipídico e nas concentrações plasmáticas das apolipoproteínas A-I e B . [Thesis]. Universidade Federal de Pernambuco; 2009. Available from: http://repositorio.ufpe.br/handle/123456789/1419

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

24. Aziz, Faisal. Contextual Analysis of IT-Business Alignment.

Degree: 2011, , School of Management

URL: http://urn.kb.se/resolve?urn=urn:nbn:se:bth-6020

► IT-Business alignment is an imperative process in the success of any business to use the competitive advantage of the information technology. In this work,… (more)

Subjects/Keywords: Business; IT-Business Alignment; B/I Alignment

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APA (6^th Edition):

Aziz, F. (2011). Contextual Analysis of IT-Business Alignment. (Thesis). , School of Management. Retrieved from http://urn.kb.se/resolve?urn=urn:nbn:se:bth-6020

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Aziz, Faisal. “Contextual Analysis of IT-Business Alignment.” 2011. Thesis, , School of Management. Accessed January 18, 2021. http://urn.kb.se/resolve?urn=urn:nbn:se:bth-6020.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Aziz, Faisal. “Contextual Analysis of IT-Business Alignment.” 2011. Web. 18 Jan 2021.

Vancouver:

Aziz F. Contextual Analysis of IT-Business Alignment. [Internet] [Thesis]. , School of Management; 2011. [cited 2021 Jan 18]. Available from: http://urn.kb.se/resolve?urn=urn:nbn:se:bth-6020.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Aziz F. Contextual Analysis of IT-Business Alignment. [Thesis]. , School of Management; 2011. Available from: http://urn.kb.se/resolve?urn=urn:nbn:se:bth-6020

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

25. Quetglas, Maria Daniela. Efeito do bloqueio meiótico na expressão, atividade e distribuição do fator promotor da meiose (MPF) e da proteína cinase ativada por mitógenos (MAPK) em oócitos bovinos.

Degree: PhD, Qualidade e Produtividade Animal, 2008, University of São Paulo

URL: http://www.teses.usp.br/teses/disponiveis/74/74131/tde-11032008-102815/ ;

►

Apesar dos grandes avanços na produção in vitro (PIV) de embriões bovinos, a produção de blastocistos se mantém ainda aquém do observado in vivo, indicando… (more)

▼

Apesar dos grandes avanços na produção in vitro (PIV) de embriões bovinos, a produção de blastocistos se mantém ainda aquém do observado in vivo, indicando que melhorais ainda são necessárias no processo de PIV. A competência para o desenvolvimento de oócitos tem sido relacionada, entre outros fatores, à interrupção do período de capacitação. Foi sugerido que o bloqueio meiótico poderia permitir ao oócito um tempo adicional para adquirir a competência. Embora ainda não se tenha melhorado o desenvolvimento embrionário com esse procedimento, o bloqueio meiótico com inibidores de cinases dependentes de ciclinas (CDK), como a butirolactona I (BLI), pode ser uma ferramenta útil na compreensão do desenvolvimento do oócito. O presente trabalho teve por objetivo averiguar o efeito da inibição de CDK com BLI, para bloquear temporariamente a retomada da meiose, sobre fatores que controlam o ciclo celular meiótico de oócitos bovinos. Oócitos bovinos obtidos de abatedouros foram bloqueados em vesícula germinativa (VG) in vitro com 10 µM de BLI por 24 h (BVG - bloqueado imaturo). Parte desses oócitos foi depois maturada in vitro por mais 24 h (BMII - bloqueado maturado). Como controles foram utilizados oócitos recém-aspirados dos folículos (VG - controle imaturo) ou maturados in vitro sem bloqueio meiótico prévio (MII - controle maturado). Os diferentes grupos de oócitos foram avaliados quanto a: 1) expressão de RNAm dos componentes do MPF (p34cdc2 e ciclina B1) e da MAPK; 2) expressão das proteínas do MPF (p34cdc2 e ciclina B1) e MAPK (p44 e p42); 3) atividade das proteínas MPF e MAPK durante a maturação in vitro de oócito submetidos ou não ao bloqueio da meiose pré-maturação e 4) a localização subcelular das proteínas p34cdc2, ciclina B1 e MAPK nos oócitos. Foi observado que: 1) a abundância relativa do RNAm de p34cdc2 e MAPK reduziu-se com a maturação, enquanto a ciclina B1 menteve-se estável; o bloqueio meiótico manteve o mesmo padrão de acordo com o estádio de maturação; 2) as proteínas de p34cdc2 e MAPK mantiveram-se estáveis durante a maturação, enquanto a ciclina B1 não foi detectada em oócitos imaturos e o foi nos maturados; o bloqueio meiótico também manteve a expressão das proteínas de acordo com o estádio de maturação; 3) as atividades de MPF e MAPK foram pouco afetadas pelo bloqueio meiótico; 4) as proteínas foram todas detectadas no citoplasma dos oócitos imaturos (bloqueados ou não) e maturados (bloqueados ou não), sendo apenas a p34cdc2 também localizada no núcleo de oócitos imaturos (bloqueados ou não). Diante dos resultados conclui-se que o bloqueio da meiose mantém o mesmo padrão de expressão, atividade e localização subcelular do MPF e da MAPK em oócitos imaturos e maturados, sugerindo que a tradução das mensagens, a ativação das cinases e a distribuição das proteínas foram controladas de acordo com o estádio da meiose, não sendo afetadas pelo bloqueio.

Although there have been great improvements in in vitro production (IVP) of bovine embryos, blastocyst production is still beyond that observed in vivo,…

Advisors/Committee Members: Leal, Cláudia Lima Verde.

Subjects/Keywords: Butirolactona I; Butyrolactone I; Competence; Competência; Expressão; Expression; Maturação; Maturation; Protein kinase; Proteína cinase

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Quetglas, M. D. (2008). Efeito do bloqueio meiótico na expressão, atividade e distribuição do fator promotor da meiose (MPF) e da proteína cinase ativada por mitógenos (MAPK) em oócitos bovinos. (Doctoral Dissertation). University of São Paulo. Retrieved from http://www.teses.usp.br/teses/disponiveis/74/74131/tde-11032008-102815/ ;

Chicago Manual of Style (16^th Edition):

Quetglas, Maria Daniela. “Efeito do bloqueio meiótico na expressão, atividade e distribuição do fator promotor da meiose (MPF) e da proteína cinase ativada por mitógenos (MAPK) em oócitos bovinos.” 2008. Doctoral Dissertation, University of São Paulo. Accessed January 18, 2021. http://www.teses.usp.br/teses/disponiveis/74/74131/tde-11032008-102815/ ;.

MLA Handbook (7^th Edition):

Quetglas, Maria Daniela. “Efeito do bloqueio meiótico na expressão, atividade e distribuição do fator promotor da meiose (MPF) e da proteína cinase ativada por mitógenos (MAPK) em oócitos bovinos.” 2008. Web. 18 Jan 2021.

Vancouver:

Quetglas MD. Efeito do bloqueio meiótico na expressão, atividade e distribuição do fator promotor da meiose (MPF) e da proteína cinase ativada por mitógenos (MAPK) em oócitos bovinos. [Internet] [Doctoral dissertation]. University of São Paulo; 2008. [cited 2021 Jan 18]. Available from: http://www.teses.usp.br/teses/disponiveis/74/74131/tde-11032008-102815/ ;.

Council of Science Editors:

Quetglas MD. Efeito do bloqueio meiótico na expressão, atividade e distribuição do fator promotor da meiose (MPF) e da proteína cinase ativada por mitógenos (MAPK) em oócitos bovinos. [Doctoral Dissertation]. University of São Paulo; 2008. Available from: http://www.teses.usp.br/teses/disponiveis/74/74131/tde-11032008-102815/ ;

University of Kentucky

26. Johnson, Jeremy Andrew. Examining the Role of Metabolic Pathways as Therapeutic Modalities for Triple Negative Breast Cancer.

Degree: 2020, University of Kentucky

URL: https://uknowledge.uky.edu/toxicology_etds/32

► Triple negative breast cancer (TNBC) comprises 15-20% of breast cancers, affects a younger patient population than other subtypes, and is very aggressive. TNBC is comprised… (more)

▼ Triple negative breast cancer (TNBC) comprises 15-20% of breast cancers, affects a younger patient population than other subtypes, and is very aggressive. TNBC is comprised of a diverse group of tumors that have proven refractory to targeted therapy and can be difficult to treat. Patients generally receive neoadjuvant chemotherapy (NAC), surgery, and radiotherapy. The standard of care for NAC includes a taxane, an anthracycline, and/or cyclophosphamide, and administration of NAC has resulted in pathological complete response (pCR) in 30-40% of patients. However, a majority of TNBC patients will not reach pCR and instead have residual disease (RD), which is associated with worse outcomes. Patients with RD are more likely to experience locoregional or distant recurrence, and they have lower rates of overall survival, breast cancer-specific survival, disease-free survival, and distant relapse-free survival. Five-year survival rates for TNBC are 91% for localized disease, 65% with regional recurrence, and only 11% with distant recurrence. The reductions in survival with metastasis indicate that patients who have RD after receiving NAC desperately need novel interventions. AMP-activated protein kinase (AMPK) and protein kinase B (Akt) are important cellular energy regulators that have been implicated in cancer therapy and progression. However, further work is needed to fully establish their roles as therapeutic modalities in TNBC. This study analyzed whether targeting the AMPK and Akt signaling pathways can enhance TNBC therapy or reduce TNBC metastasis. Chemical activation of AMPK suppresses growth of cancer cells, but many common AMPK activators—such as AICAR or 2-deoxyglucose—have low sensitivity and require dosing in the millimolar range. This has led to their unsuccessful translation to the clinic. FND-4b is a novel compound that activates AMPK at micromolar concentrations in colorectal cancer cells, but its effects in TNBC are unknown. Treatment of TNBC cells with FND-4b induced AMPK activation and signaling through its downstream pathways. Phosphorylation of acetyl CoA carboxylase (ACC)—a direct target of AMPK—was increased, indicating a decrease in fatty acid synthesis. Furthermore, activation of ribosomal protein S6 was reduced, which suggests reduced flux through the mTOR pathway. FND-4b also suppressed proliferation of TNBC in a dose-dependent manner in the low micromolar range, which is substantially lower than well-known AMPK activators. Finally, FND-4b increased apoptosis induction in TNBC cells at micromolar doses. Taken together, these findings indicate that FND-4b reduces proliferation and induces apoptosis through AMPK activation in TNBC cells at lower doses than many other AMPK activators. AMPK inhibition has increased sensitivity of cancer cells to radiotherapy due to suppression of autophagy. Chemical inhibition of the PI3K signaling cascade has also potentiated radiation-induced cell death in TNBC cells. However, the ability of individual AMPK or Akt isoforms to sensitize TNBC cells to radiotherapy…

Subjects/Keywords: Triple Negative Breast Cancer; AMP-Activated Protein Kinase; Protein Kinase B; Chemotherapy; Radiotherapy; Medical Cell Biology; Medical Molecular Biology; Oncology

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Johnson, J. A. (2020). Examining the Role of Metabolic Pathways as Therapeutic Modalities for Triple Negative Breast Cancer. (Doctoral Dissertation). University of Kentucky. Retrieved from https://uknowledge.uky.edu/toxicology_etds/32

Chicago Manual of Style (16^th Edition):

Johnson, Jeremy Andrew. “Examining the Role of Metabolic Pathways as Therapeutic Modalities for Triple Negative Breast Cancer.” 2020. Doctoral Dissertation, University of Kentucky. Accessed January 18, 2021. https://uknowledge.uky.edu/toxicology_etds/32.

MLA Handbook (7^th Edition):

Johnson, Jeremy Andrew. “Examining the Role of Metabolic Pathways as Therapeutic Modalities for Triple Negative Breast Cancer.” 2020. Web. 18 Jan 2021.

Vancouver:

Johnson JA. Examining the Role of Metabolic Pathways as Therapeutic Modalities for Triple Negative Breast Cancer. [Internet] [Doctoral dissertation]. University of Kentucky; 2020. [cited 2021 Jan 18]. Available from: https://uknowledge.uky.edu/toxicology_etds/32.

Council of Science Editors:

Johnson JA. Examining the Role of Metabolic Pathways as Therapeutic Modalities for Triple Negative Breast Cancer. [Doctoral Dissertation]. University of Kentucky; 2020. Available from: https://uknowledge.uky.edu/toxicology_etds/32

University of Illinois – Chicago

27. Taglieri, Domenico M. P21-Activated Kinase-1 Signaling in Myocardial Hypertrophy, Ischemic Heart Disease and Remodeling.

Degree: 2012, University of Illinois – Chicago

URL: http://hdl.handle.net/10027/9091

► P21-Activated Kinase-1 Signaling in Myocardial Hypertrophy, Ischemic Heart Disease and Remodeling Domenico M. Taglieri, M.D., Ph.D. Department of Physiology and Biophysics University of Illinois at… (more)

▼ P21-Activated Kinase-1 Signaling in Myocardial Hypertrophy, Ischemic Heart Disease and Remodeling Domenico M. Taglieri, M.D., Ph.D. Department of Physiology and Biophysics University of Illinois at Chicago Chicago, Illinois (2011) Dissertation Chairperson: Dr. Jesus Garcia-Martinez The role of p21-activated kinase-1 (Pak1) in the development of stress-induced cardiac growth, ischemic injury, and post-ischemic cardiac remodeling was explored. We determined the effects of ablation of the Pak1 gene on the response of the myocardium to chronic stress of isoproterenol (ISO) administration. In a separate set of experiments, we determined the effect of Pak1 on acute global cardiac ischemic/reperfusion (I/R) injury. In yet another set of experiments, we determined the effect of Pak1 on long-term myocardial remodeling after ligation of the left anterior descending coronary artery for 10 weeks. Results indicate that active Pak1 is a natural inhibitor of Erk1/2 and a novel anti-hypertrophic signaling molecule upstream of PP2A. Pak1-KO hearts have reduced recovery of myocardial performance after acute global I/R injury concomitant with changes in troponin-T and MLC2 phosphorylation. In a separate set of experiments, compared to WT controls, in vivo hearts from Pak1-KO mice subjected to ligation of the left anterior descending coronary artery for 10 weeks develop significantly reduced global systolic and diastolic function as assessed by transthoracic echocardiography, as well as significantly reduced compensatory left ventricular mass, indicative of impaired cardiac remodeling. At the end of the 10 weeks, mortality was significantly higher in the Pak1-null mice group versus WT. Pak1 signaling is protective in multiple disease models (isoproterenol-induced hypertrophy, acute global I/R injury, and left anterior descending coronary artery ligation). Our studies provide a novel target for future investigations of the molecular signaling during stress. Advisors/Committee Members: Garcia-Martinez, Jesus (advisor), Solaro, John (committee member), Ke, Yunbo (committee member), Rasenick, Mark M. (committee member), Wolska, Beata M. (committee member), Carnegie, Graeme K. (committee member).

Subjects/Keywords: Myocardial hypertrophy; P-21-Activated kinase-1Erk 1/2Cardiac Troponin I

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Taglieri, D. M. (2012). P21-Activated Kinase-1 Signaling in Myocardial Hypertrophy, Ischemic Heart Disease and Remodeling. (Thesis). University of Illinois – Chicago. Retrieved from http://hdl.handle.net/10027/9091

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16^th Edition):

Taglieri, Domenico M. “P21-Activated Kinase-1 Signaling in Myocardial Hypertrophy, Ischemic Heart Disease and Remodeling.” 2012. Thesis, University of Illinois – Chicago. Accessed January 18, 2021. http://hdl.handle.net/10027/9091.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7^th Edition):

Taglieri, Domenico M. “P21-Activated Kinase-1 Signaling in Myocardial Hypertrophy, Ischemic Heart Disease and Remodeling.” 2012. Web. 18 Jan 2021.

Vancouver:

Taglieri DM. P21-Activated Kinase-1 Signaling in Myocardial Hypertrophy, Ischemic Heart Disease and Remodeling. [Internet] [Thesis]. University of Illinois – Chicago; 2012. [cited 2021 Jan 18]. Available from: http://hdl.handle.net/10027/9091.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Taglieri DM. P21-Activated Kinase-1 Signaling in Myocardial Hypertrophy, Ischemic Heart Disease and Remodeling. [Thesis]. University of Illinois – Chicago; 2012. Available from: http://hdl.handle.net/10027/9091

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Université de Bordeaux I

28. Tauzin, Sébastien. Association oncogénique de Lyn et PAG dans les lymphomes B non Hodgkinien : Statistical problems encountered in the study of antiretroviral treatment of adults infected with HIV in sub-Saharan Africa.

Degree: Docteur es, Biologie cellulaire et physiopathologie, 2008, Université de Bordeaux I

URL: http://www.theses.fr/2008BOR13619

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Les lymphomes B non-Hodgkiniens sont caractérisés par des altérations génétiques à l’origine du syndrôme néoplasique. Dans ce travail, nous démontrons que l’association dans les microdomaines… (more)

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Les lymphomes B non-Hodgkiniens sont caractérisés par des altérations génétiques à l’origine du syndrôme néoplasique. Dans ce travail, nous démontrons que l’association dans les microdomaines rafts de la membrane de Lyn, une kinase de la famille Src, avec l’adaptateur PAG, participe également au processus néoplasique. Dans les cellules B non-néoplasiques, Lyn et PAG sont des molécules impliquées dans la signalisation du récepteur des cellules B en réponse à une stimulation antigénique. Dans ce contexte, l’adaptateur PAG est décrit comme un inhibiteur de l’activité kinase de Lyn. Au contraire, dans les rafts des lymphomes B non-Hodgkiniens, nous avons mis en évidence que PAG retient la kinase Lyn sous une conformation active. Au sein des rafts, la kinase Lyn semble responsable de l’activation oncogénique de la voie de signalisation PI3K/Akt et de la voie de signalisation STAT3. L’inhibition pharmacologique et génétique de la kinase Lyn induit l’apoptose et l’inhibition de la prolifération de lignées cellulaires dérivées de lymphomes B non-Hodgkiniens. Ce résultat est révélateur d’une dépendance des lignées cellulaires à l’association oncogénique de Lyn avec PAG. Le ciblage thérapeutique du complexe Lyn/PAG constitue donc une opportunité pour le traitement des lymphomes B non-Hodgkiniens.

Non Hodgkin B lymphomas are caracterized by genetic alerations that condition their neoplastic development. In this work, we demonstrate that an association between the Src family kinase Lyn and the PAG adaptor in rafts is also involved in the neoplastic phenotype. In normal B cells, Lyn and PAG contribute to BCR signalling, where PAG functions as a Lyn kinase inihibitor. In contrast, we demonstrate that Lyn remains active when associated with PAG in B non Hodgkin lymphomas rafts. In those rafts, the Lyn kinase participates in the oncogenic activation of the PI3K/Akt and STAT3 signaling pathways. Pharmacologic and genetic inhibition of the Lyn kinase leads to apoptosis induction and proliferation inhibition of B non Hodgkin lymphoma cell lines. Our results reveal the dependence (or addiction) of these cell lines to the Lyn and PAG complex in rafts. The Lyn/PAG complex therefore constitutes an appropriate therapeutic target in certain non Hodgkin B lymphoma treatment.

Advisors/Committee Members: Lang, Jochen (thesis director).

Subjects/Keywords: Lymphomes B non-Hodgkiniens; Lyn; Rafts; Signalisation; PAG; Oncogène; PI3K; Kinase; STAT3; B non Hodgkin lymphomas; Kinase; Lyn; Signaling; Oncogene; PAG; PI3K; STAT3; Rafts

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Tauzin, S. (2008). Association oncogénique de Lyn et PAG dans les lymphomes B non Hodgkinien : Statistical problems encountered in the study of antiretroviral treatment of adults infected with HIV in sub-Saharan Africa. (Doctoral Dissertation). Université de Bordeaux I. Retrieved from http://www.theses.fr/2008BOR13619

Chicago Manual of Style (16^th Edition):

Tauzin, Sébastien. “Association oncogénique de Lyn et PAG dans les lymphomes B non Hodgkinien : Statistical problems encountered in the study of antiretroviral treatment of adults infected with HIV in sub-Saharan Africa.” 2008. Doctoral Dissertation, Université de Bordeaux I. Accessed January 18, 2021. http://www.theses.fr/2008BOR13619.

MLA Handbook (7^th Edition):

Tauzin, Sébastien. “Association oncogénique de Lyn et PAG dans les lymphomes B non Hodgkinien : Statistical problems encountered in the study of antiretroviral treatment of adults infected with HIV in sub-Saharan Africa.” 2008. Web. 18 Jan 2021.

Vancouver:

Tauzin S. Association oncogénique de Lyn et PAG dans les lymphomes B non Hodgkinien : Statistical problems encountered in the study of antiretroviral treatment of adults infected with HIV in sub-Saharan Africa. [Internet] [Doctoral dissertation]. Université de Bordeaux I; 2008. [cited 2021 Jan 18]. Available from: http://www.theses.fr/2008BOR13619.

Council of Science Editors:

Tauzin S. Association oncogénique de Lyn et PAG dans les lymphomes B non Hodgkinien : Statistical problems encountered in the study of antiretroviral treatment of adults infected with HIV in sub-Saharan Africa. [Doctoral Dissertation]. Université de Bordeaux I; 2008. Available from: http://www.theses.fr/2008BOR13619

Université Montpellier II

29. Brioudes, Estelle. RSK2 et Greatwall, deux AGC kinases actrices de la mitose : RSK2 and Greatwall, two AGC kinases involved in the regulation of mitosis.

Degree: Docteur es, Biologie cellulaire et moléculaire. Biochimie, 2010, Université Montpellier II

URL: http://www.theses.fr/2010MON20251

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La mitose est une phase importante du cycle cellulaire. Les mécanismes de surveillance s'assurent de l'ordre et de l'exécution correcte des événements du cycle cellulaire… (more)

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La mitose est une phase importante du cycle cellulaire. Les mécanismes de surveillance s'assurent de l'ordre et de l'exécution correcte des événements du cycle cellulaire dont les erreurs peuvent conduire à l'aneuploïdie. Pendant la mitose, la séparation des chromatides sœurs est régulée par le point de contrôle du fuseau mitotique qui s'assure que tous les chromosomes sont correctement alignés sur la plaque métaphasique. L'entrée et la sortie de mitose sont régulées par l'activation et l'inactivation du complexe cycline B/Cdk1. Cette fine régulation fait intervenir de nombreuses kinases et phosphatases. Dans ce projet nous nous sommes intéressés plus particulièrement à deux AGC kinases : RSK2 et Greatwall (Gwl).Au cours de cette étude nous nous sommes proposés d'analyser l'implication de RSK2, substrat majeur de la MAPK, dans le point de contrôle du fuseau mitotique. Nos résultats montrent que RSK2 est essentielle pour l'activité du point de contrôle du fuseau mitotique dans les extraits d'œufs de xénope ainsi que pour la localisation des autres protéines de ce mécanisme de surveillance localisées aux kinétochores. Nous montrons également que RSK2 participe au point de contrôle dans les cellules humaines. En effet, RSK2 est nécessaire à la localisation aux kinétochores de Mad1, Mad2 et Cenp-E, protéines essentielles à l'activité de ce checkpoint. L'entrée et la sortie de mitose sont régulées par le complexe cycline B/Cdk1 et des phosphatases. Gwl est une nouvelle kinase essentielle à l'entrée en mitose et au maintien de l'état mitotique dans les extraits d'œufs de xénope. En effet, nos résultats montrent que Gwl maintient l'état mitotique indépendamment du complexe cycline B/Cdk1, en régulant négativement PP2A, une phosphatase responsable de la déphoshorylation des substrats mitotiques.

Mitosis is an important phase of cell cycle. The Spindle Assembly Checkpoint (SAC) verifies the orders and the events correct execution of the cell cycle, as errors may lead to aneuploidy. During the mitosis, the checkpoint delays the anaphase onset until all chromosomes are correctly attached to the spindle‘s microtubules. Entry and Exit of mitosis are regulated by the activation and inactivation of cyclin B/Cdk1. A lot of kinases and phosphatases are involved in this fine regulation. In this project, we are particularly focusing on two AGC kinases: RSK2 and Greatwall (Gwl).In this study, we analyzed RSK2, a major substrates of MAPK, involvement in SAC. Our results show that RSK2 is essential to the activation of SAC in xenopus egg extracts and for the localization at the kinétochores of the others SAC components. We also show that RSK2 participate in the maintenance of the SAC in human cells. Indeed, RSK2 is necessary for Mad1, Mad2 and Cenp-E localization, essential proteins for SAC activation.Entry and exit of mitosis are regulated by cyclin B/Cdk1 complex and phosphatases. Gwl is a new kinase essential to the entry into mitosis and maintenance of the mitotic state in xenopus egg extracts. Indeed, our results showed that Gwl…

Advisors/Committee Members: Castro, Anna (thesis director).

Subjects/Keywords: Mitose; Point de contrôle du fuseau mitotique; Rsk2; Greatwall; AGC kinase; Cycline B/cdk1; Mitosis; Spindle assembly checkpoint; Rsk2; Greatwall; AGC kinase; Cyclin B/Cdk1

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

Brioudes, E. (2010). RSK2 et Greatwall, deux AGC kinases actrices de la mitose : RSK2 and Greatwall, two AGC kinases involved in the regulation of mitosis. (Doctoral Dissertation). Université Montpellier II. Retrieved from http://www.theses.fr/2010MON20251

Chicago Manual of Style (16^th Edition):

Brioudes, Estelle. “RSK2 et Greatwall, deux AGC kinases actrices de la mitose : RSK2 and Greatwall, two AGC kinases involved in the regulation of mitosis.” 2010. Doctoral Dissertation, Université Montpellier II. Accessed January 18, 2021. http://www.theses.fr/2010MON20251.

MLA Handbook (7^th Edition):

Brioudes, Estelle. “RSK2 et Greatwall, deux AGC kinases actrices de la mitose : RSK2 and Greatwall, two AGC kinases involved in the regulation of mitosis.” 2010. Web. 18 Jan 2021.

Vancouver:

Brioudes E. RSK2 et Greatwall, deux AGC kinases actrices de la mitose : RSK2 and Greatwall, two AGC kinases involved in the regulation of mitosis. [Internet] [Doctoral dissertation]. Université Montpellier II; 2010. [cited 2021 Jan 18]. Available from: http://www.theses.fr/2010MON20251.

Council of Science Editors:

Brioudes E. RSK2 et Greatwall, deux AGC kinases actrices de la mitose : RSK2 and Greatwall, two AGC kinases involved in the regulation of mitosis. [Doctoral Dissertation]. Université Montpellier II; 2010. Available from: http://www.theses.fr/2010MON20251

Columbia University

30. De, Arnab. Understanding two inhibitors of NF-κB: A20 and IκBβ.

Degree: 2014, Columbia University

URL: https://doi.org/10.7916/D8QC01JX

► While prompt activation of NF-κB is essential for optimal immune response, it is equally important to terminate the response to avoid tissue damage and perhaps… (more)

▼ While prompt activation of NF-κB is essential for optimal immune response, it is equally important to terminate the response to avoid tissue damage and perhaps even death resulting from organ failure. This thesis describes two inhibitors of NF-κB, A20 and IκBβ. A20 is an essential inhibitor of NF-κB mediated inflammation as mice lacking A20 die from multi-organ inflammation and cachexia. Multiple biochemical approaches have suggested that A20 functions as a deubiquitinase by disassembling K63-linked regulatory ubiquitin chains from upstream adapter molecules like RIP1. To determine the contribution of the deubiquitinase role of A20 in downregulating NF-κB, we generated and characterized a knock-in mouse lacking the deubiquitinase activity of A20. However, we find that these mice display normal NF-κB activation and show no signs of inflammation. Our results suggest that the deubiquitinase activity of A20 is dispensable for downregulating NF-κB. The second part of this thesis unravels a new biological pathway mediated by IκBβ. Unlike IκBα, which functions solely as an inhibitor of NF-κB, IκBβ can both inhibit and activate NF-κB depending on the physiological context. We hypothesized that this may be because IκBβ (unlike IκBα ) exists in two forms, a constitutively phosphorylated form and an unphosphorylated form. Prior work from our group has demonstrated that hypophosphorylated IκBβ complexes with p65:cRel and mediates the expression of certain inflammatory genes like TNFα . We report here that Glycogen Synthase Kinase 3β (GSK-3β ) interacts with and phosphorylates IκBβ at Serine-346. This phosphorylation masks the NLS of p65 in the phospho-IκBβ:p65:cRel complex, thereby sequestering the complex in the cytoplasm and mediating the anti-inflammatory role of IκBβ. We discovered a peptide that can inhibit this phosphorylation by abrogating the interaction between GSK-3β and IκBβ. Mice succumb to a sublethal dose of LPS when injected with this peptide because of increased production of TNFα (but not IL-6); thereby demonstrating the inflammatory role of unphosphorylated IκBβ in upregulating specific genes like TNFα. We propose a signaling model by which phosphorylation by GSK-3β can regulate the functions of IκBβ in response to LPS.

Subjects/Keywords: Glycogen synthase kinase-3; NF-kappa B (DNA-binding protein); Immunology; Biochemistry; Chemistry

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6^th Edition):

De, A. (2014). Understanding two inhibitors of NF-κB: A20 and IκBβ. (Doctoral Dissertation). Columbia University. Retrieved from https://doi.org/10.7916/D8QC01JX

Chicago Manual of Style (16^th Edition):

De, Arnab. “Understanding two inhibitors of NF-κB: A20 and IκBβ.” 2014. Doctoral Dissertation, Columbia University. Accessed January 18, 2021. https://doi.org/10.7916/D8QC01JX.

MLA Handbook (7^th Edition):

De, Arnab. “Understanding two inhibitors of NF-κB: A20 and IκBβ.” 2014. Web. 18 Jan 2021.

Vancouver:

De A. Understanding two inhibitors of NF-κB: A20 and IκBβ. [Internet] [Doctoral dissertation]. Columbia University; 2014. [cited 2021 Jan 18]. Available from: https://doi.org/10.7916/D8QC01JX.

Council of Science Editors:

De A. Understanding two inhibitors of NF-κB: A20 and IκBβ. [Doctoral Dissertation]. Columbia University; 2014. Available from: https://doi.org/10.7916/D8QC01JX

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Open Access Theses and Dissertations