Download or read book Inactivation of Transcription Factor NF kappa B Through Its Association with the I kappa B alpha Inhibitor Protein written by Tom Huxford and published by . This book was released on 2001 with total page 360 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book The Role of Protein Structure and Dynamics in the Inhibition of NF kappaB by IkappaB Proteins written by Kristen Michelle Ramsey and published by . This book was released on 2018 with total page 157 pages. Available in PDF, EPUB and Kindle. Book excerpt: The NF[kappa]B signaling pathway is a central regulator of inflammatory and immune responses in virtually all human cell and tissue types, and aberrant signaling by NF[kappa]B has been implicated in a wide array of disease states including cancer, autoimmune diseases, and Alzheimer's disease among others. Inhibition of NF[kappa]B by binding of I[kappa]B proteins represents the most robust regulatory mechanism for controlling the initiation and duration of the NF[kappa]B signaling event. NF[kappa]B and I[kappa]B both denote families of dimeric transcription factors and their inhibitor proteins, respectively. NF[kappa]B transcription factors self associate to form functionally active dimers which then bind in a specific manner to different I[kappa]B family members. Here I present an extensive review of transcription factors and the NF[kappa]B pathway (Chapter I) to provide context for my work. I then describe a detailed analysis using hydrogen-deuterium exchange mass spectrometry (HDXMS) to probe the impact of I[kappa]B[alpha] binding on the internal dynamics of the p50/RelA NF[kappa]B heterodimer and demonstrate that long-range conformational changes induced by I[kappa]B[alpha] binding are of central importance to the inhibitory nature of the I[kappa]B[alpha] binding event (Chapter II). Chapter III describes the first detailed biophysical analysis of the most recently discovered I[kappa]B protein, I[kappa]B[epsilon]. I combined homology modeling and HDXMS to establish the presence of a seventh ankyrin repeat (AR) in I[kappa]B[epsilon] and further provide a framework for utilizing HDXMS as a tool to complement homology modeling of proteins with no known structures. After identifying the seventh AR in I[kappa]B[epsilon], I performed the first comprehensive examination of I[kappa]B[epsilon]'s ability to bind all NF[kappa]B dimers and the biophysical consequences on I[kappa]B[epsilon]'s internal dynamics upon binding to its preferred NF[kappa]B dimers (Chapter IV). Finally, to further probe the interaction of I[kappa]B[epsilon] with its preferred NF[kappa]B binding partners, I describe the impact of I[kappa]B[epsilon] binding on the dynamics of the cRel heterodimers which are the NF[kappa]B proteins which bind I[kappa]B[epsilon] with the highest affinity and discover the importance of entropic forces in driving these high affinity interactions (Chapter V).

Download or read book Molecular and Biological Studies on the Regulation of Transcription Factor Nuclear Factor kappa B written by Daniel Janse Van Antwerp and published by . This book was released on 1999 with total page 192 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Insights Into the Homeostatic Regulation of I Kappa B Alpha written by Erika Mathes Lisabeth and published by . This book was released on 2009 with total page 153 pages. Available in PDF, EPUB and Kindle. Book excerpt: The regulation of the transcription factor NF-[kappa]B is crucial to proper cell physiology, as misregulation of this transcription factor can lead to many disease states, including chronic inflammation and cancer. NF-[kappa]B is inhibited by a class of inhibitor proteins known as I kappa B; the most effective I[kappa]B is I[kappa]B[alpha]. Signal induced degradation of I[kappa]B[alpha] leading to NF-[kappa]B translocation and activation is well documented and requires post-translational modifications such as phosphorylation and ubiquitination. It has recently been demonstrated that I[kappa]B alpha also undergoes stimulus-independent degradation and this degradation pathway might be important for NF-[kappa]B activity regulation. The focus of this study is to investigate the mechanism of stimulus independent degradation of I[kappa]B alpha and its effect on NF-[kappa]B activity. Chapter 1 introduces the NF-[kappa]B:I[kappa]B signaling system, ubiquitin-independent degradation of several substrates, and also various regulatory proteasome complexes. Chapter 3 describes the delineation of the pathways regulating the degradation of I[kappa]B[alpha]. Results presented here show that the degradation pathway of I[kappa]B alpha is determined by binding to NF-[kappa]B subunits. It is further shown that perturbations of ubiquitin-independent degradation pathway alter NF-[kappa]B activation. Chapter 4 focuses on the ankyrin repeat sequence of I[kappa]B alpha. Of the six ankyrin repeats present in I[kappa]B alpha, several deviate from the consensus ankyrin repeat sequence. Mutations back to the consensus sequence in several ankyrin repeats demonstrate that the location of thermodynamic stabilization determines the degradation rate of I[kappa]B[alpha]. Finally, Chapter 5 dissects the degradation requirements of I[kappa]B alpha. Our results show that there are two degrons within I[kappa]B[alpha]; one located in the 5th ankyrin repeat, and the other within the PEST domain of I[kappa]B[alpha]. Both degrons are controlled by hydrophobic residues within long stretches of flexible regions.

Download or read book Cell specific Association Between NF kappa B Component C Rel and Its Inhibitor I kappa B alpha written by Kara Smith and published by . This book was released on 2005 with total page 86 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Identification of NF kappa B and DNA dependent Protein Kinase DNA PK as New Players in the Regulation and Signaling of the Oncogenic Phosphatase Wip1 written by Julie Lowe and published by . This book was released on 2010 with total page 133 pages. Available in PDF, EPUB and Kindle. Book excerpt: Wild-type p53-induced phosphatase 1 (Wip1) is a stress-induced nuclear type 2C protein phosphatase (PP2C) that is over-expressed and amplified in many types of cancers. Further studies have shown Wip1 to act as an oncogene by inhibiting tumor suppressors such as p16/p19, p53, and ATM. The physiological role of Wip1 is to facilitate the return of the cell to homeostasis by inhibiting apoptosis and cell cycle arrest through the inactivation of several key stress signaling proteins such as p38, p53, and ATM. However, this physiological function may possibly be an additional oncogenic property of Wip1, since this may lead to premature inhibition of stress signaling and genomic instability in cases when Wip1 is over-expressed. Due to its oncogenic properties, Wip1 is an attractive drug target for human cancers, and, therefore, understanding Wip1 molecular functions is important. The studies outlined in this project identify novel regulation of Wip1 as well as novel Wip1 targets after stress and in a cancer setting. Nuclear factor- kappa B (NF-kappa B) directly induced or inhibited Wip1 expression at the transcriptional level depending on the cellular context. Additionally, Wip1 enhanced NF-kappa B activation in certain contexts by reducing the expression of the NF-kappa B inhibitor, Inhibitor of NF-kappa B-alpha (IkappaBalpha). DNA-PK, a major enzymatic complex important for the Non-Homologous End-Joining DNA double strand break repair process, was identified as a Wip1 target. Specifically, Wip1 reduced phosphorylation levels of the catalytic subunit of DNA-PK (DNA-PKcs) at the activating residue Thr2609. As a consequence, Wip1 inhibited NHEJ after genotoxic stress. These results contribute to the understanding of the functions of Wip1 in both a physiological and tumorigenic setting. New roles for NF-kappa B and DNA-PK in Wip1 signaling were identified, which have direct implications in the understanding of Wip1 oncogenic functions and the treatment of human cancer.

Download or read book Inhibition of NF kappa B I kappa B Transcription Factor Activation by Antioxidants written by and published by . This book was released on 1997 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Investigating the Role of Intra and Extra cellular Modulators of the Transcription Factor NF kappaB written by Hung Nhat Nguyen and published by . This book was released on 2011 with total page 148 pages. Available in PDF, EPUB and Kindle. Book excerpt: The nuclear factor-kappa B (NF-kappaB) family of transcription factors play a pivotal role in the inflammatory and immune responses, as well as cell growth and survival. Since its discovery 25 years ago, NF-kappaB has emerged as one of the most intensely studied eukaryotic transcription factors, due to its pleiotropic functions and its inducible pattern of expression that is subject to multi-level regulation. Many modulatory events affect NF-kappaB function and thus to have a better understanding of the NF-kappaB pathway and its gene regulation will require additional studies of NF-kappaB's modulators. The goal of this thesis was to investigate the role of intra- and extra-cellular modulators of NF-kappaB. To study how intracellular modulators affect NF-kappaB function, various genetic and biochemical approaches were used to identify potentially new NF-kappaB's interacting proteins. Two AGC family kinases, STK38 and STK38L, were chosen for further study. These two proteins were found to not only interact with NF-kappaB's p65 subunit but also act as its kinases in vitro. shRNA mediated knockdown combined with gene expression analysis revealed that STK38 and STK38L via their kinase function regulated p65 activity on some, but not all NF-kappaB-responsive inflammatory genes in response to TNFa stimulation. To study the role of extracellular modulators on the apoptotic behaviors of cells, a panel of human immortalized and cancer liver cell lines were pre-treated with pro-inflammatory cytokines TNFa and IL-1a followed by TRAIL, a potent inducer of cell death. This context-dependent approach revealed that TNFa and IL-1a had diverse effects on cell death behaviors and inhibiting the NF-kappaB pathway was enough to block pro-inflammatory cytokines-mediated pro-death or pro-survival outcomes. Chromatin immunoprecipitation followed by high throughput sequencing, realtime PCR and Western blotting were used to identify NF-kappaB's target genes involved in the cell death pathway. From these data, new regulatory mechanisms that affect cell death behaviors were proposed. Dysregulation of NF-kappaB activation has been implicated in various pathologies including inflammatory diseases and cancer. The results described here represent progress toward understanding the NF-kB pathway and its gene regulation program. The more we understand this pathway, the better we are at targeting it for disease treatments.

Download or read book Inhibition of NF Kappa B I Kappa B Transcription Factor Activation by Antioxidants written by Raymond Min Hang Lee and published by . This book was released on 1997 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Insights Into the Regulation of NF kappaB and Mediation of the Cellular Stress Response by NF kappaB written by Jessica Q. Ho and published by . This book was released on 2010 with total page 190 pages. Available in PDF, EPUB and Kindle. Book excerpt: NF-[kappa]B is a pleiotropic transcription factor, which is instrumental in regulating diverse cellular processes such as inflammation and cell survival. Enhanced NF-[kappa]B activity, due either to prolonged NF-[kappa]B activation upon exposure to cellular stress or misregulation of NF-[kappa]B, can lead to many neurodegenerative diseases as well as cancer. Thus, in this study, biological and biochemical approaches were used to characterize how NF-[kappa]B regulates the cellular stress response and how NF-[kappa]B activity itself is regulated. Chapter 1 introduces oxidative stress, which is the specific cellular stress used in this study, and reviews how oxidative stress affects all cellular components, including the proteasome and NF-[kappa]B. Chapter 2 characterizes the mechanism of NF-[kappa]B's cell death promoting function in response to oxidative stress and shows that NF-[kappa]B signaling actually promotes cell death. Furthermore, we suggest that NF-[kappa]B promotes cell death through the repression of pro-survival genes and induction of pro-death genes. Chapter 3 focuses on whether oxidized 20S proteasome enhances the ubiquitin independent degradation of NF-[kappa]B inhibitor molecule I[kappa]B[gamma]. We clearly show that the 20S proteasome is able to degrade I[kappa]B[gamma] in an ubiquitin independent manner. Preliminary LC-MS/MS data suggests that the 20S proteasome, which displays enhanced activity towards I[kappa]B[gamma], can undergo cysteic acid modification. We suggest that mild oxidative stress can enhance proteasome activity, while severe oxidative stress impairs proteasomal activity. Chapter 4 provides strong evidence suggesting that PA28[alpha][beta] bound 20S proteasome is responsible for the ubiquitin independent degradation of another NF-[kappa]B inhibitor molecule, free I[kappa]B[alpha]. All together, this work delineates how NF-[kappa]B signaling can mediate cell death in response to oxidative stress, how oxidative stress can potentially increase the ubiquitin independent degradation of I[kappa]B[gamma] by enhancing the proteolytic activity of the 20S proteasome, and how PA28[alpha][beta] bound 20S proteasome is responsible for the ubiquitin independent degradation of free I[kappa]B[alpha].

Download or read book Molecular Biology of the Cell written by and published by . This book was released on 2002 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Identification of Novel Regulators of the Nuclear Factor Kappa B Pathway in Human Macrophages written by Suneer Verma and published by . This book was released on 2017 with total page 144 pages. Available in PDF, EPUB and Kindle. Book excerpt: The nuclear factor-kappa B (NF-[kappa]B) family of transcription factors has a central role in coordinating the expression of genes that control inflammation, immune responses, cell-proliferation, and a variety of other processes. Ever since its discovery in 1986 in David Baltimore's lab, the NF-[kappa]B pathway has been the prime model of inducible transcription in various cell types, and in response to multiple stimuli. Despite being one of the most well-studied pathway in biology, it still has a lot of unanswered questions associated with it including the events that lead up to its activation in the cytoplasm as well as the sequence of events that lead to the transcription of hundreds of its target genes in the nucleus. Given the pathway's implication in development and diseases, it has become increasingly important to answer these questions. Here, we present two whole-genome RNAi screens conducted to find novel regulators of this pathway in the physiologically relevant human macrophages in response to Lipopolysaccharides (LPS) and Tumor Necrosis Factor Alpha (TNF). After three levels of screening we have found over 25 potential novel regulators of this pathway, summarized in Chapters 2 and 4. The top hit is the splicing factor and transcriptional co-activator SNW1. We have further validated it as a regulator of the NF-[kappa]B pathway in response to multiple stimuli and in five different cell lines (THP-1, U87, 293T, A549, and U2-OS). SNW1 does not seem to affect general constitutive transcription in THP-1 cells but does seem to repress some transcription programs e.g. CREB and NFE2. SNW1 does not regulate the cytoplasmic part of the NF-[kappa]B pathway but does complex with the NF-[kappa]B hetero dimer in the nucleus on pathway activation. We have shown that it binds to NF-[kappa]B's transcriptional elongation partner p-TEFb and helps recruit it to the NF-[kappa]B nuclear complex that contains RNA Polymerase II. We have also shown that SNW1 loses binding from its splicing complex (SNRNP200, SNRNP220) on NF-[kappa]B activation. SNW1 is a unique protein shown to be involved in both splicing and transcription and in the case of NF-[kappa]B, its role seems to involve recruitment of p-TEFb for effective transcriptional elongation of NF-[kappa]B target genes.

Download or read book Myeloma Bone Disease written by G. David Roodman and published by Springer Science & Business Media. This book was released on 2010-04-28 with total page 257 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book presents the forefront in the science and clinical management of myeloma bone disease. Coverage begins with sections on clinical presentation, imaging, and biochemical markers and goes on to discuss radiation, surgical, and medical therapies.

Download or read book The Transcription Factor NF kappaB in Chronic and Acute Inflammation Role of IKK Complex associated Signaling written by Claudia Fischer and published by Cuvillier Verlag. This book was released on 2001 with total page 136 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book How Tobacco Smoke Causes Disease written by United States. Public Health Service. Office of the Surgeon General and published by . This book was released on 2010 with total page 728 pages. Available in PDF, EPUB and Kindle. Book excerpt: This report considers the biological and behavioral mechanisms that may underlie the pathogenicity of tobacco smoke. Many Surgeon General's reports have considered research findings on mechanisms in assessing the biological plausibility of associations observed in epidemiologic studies. Mechanisms of disease are important because they may provide plausibility, which is one of the guideline criteria for assessing evidence on causation. This report specifically reviews the evidence on the potential mechanisms by which smoking causes diseases and considers whether a mechanism is likely to be operative in the production of human disease by tobacco smoke. This evidence is relevant to understanding how smoking causes disease, to identifying those who may be particularly susceptible, and to assessing the potential risks of tobacco products.

Download or read book Cumulated Index Medicus written by and published by . This book was released on 1999 with total page 1860 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Identification of Novel Regulators of Nuclear Factor Kappa B Repression by the Glucocorticoid Receptor written by Samantha Harriet Murphy and published by . This book was released on 2011 with total page 156 pages. Available in PDF, EPUB and Kindle. Book excerpt: Nuclear factor kappa B (NF-kappaB) is a family of transcription factors that has an essential regulatory function in inflammation, the immune response, cell proliferation, and apoptosis. Constitutive activation of the NF-kappaB pathway is often associated with cancer and chronic inflammatory diseases such as multiple sclerosis, inflammatory bowel disease, rheumatoid arthritis, and asthma. Glucocorticoids, which bind to the glucocorticoid receptor (GR), are among the strongest anti-inflammatory agents and one of the most common forms of treatment to suppress inflammation. GR is a transcription factor that plays an important role in a variety of cellular processes including reproduction, development, differentiation, and metabolism, and it is fundamental to the counteraction of immune and inflammatory responses by acting as a key repressor of NF-kappaB. Proposed mechanisms of NF-kappaB repression by GR are complex and varied, and a universal mechanism of repression has yet to be elucidated. By discovering novel genes that play a role in GR repression of NF-kappaB, potential therapeutic targets and their molecular mechanisms can be identified to specifically improve the use of glucocorticoids in clinical applications. We performed high throughput screens using siRNA oligonucleotide library collections to identify novel genes that affect glucocorticoid repression of NF-kappaB activity after activation of both the NF-kappaB and GR pathways. The work presented in this thesis provides evidence that p53 is involved in glucocorticoid receptor repression of NF-kappaB. We initially establish p53 as a gene of interest by high throughput screening, and validate this finding using luciferase assays in physiologically relevant cell lines and by qPCR. We also confirm its biological significance in vivo in a mouse model of LPS shock. Additionally, we demonstrated that p53 does not play a role in upstream NF-kappaB or GR signaling cascades, that p53 loss impairs glucocorticoid repression of NF-kappaB target gene transcription, and that p53 loss impairs GR target gene transcription. We conclude that p53 is an important gene involved in GR repression of NF-kappaB, a finding that may explain why glucocorticoid treatment is often an ineffective therapy in the repression of inflammation associated with the tumor microenvironment and why NF-kappaB is often up-regulated in many human cancers. Additionally, we have identified 24 other novel genes that play a role in NF-kappaB repression by GR, and have created a survey outlining which of these genes affect aspects of certain NF-kappaB signaling components. Ultimately, we believe that agonist development targeting one of these genes may have the potential to lead to better anti-inflammatory therapies.