The Role of the Nucleosome Remodeling Factor NURF in Inhibiting T and Natural Killer Cell Mediated Antitumor Immunity by Suppressing Tumor Antigenicity and Natural Cytotoxicity Receptor Co-ligands PDF Download
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Author: Kimberly Christine Mayes
Publisher:
ISBN:
Category :
Languages : en
Pages : 179
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Book Description
Tumor immunoediting is a dynamic process in which the immune response attacks tumor cells by detecting danger signals and tumor antigens. In order to survive, tumor cells develop mechanisms to avoid detection or destruction by the immune system. To counteract this, several strategies are being developed to enhance the antitumor immune response, including the depletion of immunosuppressive cells, enhancing the activation of antitumor immune cells and increasing tumor cell immunogenicity. These therapies have seen limited success individually, however, and it is likely that combination therapy with novel targets will be necessary to see reproducible beneficial responses. Epigenetic modifications are attractive therapeutic targets because they are reversible and affect gene expression in cancer cells. Within this framework, this study aimed to elucidate the role of the chromatin remodeling complex nucleosome remodeling factor (NURF) in cancer immunoediting by silencing of bromodomain PHD-finger containing transcription factor (BPTF), the largest and essential subunit of NURF. Using two syngeneic mouse models of cancer, BPTF was found to suppress T cell antitumor activity in the tumor microenvironment. In vitro, enhanced cytolytic activity was observed for individual CD8 T cell clones only from mice bearing BPTF-silenced tumors, implicating the involvement of novel antigens. Mechanistic investigations revealed that NURF directly suppresses the expression of genes encoding immunoproteasome subunits Psmb8 and Psmb9 and the antigen transporter genes Tap1 and Tap2. PSMB8 inhibition reversed the effects of BPTF ablation, consistent with a critical role for the immunoproteasome in improving tumor immunogenicity. Thus, NURF normally suppresses tumor cell antigenicity and its depletion improves CD8 T cell antitumor immunity. In a concurrent study using different tumor lines, BPTF was also found to suppress natural killer (NK) cell antitumor immunity in vivo. Enhanced NK cell cytolytic activity toward BPTF-depleted targets in vitro was dependent on the natural cytotoxicity receptors (NCR). Molecular studies revealed that BPTF directly activates heparanase (Hpse) expression, resulting in reduced cell surface abundance of the NCR co-ligands: heparan sulfate proteoglycans. Thus, NURF represses NCR co-ligand abundance and its depletion enhances NK cell cytotoxicity. Therefore, NURF emerges as a candidate therapeutic target to enhance CD8 T or NK cell antitumor immunity.
Author: Kimberly Christine Mayes
Publisher:
ISBN:
Category :
Languages : en
Pages : 179
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Book Description
Tumor immunoediting is a dynamic process in which the immune response attacks tumor cells by detecting danger signals and tumor antigens. In order to survive, tumor cells develop mechanisms to avoid detection or destruction by the immune system. To counteract this, several strategies are being developed to enhance the antitumor immune response, including the depletion of immunosuppressive cells, enhancing the activation of antitumor immune cells and increasing tumor cell immunogenicity. These therapies have seen limited success individually, however, and it is likely that combination therapy with novel targets will be necessary to see reproducible beneficial responses. Epigenetic modifications are attractive therapeutic targets because they are reversible and affect gene expression in cancer cells. Within this framework, this study aimed to elucidate the role of the chromatin remodeling complex nucleosome remodeling factor (NURF) in cancer immunoediting by silencing of bromodomain PHD-finger containing transcription factor (BPTF), the largest and essential subunit of NURF. Using two syngeneic mouse models of cancer, BPTF was found to suppress T cell antitumor activity in the tumor microenvironment. In vitro, enhanced cytolytic activity was observed for individual CD8 T cell clones only from mice bearing BPTF-silenced tumors, implicating the involvement of novel antigens. Mechanistic investigations revealed that NURF directly suppresses the expression of genes encoding immunoproteasome subunits Psmb8 and Psmb9 and the antigen transporter genes Tap1 and Tap2. PSMB8 inhibition reversed the effects of BPTF ablation, consistent with a critical role for the immunoproteasome in improving tumor immunogenicity. Thus, NURF normally suppresses tumor cell antigenicity and its depletion improves CD8 T cell antitumor immunity. In a concurrent study using different tumor lines, BPTF was also found to suppress natural killer (NK) cell antitumor immunity in vivo. Enhanced NK cell cytolytic activity toward BPTF-depleted targets in vitro was dependent on the natural cytotoxicity receptors (NCR). Molecular studies revealed that BPTF directly activates heparanase (Hpse) expression, resulting in reduced cell surface abundance of the NCR co-ligands: heparan sulfate proteoglycans. Thus, NURF represses NCR co-ligand abundance and its depletion enhances NK cell cytotoxicity. Therefore, NURF emerges as a candidate therapeutic target to enhance CD8 T or NK cell antitumor immunity.
Author: Zeinab Elsayed
Publisher:
ISBN:
Category :
Languages : en
Pages : 150
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Book Description
Understanding how an epigenetic regulator such as ATP-dependent chromatin-remodeling complexes modulate processes such as development and/or immune response is essential for our comprehension of cell biology. Deletion of the ATP-dependent chromatin remodeling factor INO80 is known to be embryonically lethal, however, the mechanism is not known. To identify roles for INO80 in mouse early development we generated Ino80 KO mice. Ino80 KO ESCs (Embryonic stem cells) were viable when maintained at ground state pluripotency but fail to differentiate in vitro and in vivo. Gene expression analysis of Ino80 KO early embryos by in situ hybridization showed elevated Bmp4 expression and reduced expression of DVE (distal visceral endoderm) markers Cer1, Hex, and Lefty1. BMP4 is a known negative regulator of DVE differentiation in the early embryo. Molecular studies in Ino80 KO ESCs demonstrated that INO80 is bound to the Bmp4 promoter, and regulates its chromatin structure, to suppress the positive regulator SP1 from stimulating its transcription. These results, suggest that INO80 directly regulates the chromatin structure of the Bmp4 promoter with consequences to mouse embryo development. These results are significant because they demonstrate a specific role of INO80 in establishing P-D embryonic axis. NURF (Nucleosome remodeling factor) is another ATP-dependent chromatin remodeling complex that is overexpressed in many cancer types including breast cancer. To demonstrate the roles of NURF in breast cancer biology, we knocked-down the NURF essential subunit BPTF (bromodomain PHD finger transcription factor) in mouse breast cancer cell lines. Transplantation of these cell lines into immune-competent mice revealed that BPTF KD enhances NK cell antitumor activity. BPTF KD enhanced NK-92 cytotoxic activity toward BPTF KD cells by NKp30 activation in vitro. NK-92 activity is reduced by the addition of heparin to the culture medium, further indicating the involvement of NKp30 (in human) and NCR1 (in mice) in killing of tumor cells. We found that BPTF controls the abundance of NKp30/NCR1 ligands (heparin sulfate proteoglycans (HSPGs) by regulation of heparanase expression (endoglycosidase that degrades HSPGs). In addition, BPTF depletion in established mouse breast tumors enhanced anti-tumor immunity, without affecting NK or T cell cytotoxic activity, providing a novel immunotherapy target.
Author: Mark G. Roberts
Publisher:
ISBN:
Category :
Languages : en
Pages : 128
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Book Description
The nucleosome remodeling factor (NURF) is a chromatin remodeling complex involved in early animal development and is implicated in a number of cancers. In previous work, knockdown of NURF's largest subunit, BPTF, resulted in diminished tumor growth in mouse cancer cell lines. Other studies in our lab demonstrated increased activation of T-lymphocytes into BPTF KD tumors. In order to examine if this approach has any therapeutic potential, this work investigates the effects of BPTF knockdown in established tumors by using recombinant adenoviruses (rAd), as well as observe the way the immune system interacts with BPTF knockdown cells, both in vivo by flow cytometry and in culture with cytotoxicity assays.
Author: Suehyb Alkhatib
Publisher:
ISBN:
Category :
Languages : en
Pages :
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Book Description
Increasingly the role of epigenetic machinery as a bridge between underlying DNA sequence and cellular phenotype is being discovered. The establishment of a myriad of unique cellular types sharing identical gene sequences in a multicellular organism gives a broad sense for the inherent role of epigenetic influence on cell differentiation. Importantly, the epigenetic mechanisms involved in establishing cell identity unsurprisingly contribute to diseased states, including cancer. Recent research continues to elucidate contributory roles of epigenetic mechanisms, such as DNA methylation, histone modification, and microRNA regulation, in human cancers. Additionally, chromatin remodelers, such as the Nucleosome Remodeling Factor (NURF), have been identified as important regulators for normal cell biology. While much has been done to identify and characterize the role of NURF chromatin remodeling complex as a key regulator of development in a number of model organisms, little has been published on the implications of NURF in diseases such as cancer. Our preliminary data shows dysregulation of E-cadherins, N-cadherins, and MHC-I genes in Bptf (an essential subunit of NURF) knocked down murine breast cancer cell lines. These proteins have well documented roles in the development and metastatic progression of cancers. To study the effect of Bptf knockdown on the development and progression of cancer we injected Bptf knocked down mouse breast cancer cell lines, 4T1, 66cl4, and 67NR, into syngenic BALB/c mice. Our findings reveal decreased tumor growth in 66cl4 and 67NR as measured by tumor weight at 3-4 weeks post injection. Tumor growth did not appear to be significantly affected in 4T1 challenged mice. However, mice inoculated with Bptf knockdown 4T1 cell lines have decreased metastasis to lungs as compared to control while metastasis of 66cl4 tumors to the lungs appear unaffected. To assess the role of the immune system in decreasing tumor growth in BALB/c mice, we injected 66cl4 tumors into NOD-SCID-Gamma (NSG) immune deficient mice. The tumors from these mice show no difference in tumor growth between Bptf knockdown and control tumors, implicating a role for the immune system regulating the decreased tumor weight in BALB/c mice. To delineate which immune cell effector may impede breast cancer carcinogenesis, we performed an in vitro natural killer (NK) cell cytotoxicity assay against 66cl4 tumors and found greater susceptibility to NK killing in Bptf knockdown tumors.
Author: A. Cato
Publisher: Springer Science & Business Media
ISBN: 3662046601
Category : Science
Languages : en
Pages : 410
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Book Description
The long-term use of glucocorticoids is associated with several deleterious effects. Attempts to separate the beneficial from the adverse effects of these compounds have met with varying degrees of difficulty. The discovery of distinct modes of action of the glucocorticoid receptor, the protein that mediates glucocorticoid action has opened up many possibilities for improving glucocorticoid therapy. This book provides an in-depth overview of the molecular actions of the glucocorticoid receptor and discusses the chances of an imminent identification of selective glucocorticoid agonists. Such componds should fulfill all the criteria of a glucocorticoid but should lack the sideeffects so far linked with classical glucocorticoids.
Author: Tamas Balla
Publisher: Springer Science & Business Media
ISBN: 940073011X
Category : Medical
Languages : en
Pages : 361
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Book Description
Phosphoinositides play a major role in cellular signaling and membrane organization. During the last three decades we have learned that enzymes turning over phosphoinositides control vital physiological processes and are involved in the initiation and progression of cancer, inflammation, neurodegenerative, cardiovascular, metabolic disease and more. In two volumes, this book elucidates the crucial mechanisms that control the dynamics of phosphoinositide conversion. Starting out from phosphatidylinositol, a chain of lipid kinases collaborates to generate the oncogenic lipid phosphatidylinositol(3,4,5)-trisphosphate. For every phosphate group added, there are specific lipid kinases – and phosphatases to remove it. Additionally, phospholipases can cleave off the inositol head group and generate poly-phosphoinositols, which act as soluble signals in the cytosol. Volume I untangles the web of these enzymes and their products, and relates them to function in health and disease. Phosphoinositide 3-kinases and 3-phosphatases have received a special focus in volume I, and recent therapeutic developments in human disease are presented along with a historical perspective illustrating the impressive progress in the field.
Author: Jean-Pierre Schermann
Publisher: Elsevier
ISBN: 0080558224
Category : Science
Languages : en
Pages : 499
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Book Description
Spectroscopy and Modeling of Biomolecular Building Blocks presents an overview of recent advances in the intertwining of the following research fields: photon and electron spectroscopy, quantum chemistry, modelling and mass-spectrometry. The coupling of these disciplines offers a new point of view to the understanding of isolated elementary building blocks of biomolecules and their assemblies. It allows the unambiguous separation between intrinsic properties of biomolecular systems and those induced by the presence of their environment. The first chapters provide background in modelling (I), frequency-resolved spectroscopy using microwave, infrared and UV photons, time-resolved spectroscopy in the femtosecond domain and energy-resolved electron spectroscopy (II) and production of gas-phase neutral and ionic biomolecular species, mass-spectrometry, ion mobility and BIRD techniques (III). Chapter IV is devoted to case studies of gas-phase experimental investigations coupled to quantum or classical calculations. The topics are structural studies of nucleobases and oligonucleotides, peptides and proteins, sugars; neuromolecules; non-covalent complexes; chiral systems, interactions of low-energy electrons with biomolecules in the radiation chemistry context and very large gas-phase biomolecular systems. The fifth chapter concerns the link between gas-phase and liquid-phase. Different treatments of solvation are illustrated through examples pointing out the influence of progressive addition of water molecules upon properties of nucleobases, peptides, sugars and neuromolecules. Offer a new perspective to the understanding of isolated elementary building blocks of bio molecules Includes case studies of experimental investigations coupled to quantum or classical calculations
Author: Tapas Kumar Kundu
Publisher: Springer Science & Business Media
ISBN: 9400745257
Category : Medical
Languages : en
Pages : 698
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Book Description
Epigenetics fine-tunes the life processes dictated by DNA sequences, but also kick-starts pathophysiological processes including diabetes, AIDS and cancer. This volume tracks the latest research on epigenetics, including work on new-generation therapeutics.
Author: Ralph Rapley
Publisher: John Wiley & Sons
ISBN: 047002495X
Category : Science
Languages : en
Pages : 33
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Book Description
Molecular Forensics offers a comprehensive coverage of the increasingly important role that molecular analysis plays within forensic science. Starting with a broad introduction of modern forensic molecular technologies, the text covers key issues from the initial scenes of crime sampling to the use of evidential material in the prosecution of legal cases. The book also explores the questions raised by the growing debate on the applications of national DNA databases and the resulting challenges of developing, maintaining and curating such vast data structures. The broader range of applications to non-human cases is also discussed, as are the statistical pitfalls of using so-called unique data such as DNA profiles, and the ethical considerations of national DNA databases. An invaluable reference for students taking courses within the Forensic and Biomedical sciences, and also useful for practitioners in the field looking for a broad overview of the subject. Provides a comprehensive overview of modern forensic molecular technologies. Explores the growing debate on the applications of national DNA databases. Discusses the initial phases of investigation to the conclusion of cases involving molecular forensic analysis.
Author: Eric T. Kool
Publisher: Pergamon
ISBN: 9780080431659
Category : DNA.
Languages : en
Pages : 0
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Book Description
This volume is intended to cover the chemistry of one of the most widely studied and important natural products, DNA. Discussed in detail are physicochemical properties of the molecule itself as well as small-molecule natural products that are known to interact with it. Also included are methods to synthesize and manipulate DNA and modified analogues. Twenty chapters are devoted to this overall topic. thermodynamics and kinetics of double helix formation; the next two describe triple- and tetra- helical structures formed by DNA; and the last two focus on methods for probing DNA structure (specifically, NMR methods and chemical probing methods, respectively). analogues. The first of these addresses nonenzymatic methods for synthesizing DNA, and the next chapter, methods for attachment of reporter groups to it. Modifications of DNA structure are discussed in chapters eight to eleven; the first of these addresses nucleoside analogues useful as biochemical probes, while others discuss alterations to the DNA backbone, bases, and topology, respectively. The extensive chemistry of DNA damage is reviewed in the last chapter (chapter 12). Included in this group are a large number of natural and non-natural products, which fall into the classes of intercalators (chapter 13), minor groove binders (chapter 14), DNA-binding peptides (chapter 15), and DNA-damaging natural products (chapter 16). The last two chapters focus more specifically on two broad classes of medicinally important agents which interact with DNA; specifically, the enediyne natural products (chapter 17), and topoisomerase inhibitors (chapter 18). are being used in many chemically-oriented laboratories. The first (chapter 19) covers selection of novel ligands and catalysts from sequence-randomized libraries of DNA. The second (chapter 20) covers other useful molecular biology methods such as cloning and the polymerase chain reaction.
