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Journal articleIto K, Yamamura S, Essilfie-Quaye S, et al., 2006,
Histone deacetylase 2-mediated deacetylation of the glucocorticoid receptor enables NF-kappa B suppression
, Journal of Experimental Medicine, Vol: 203, Pages: 7-13, ISSN: 1540-9538 -
Book chapterAdcock IM, Hayashi R, Ito K, et al., 2006,
CORTICOSTEROIDS
, Encyclopedia of Respiratory Medicine Volume 1 4Corticosteroids bind to and activate a cytoplasmic glucocorticoid receptor (GR) which exists as several isoforms derived from a single gene product by alternative splicing. The activated glucocorticoid receptor translocates into the nucleus and binds to specific response elements in the promoter regions of anti-inflammatory genes such as lipocortin-1 and secretory leukocyte protease inhibitor. However, the major anti-inflammatory effects of glucocorticoids appear to be due largely to interaction between the activated glucocorticoid receptor and transcription factors, notably nuclear factor kappa B (NF- κB) and activator protein-1, that mediate the expression of inflammatory genes. NF- κB switches on inflammatory genes via a process involving recruitment of transcriptional coactivator proteins and changes in chromatin modifications such as histone acetylation. The interactions between NF- κB and the glucocorticoid receptor result in differing effects on histone modifications and subsequent chromatin remodeling. GR is subjected to posttranslational modifications and these may influence hormone binding and nuclear translocation, alter glucocorticoid receptor interactions and protein half-life. Therapeutically, drugs that enhance glucocorticoid receptor nuclear translocation (long-acting β-agonists) and GR-associated histone deacetylase activity (theophylline) have been shown to be effective add-on therapies. In addition, dissociated glucocorticoids that target NF- κB preferentially have also been successful in the treatment of allergic disease in the skin.
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Book chapterAdcock IM, Hayashi R, Ito K, et al., 2006,
Corticosteroids: Glucocorticoid Receptors
, Encyclopedia of Respiratory Medicine Four Volume Set, Pages: 568-576Corticosteroids bind to and activate a cytoplasmic glucocorticoid receptor (GR) which exists as several isoforms derived from a single gene product by alternative splicing. The activated glucocorticoid receptor translocates into the nucleus and binds to specific response elements in the promoter regions of anti-inflammatory genes such as lipocortin-1 and secretory leukocyte protease inhibitor. However, the major anti-inflammatory effects of glucocorticoids appear to be due largely to interaction between the activated glucocorticoid receptor and transcription factors, notably nuclear factor kappa B (NF-κB) and activator protein-1, that mediate the expression of inflammatory genes. NF-κB switches on inflammatory genes via a process involving recruitment of transcriptional coactivator proteins and changes in chromatin modifications such as histone acetylation. The interactions between NF-κB and the glucocorticoid receptor result in differing effects on histone modifications and subsequent chromatin remodeling. GR is subjected to posttranslational modifications and these may influence hormone binding and nuclear translocation, alter glucocorticoid receptor interactions and protein half-life. Therapeutically, drugs that enhance glucocorticoid receptor nuclear translocation (long-acting β-agonists) and GR-associated histone deacetylase activity (theophylline) have been shown to be effective add-on therapies. In addition, dissociated glucocorticoids that target NF-κB preferentially have also been successful in the treatment of allergic disease in the skin.
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Book chapterAdcock IM, Ito K, Caramori G, 2006,
Transcription Factors: Overview
, Encyclopedia of Respiratory Medicine Four Volume Set, Pages: 243-251The term 'transcription factor' refers to a large family of proteins, which exert transcriptional control via specific interactions with regulatory gene sequences. Here, we provide a summary of the different classes of the transcription factor divided according to their DNA-binding motifs. The modular structure of transcription factors and the presence of distinct interacting domains determine the ability of these factors to associate with each other and with coactivating/repressing proteins. By recruiting transcriptional coactivators, transcription factors can induce changes in chromatin structure enabling gene expression to occur. We use the activation of the Rel transcription factor NF-B and the nuclear receptor GR as examples to indicate some of the intricacies and subtleties of DNA binding, chromatin remodeling, and transcription factor cross-talk. Finally, we review the evidence for the involvement of select transcription factors in allergic and inflammatory diseases of the lung, and how changes in the expression and/or activity of these factors may vary in disease and provide important targets for future drug development.
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Journal articleLee KY, Ito K, Hayashi R, et al., 2006,
NF-κB and activator protein 1 response elements and the role of histone modifications in IL-1-β-induced TGF-β1 gene transcription
, JOURNAL OF IMMUNOLOGY, Vol: 176, Pages: 603-615, ISSN: 0022-1767- Cite
- Citations: 142
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Journal articleLee KY, Ito K, Hayashi R, et al., 2006,
NF-κB and activator protein 1 response elements and the role of histone modifications in IL-1β-induced TGF-β1 gene transcription
, Journal of Immunology, Vol: 176, Pages: 603-615, ISSN: 0022-1767Abnormal expression of TGF-β1 is believed to play an important role in the pathogenesis of a number of chronic inflammatory and immune lung diseases, including asthma, chronic obstructive pulmonary disease, and pulmonary fibrosis. Gene activation in eukaryotes requires coordinated use of specific cell signals, chromatin modifications, and chromatin remodeling. We studied the roles of the ubiquitous inflammatory transcription factors, NF-κB and AP-1, in activation of the TGF-β1 gene and histone acetylation at the TGF-β1 promoter. IL-1β-induced TGF-β1 protein secretion and mRNA expression were prevented by actinomycin D and were attenuated by the inhibitor of κB kinase 2 inhibitor AS602868 and the JNK inhibitor SP600125, suggesting a degree of transcriptional regulation mediated by the NF-κB and AP-1 pathways. We demonstrated that IL-1β activated the p65 subunit of NF-κB and the c-Jun subunit of AP-1. Using chromatin immunoprecipitation assays, we observed a sequential recruitment of p65 and c-Jun, accompanying ordered elevation of the levels of histone H4 and H3 acetylation and recruitment of RNA polymerase II at distinct regions in the native TGF-β1 promoter. The specific NF-κB and AP-1 binding sites in the TGF-β1 promoter were confirmed by an ELISA-based binding assay, and evidence for histone hyperacetylation in TGF-β1 induction was supported by the observation that the histone deacetylase inhibitor trichostatin A enhanced basal and IL-1β-induced TGF-β1 mRNA expression. Our results suggest that IL-1β-stimulated transcription of TGF-β1 is temporally regulated by NF-κB and AP-1 and involves histone hyperacetylation at distinct promoter sites. Copyright © 2005 by The American Association of Immunologists, Inc.
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Book chapterAdcock IM, Ito K, Caramori G, 2006,
TRANSCRIPTION FACTORS
, Encyclopedia of Respiratory Medicine Volume 1 4The term ‘transcription factor’ refers to a large family of proteins, which exert transcriptional control via specific interactions with regulatory gene sequences. Here, we provide a summary of the different classes of the transcription factor divided according to their DNA-binding motifs. The modular structure of transcription factors and the presence of distinct interacting domains determine the ability of these factors to associate with each other and with coactivating/repressing proteins. By recruiting transcriptional coactivators, transcription factors can induce changes in chromatin structure enabling gene expression to occur. We use the activation of the Rel transcription factor NF- κB and the nuclear receptor GR as examples to indicate some of the intricacies and subtleties of DNA binding, chromatin remodeling, and transcription factor cross-talk. Finally, we review the evidence for the involvement of select transcription factors in allergic and inflammatory diseases of the lung, and how changes in the expression and/or activity of these factors may vary in disease and provide important targets for future drug development.
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Book chapterMoffatt MF, Cookson WOC, 2006,
Fine mapping and whole genome association studies in Asthma and chronic obstructive pulmonary disease
, Genetics of Asthma and Chronic Obstructive Pulmonary Disease, Pages: 223-238Positional cloning is much more likely to identify novel genetic effects than candidate gene studies. Genetic linkage studies are very powerful for the study of single gene disorders, but have limited power in complex genetic disorders when many genes are likely to be acting and there is no established model for the inheritance of a given disease. Genetic linkage studies in a complex disorder such as Asthma typically give an imprecise signal for the localization of the diseased gene that may extend over tens of megabases of DNA. This is because only a proportion of families will actually be linked to the locus, while others will appear randomly linked and nonlinked. In addition, the proportion of individuals with susceptibility alleles who develop the disease will vary between families (i.e., the alleles will have variable penetrance). For this reason, even highly ambitious genetic linkage studies involving several hundreds of families have often failed to deliver conclusive results.
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BookDesai SR, 2006,
Introduction
In the United Kingdom well over 30,000 new cases of lung cancer are diagnosed each year and there are a roughly similar number of deaths attibutable to the disease annually. In recent years there has been a paradigm shift in emphasis in the management of patients with lung cancer: a ‘team approach’ is now considered most appropriate and most institutions now have dedicated groups of multidisciplinary specialists who contribute to clinical management. This multidisciplinary approach is reflected in the present volume dedicated to lung cancer. Individual chapters focus on the clinical aspects, pathology, radiology (including screening, diagnosis of symptomatic cases and staging) and treatment options in lung cancer. Because of the recent interest in the potential role of positron emission tomography for a variety of malignancies, a separate chapter is devoted to this technique. Whilst the volume is primarily directed at radiologists, it is hoped that the volume will also be of value to other medical specialists who regularly manage patients with lung cancer.
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Journal articleDavies J, Chaudry R, LaRovere J, et al., 2006,
Cystic fibrosis presenting as acute upper airway obstruction
, THORAX, Vol: 61, Pages: 92-92, ISSN: 0040-6376- Author Web Link
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- Citations: 2
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