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Novel ARNT-mediated Regulatory Paradigm of AhR signaling

新型 ARNT 介导的 AhR 信号调节范式

基本信息

批准号：
9107149
负责人：
Casey W Wright
金额：
$ 34.56万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9107149
关键词：
ARNT gene Affect Affinity Alternative Splicing Amino Acids Antigen-Presenting Cells Aromatic Hydrocarbons Aryl Hydrocarbon Receptor Autoimmune Diseases Autoimmune Process Binding CD4 Positive T Lymphocytes CRISPR/Cas technology Cancer Cell Growth Cells Cellular biology Complex Cytoplasmic Receptors DNA Data Development Diet Dioxins EMSA Enhancers Environmental Pollution Event Exhibits Future Gatekeeping Gene Targeting Goals Hematopoiesis Immune Immune Tolerance Individual Knock-out Laboratories Lentivirus Vector Ligand Binding Ligands Light Lymphocyte Lymphoid Lymphoma Malignant Neoplasms Mediating Molecular Mus Mutate NF-kappa B Nuclear Nuclear Translocation Organ Outcome Phosphorylation Phosphorylation Site Physiological Process Protein Isoforms RNA Polymerase II RNA Splicing Regulation Research Role Signal Pathway Signal Transduction Sum System T cell differentiation T-Lymphocyte Techniques Testing Tissues Toxic Environmental Substances Transactivation Transgenic Mice Tryptophan Work Xenobiotics aryl hydrocarbon receptor ligand base cell growth cell type chromatin immunoprecipitation cofactor immunoregulation in vivo innovation mouse model mutant novel prevent public health relevance reconstitution research study response therapy development transcription factor

项目摘要

DESCRIPTION (provided by applicant): AHR is a cytoplasmic receptor that has affinity for numerous xenobiotic ligands, which include halogenated aromatic hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), one of the most potent AHR activators, and AHR signaling mediates the detrimental effects of environmental contaminants on body tissues and organs. Ligand binding induces nuclear translocation of AHR and interaction with the AHR binding partner, aryl hydrocarbon receptor nuclear translocator (ARNT), allowing recognition of specific DNA enhancer sequences. More recently endogenous and natural AHR ligands, such as tryptophan metabolites and dietary compounds, have been identified. These ligands induce AHR-mediated immunomodulatory effects such as controlling normal T cell differentiation and immune tolerance. However, little is known about the role of ARNT in AHR immune signaling. Initial studies by our laboratory, and others, into the regulatory role of ARNT in AHR-mediated immunomodulation have suggested that ARNT is an integral cofactor in different immune signaling pathways, including AHR and NF-κB signaling. ARNT is often described in AHR signaling as a constitutively expressed, non-regulated, nuclear binding partner for AHR. However, our data challenge this assumption and show that the actual regulatory paradigm is more intricate. For instance, ARNT is expressed as two isoforms, isoform 1 and 3, which differ in only 15 amino acids present in isoform 1. Despite their sequence similarity, we have found that the ARNT isoforms appear to have opposing functions in AHR signaling. Intriguingly, the extra 15 amino acids in isoform 1 include a unique phosphorylation site, where we have observed TCDD-induced phosphorylation. Furthermore, we find that the phosphorylation of ARNT isoform 1 is crucial for the recruitment of RNA polymerase II and transactivation of AHR/ARNT target genes. We predict that ARNT activity is a function of both unique phosphorylation of isoform 1 and the given isoform ratio within a particular cell type, which in turn is likely important for regulating the magnitude/outcome of the AHR response. To investigate our hypothesis we propose to 1) Define a comprehensive molecular framework for AHR regulation by the ARNT isoforms, 2) Examine the role of AHR activity, as governed by the ARNT isoforms, in lymphoma cell growth, and 3) Characterize the regulation of AHR signaling by ARNT isoforms in vivo. Ultimately, these studies will lay the groundwork for ARNT-based therapies such as splice modulation as a means of manipulating the ARNT isoforms to control AHR signaling in autoimmune diseases and cancer.