Molecular Regulation of CIITA Function by GTP-Binding

GTP 结合对 CIITA 功能的分子调控

基本信息

批准号：
7270660
负责人：
JONATHAN A HARTON
金额：
$ 14.92万
依托单位：
ALBANY MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-08-01 至 2009-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7270660
关键词：
Accounting Antibodies Antibody Formation Antigen Presentation Antigen Presentation Pathway Area Attention Autoimmune Diseases C-terminal CD4 Positive T Lymphocytes CD8B1 gene Cancer Biology Cell Nucleus Class Complex DNA Binding Data Defect Event GTP Binding GTP Binding Domain GTPase-Activating Proteins Gene Expression Regulation Genes Genetic Transcription Goals Guanine Nucleotide Exchange Factors Human Ii-Key Immune Immune Response Genes Immune response Immunity Immunoglobulin Class Switching Immunologic Surveillance Immunotherapy Infectious Agent Interferon Type II Knockout Mice Knowledge Laboratories Lead Leucine-Rich Repeat Link MHC Class I Genes MHC Class II Genes MHC class II transactivator protein Major Histocompatibility Complex Malignant Neoplasms Mediating Messenger RNA Modeling Molecular Mus Nature Neoplasm Metastasis Nuclear Import Nucleotides Outcome Pathway interactions Patients Pattern Personal Satisfaction Phosphorylation Process Production Proteins Regulation Role T-Lymphocyte Trans-Activators Transcription Coactivator Transcriptional Activation Transcriptional Regulation Transplantation Tumor Antigens Tumor Biology Tumor Immunity Tumorigenicity Up-Regulation antigen processing cancer cell cytokine immunogenicity improved interest invariant chain melanoma neoplastic cell promoter protein expression response transcription factor tumor

项目摘要

DESCRIPTION (provided by applicant): The induction of class II MHC genes is a central event in the augmentation of immune responses by the anti-tumor cytokine, IFN-gamma. The class II transactivator (CIITA) is a master transcriptional switch for class II MHC, DM, and invariant chain and participates in transcription of class I MHC and beta2-microglobulin genes. CIITA is thus a link between IFN-gamma and the upregulation of genes important for antigen presentation and modulation of immune responses. Defects in CIITA result in a loss of both constitutive and inducible class II MHC expression which leads to a combined loss of T-cell and antibody mediated immunity. CIITA has become the major area of interest in the study of class II MHC gone regulation and is the target of numerous strategies to control class II MHC expression and antigen presentation thereby altering immune responses. Altered regulation of genes involved in antigen processing and presentation is a mechanism by which tumors cells escape immune surveillance and correlates with metastasis in some tumors. The ability to alter class II MHC expression has broad implications not only in tumor biology but in immune responses to infectious agents, autoimmune disease, and transplantation as well. A clear understanding of CIITA function is crucial for devising and implementing strategies aimed at manipulation of immune response genes for tumor immunotherapy. Despite recent advances, our understanding of CIITA's mode-of-action remains limited. CIITA is an unconventional and unique non-DNA binding transcriptional coactivator that utilizes GTP-binding and leucine-rich repeats to deliver a potent activation domain to a broad set of related promoters. Arrival of CIITA in the nucleus commands both promoter accessibility and transcriptional activation. This proposal seeks to elucidate mechanism(s) central to regulating CIITA's function by 1) understanding the role of GTP-binding in regulating CIITA's transactivator function, 2) exploring the contributions of CIITA's C-terminus in regulating transcription, and 3) investigating how CIITA regualtion can be manipulated to impact the expression of the various genes it can influence. This knowledge will help establish a framework that may ultimately lead not only to an accurate view of CIITA's function in transcriptional control, but avenues for improved immunotherapies.

描述（由申请人提供）：II类MHC基因的诱导是抗肿瘤细胞因子IFN-GAMMA增强免疫反应的中心事件。 II类反式激活器（CIITA）是II类MHC，DM和不变链的主转录开关，参与I类MHC和Beta2-Microglobolin基因的转录。因此，CIITA是IFN-GAMMA与对免疫反应抗原表现和调节重要的基因上调之间的联系。 CIITA的缺陷导致构成型和诱导II类MHC表达的丧失，从而导致T细胞和抗体介导的免疫的综合损失。 CIITA已成为研究II类MHC研究的主要领域，并且是控制II类MHC表达和抗原表现的众多策略的目标，从而改变了免疫反应。改变参与抗原加工和表现的基因的调节是一种机制，肿瘤细胞通过某些肿瘤中的转移避免了免疫监测并与转移相关。改变II类MHC表达的能力不仅在肿瘤生物学上，而且对感染剂，自身免疫性疾病和移植的免疫反应具有广泛的影响。对CIITA功能的清晰了解对于设计和实施旨在操纵免疫反应基因进行肿瘤免疫疗法的策略至关重要。尽管有最近的进步，但我们对CIITA行动方式的理解仍然有限。 CIITA是一种非常规且独特的非DNA结合转录共激活因子，它利用GTP结合和富含亮氨酸的重复序列将有效的激活结构域传递到一组相关的启动子集中。 CIITA在细胞核中的到来既可以启动子的可及性和转录激活。 This proposal seeks to elucidate mechanism(s) central to regulating CIITA's function by 1) understanding the role of GTP-binding in regulating CIITA's transactivator function, 2) exploring the contributions of CIITA's C-terminus in regulating transcription, and 3) investigating how CIITA regualtion can be manipulated to impact the expression of the various genes it can influence.这些知识将有助于建立一个框架，该框架最终可能不仅可以准确地看待Ciita在转录控制中的功能，而且还可以促进改进免疫疗法的途径。