Gene Regulation In The Immune System

免疫系统中的基因调控

• 批准号: 6549690
• 负责人: Keiko Ozato
• 金额: --
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6549690
• 关键词: 3T3 cells; cell growth regulation; chronic myelogenous leukemia; genetic regulation; genetic regulatory element; genetic transcription; immune system; immunogenetics; interferon gamma; interferons; laboratory mouse; lipopolysaccharides; neoplasm /cancer immunology; polymerase chain reaction; protein structure function; tissue /cell culture; transcription factor; transfection; tumor suppressor proteins

This section works on ICSBP (also IRF-8), an immune system specific member of the IRF family. ICSBP is a ~55 kD nuclear protein expressed in macrophages in response to interferon (IFN)-gamma and bacterial lipopolysaccharides (LPS). ICSBP-/- mice display a syndrome similar to chronic myelogenous leukemia (CML) with abnormal expansion of granulocytes. They are also immunodeficient with defective functions. CML is a malignancy of myeloid progenitor cells that is caused by a c-abl-BCR fusion protein created by chromosomal translocation. In order to investigate the role for ICSBP in the CML, we have introduced the ICSBP gene into ICSBP-/- bone marrow myeloid progenitor cells by means of a MSCV retrovirus vector. ICSBP transduction led to macrophage differentiation that accompanied induction of cytokine production and phagocytosis. These cells ceased to divide and expressed a number of macrophage specific genes, and repressed granulocyte specific genes. Recent data demonstrated that ICSBP also regulate the development of dentritic cells (DC) important for innate immunity. These results indicate that ICSBP plays a critical role in the differentiation of myeloid progenitor cells to antigen presenting cells, thereby negatively affecting CML pathogenesis. In addition to studying ICSBP, we have been interested in proteins that modulate chromatin. Screening a library for a conserved bromodomain motif believed to be involved in interacting with chromatin, we have isolated a novel protein of 200 kD named Brd4. Brd4 carries two bromodomains and belongs to the BET subgroup of bromodomain proteins. Although BET group proteins share a conserved domain composition, their function is unknown. We observed that Brd4 interacts with a conserved replication factor C and when Brd4 is ectopically expressed in NIH-3T3 cells cell cycle progression from G1to S is blocked indicating that Brd4 plays a critical role in the initiation of DNA replication.

本节针对IRF家族的特定于免疫系统成员ICSBP（也是IRF-8）。 ICSBP是一个〜55 kd的核蛋白，该核蛋白在巨噬细胞中响应干扰素（IFN）-Gamma和细菌脂多糖（LPS）。 ICSBP - / - 小鼠表现出类似于慢性粒细胞性白血病（CML）的综合征，粒细胞异常膨胀。它们也具有缺陷功能的免疫缺陷。 CML是髓样祖细胞的恶性肿瘤，是由由染色体易位产生的C-ABL-BCR融合蛋白引起的。为了研究ICSBP在CML中的作用，我们通过MSCV逆转录病毒载体将ICSBP基因引入ICSBP - / - 骨髓髓样祖细胞。 ICSBP转导导致巨噬细胞分化，伴随细胞因子的产生和吞噬作用。这些细胞停止分裂并表达许多巨噬细胞特异性基因，并抑制了粒细胞特异性基因。最近的数据表明，ICSBP还调节了对先天免疫力很重要的齿状细胞（DC）的发展。这些结果表明，ICSBP在髓样祖细胞与抗原呈递细胞的分化中起着至关重要的作用，从而对CML发病产生了负面影响。 除了研究ICSBP外，我们还对调节染色质的蛋白质感兴趣。筛选一个据信与染色质相互作用的保守溴结构域基序的文库，我们分离了一种名为BRD4的新型蛋白质。 BRD4携带两个溴结构域，属于溴ab蛋白的BET亚组。尽管BET组蛋白具有保守的域组成，但其功能尚不清楚。我们观察到BRD4与保守的复制因子C相互作用，并且当BRD4在NIH-3T3细胞细胞周期中从G1TO S中进行定位表达时，从G1TO S中进行了阻断，表明BRD4在DNA复制的启动中起关键作用。