Function and Regulation of Early B Cell Factor (EBF)

早期 B 细胞因子 (EBF) 的功能和调节

• 批准号: 6866471
• 负责人: James R. Hagman
• 金额: $ 33.85万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6866471
• 关键词: B cell receptor; B lymphocyte; DNA binding protein; SDS polyacrylamide gel electrophoresis; binding sites; biological signal transduction; cell differentiation; cell membrane; cell surface receptors; genetic transcription; genetically modified animals; humoral immunity; immunoprecipitation; laboratory mouse; polymerase chain reaction; protein protein interaction; protein structure function; receptor expression; recombinant proteins; transcription factor

DESCRIPTION (provided by applicant): Early B cell Factor (EBF) is essential for the development of B lymphocytes from early progenitor cells. EBF regulates the mb-1 gene, which encodes Ig-alpha a protein required for display of immunoglobulin (Ig) on the plasma membrane and transmembrane signaling following stimulation of the B cell receptor (BCR). Cell surface expression of the BCR and the surrogate pro-BCR and pre-BCR at early stages of development is very precisely regulated, and this regulation is critical for proper development and function of B cells. We have observed changes in levels of mb-1 transcripts in cell lines representing different stages of development and in ex vivo B cells following stimulation by polyvalent antigen. As a potential mechanism for setting the level of Ig-alpha in B cells, we recently defined constellations of nuclear factors required for high vs. low level mb-1 transcription at different stages of B cell development. High level transcription requires EBF, the basic-helix-loop-helix (HLH) factor E2A, and the Runt domain protein Runxl (and its coactivator CBFbeta), which assemble higher order complexes on the mb-1 promoter. We propose that the intracellular concentration of Ig-alpha, and thus, expression of the BCR on the surface of B cells, is regulated by EBF and associated proteins. To better understand the molecular biology of EBF, we will determine how it controls B cell development and BCR density, and thus, the response of B cells to antigen.

描述（由申请人提供）：早期 B 细胞因子 (EBF) 对于从早期祖细胞发育成 B 淋巴细胞至关重要。 EBF 调节 mb-1 基因，该基因编码 Ig-α，这是在质膜上展示免疫球蛋白 (Ig) 和刺激 B 细胞受体 (BCR) 后跨膜信号传导所需的蛋白质。 BCR 以及替代 BCR 前体和前 BCR 的细胞表面表达在发育早期受到非常精确的调节，这种调节对于 B 细胞的正常发育和功能至关重要。我们观察到代表不同发育阶段的细胞系和体外 B 细胞在多价抗原刺激后 mb-1 转录物水平的变化。作为设定 B 细胞中 Ig-α 水平的潜在机制，我们最近定义了 B 细胞发育不同阶段高水平与低水平 mb-1 转录所需的核因子群。高水平转录需要 EBF、碱性螺旋环螺旋 (HLH) 因子 E2A 和 Runt 结构域蛋白 Runxl（及其共激活子 CBFbeta），它们在 mb-1 启动子上组装更高阶复合物。我们认为 Ig-α 的细胞内浓度以及 B 细胞表面 BCR 的表达受 EBF 和相关蛋白的调节。为了更好地了解 EBF 的分子生物学，我们将确定它如何控制 B 细胞发育和 BCR 密度，从而控制 B 细胞对抗原的反应。